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Prognosis 5

Accordingly, the resistance rates of viridans group streptococci are similarly high in otherwise healthy individuals and in patients with serious underlying diseases. The impact of viridans group streptococcal resistance on antibiotic prevention of IE is unknown. If resistance in vitro is predictive of lack of clinical efficacy, the high resistance rates of viridans group streptococci provide additional support for the assertion that prophylactic therapy for a dental procedure is of little, if any, value. It is impractical to recommend prophylaxis with only those antibiotics, such as vancomycin or a fluoroquin- olone, that are highly active in vitro against viridans group streptococci. There is no evidence that such therapy is effective for prophylaxis of IE, and their use might result in the develop- ment of resistance of viridans group streptococci and other microorganisms to these and other antibiotics. In Table 5, amoxicillin is the preferred choice for oral therapy because it is well absorbed in the GI tract and provides high and sustained serum concentrations. For indi- viduals who are allergic to penicillins or amoxicillin, the use of cephalexin or another first-generation oral cephalosporin, clindamycin, azithromycin, or clarithromycin is recom- mended. Even though cephalexin was less active against viridans group streptococci than other first-generation oral cephalosporins in 1 study,136 cephalexin is included in Table 5. No data show superiority of 1 oral cephalosporin over another for prevention of IE, and generic cephalexin is widely available and relatively inexpensive. Because of possible cross-reactions, a cephalosporin should not be administered to patients with a history of anaphylaxis, angioedema, or urticaria after treatment with any form of penicillin, including ampicillin or amoxicillin. Patients who are unable to tolerate an oral antibiotic may be treated with ampicillin, ceftriaxone, or cefazolin administered intramuscularly or intravenously.

Patients who are unable to tolerate an oral antibiotic may be treated with ampicillin, ceftriaxone, or cefazolin administered intramuscularly or intravenously. For ampicillin-allergic patients who are unable to tolerate an oral agent, therapy is recommended with parenteral cefazolin, ceftriaxone, or clindamycin. Regimens for Respiratory Tract Procedures A variety of respiratory tract procedures reportedly cause tran- sient bacteremia with a wide array of microorganisms1; how- ever, no published data conclusively demonstrate a link between these procedures and IE. Antibiotic prophylaxis with a regimen listed in Table 5 is reasonable (Class IIa, LOE C) for patients with the conditions listed in Table 3 who undergo an invasive procedure of the respiratory tract that involves incision or biopsy of the respiratory mucosa, such as tonsillectomy and adenoid- ectomy. We do not recommend antibiotic prophylaxis for bronchoscopy unless the procedure involves incision of the respiratory tract mucosa. For patients listed in Table 3 who undergo an invasive respiratory tract procedure to treat an established infection, such as drainage of an abscess or empy- ema, we recommend that the antibiotic regimen administered to these patients contain an agent active against viridans group streptococci (Table 5). If the infection is known or suspected to be caused by Staphylococcus aureus, the regimen should contain an agent active against S aureus, such as an antistaphylococcal penicillin or cephalosporin, or vancomycin in patients unable to tolerate a -lactam. Vancomycin should be administered if the infection is known or suspected to be caused by a methicillin- resistant strain of S aureus. Recommendations for GI or GU Tract Procedures Enterococci are part of the normal flora of the GI tract. These microorganisms may cause intra-abdominal infection or infection of the hepatobiliary system.

These microorganisms may cause intra-abdominal infection or infection of the hepatobiliary system. Such infections are often polymicrobial, with a mix of aerobic and anaerobic Gram-negative and Gram- positive microorganisms, but among these varied bacteria, only enterococci are likely to cause IE. Enterococci may cause urinary Table 5. Regimens for a Dental Procedure Situation Agent Regimen: Single Dose 30 to 60 min Before Procedure Adults Children Oral Amoxicillin 2 g 50 mg/kg Unable to take oral medication Ampicillin OR Cefazolin or ceftriaxone 2 g IM or IV 1 g IM or IV 50 mg/kg IM or IV 50 mg/kg IM or IV Allergic to penicillins or ampicillin oral Cephalexin* OR Clindamycin OR Azithromycin or clarithromycin Allergic to penicillins or ampicillin and unable to take oral medication Cefazolin or ceftriaxone OR Clindamycin 1 g IM or IV 600 mg IM or IV 50 mg/kg IM or IV 20 mg/kg IM or IV IM indicates intramuscular; IV, intravenous. *Or other first- or second-generation oral cephalosporin in equivalent adult or pediatric dosage. Cephalosporins should not be used in an individual with a history of anaphylaxis, angioedema, or urticaria with penicillins or ampicillin. Wilson et al Prevention of Infective Endocarditis 1747 tract infections, particularly in older males with prostatic hypertro- phy and obstructive uropathy or prostatitis. The administration of prophylactic antibiotics solely to pre- vent endocarditis is not recommended for patients who undergo GU or GI tract procedures, including diagnostic esopha- gogastroduodenoscopy or colonoscopy (Class III, LOE B). This is in contrast to previous AHA guidelines that listed GI or GU tract procedures for which IE prophylaxis was recommended and those for which prophylaxis was not recommended.1 A large number of diagnostic and therapeutic procedures that involve the GI, hepatobiliary, or GU tract may cause transient enterococcal bacteremia.

This is in contrast to previous AHA guidelines that listed GI or GU tract procedures for which IE prophylaxis was recommended and those for which prophylaxis was not recommended.1 A large number of diagnostic and therapeutic procedures that involve the GI, hepatobiliary, or GU tract may cause transient enterococcal bacteremia. The possible association between GI or GU tract proce- dures and IE has not been studied as extensively as the possible association with dental procedures.145 The cases of IE temporally associated with a GI or GU tract proce- dure are anecdotal, with either a single or very small number of cases reported.83 No published data demonstrate a conclusive link between procedures of the GI or GU tract and the development of IE.145 Moreover, no studies exist that demonstrate that the administration of antimicrobial prophylaxis prevents IE in association with procedures performed on the GI or GU tract. There has been a dramatic increase in the frequency of antimicrobial-resistant strains of enterococci to penicillins, vanco- mycin, and aminoglycosides.146 151 These antibiotics were recom- mended for IE prophylaxis in previous AHA guidelines.1 The significance of the increased frequency of multiresistant strains of enterococci on prevention of IE in patients who undergo GI or GU tract procedures is unknown. The high prevalence of resistant strains of enterococci adds further doubt about the efficacy of prophylactic therapy for GI or GU tract procedures. Patients with infections of the GI or GU tract may have intermittent or sustained enterococcal bacteremia.

Patients with infections of the GI or GU tract may have intermittent or sustained enterococcal bacteremia. For patients with the conditions listed in Table 3 who have an established GI or GU tract infection or for those who receive antibiotic therapy to prevent wound infection or sepsis associated with a GI or GU tract procedure, it may be reasonable that the antibiotic regimen include an agent active against enterococci, such as penicillin, ampicillin, piperacillin, or vancomycin (Class IIb, LOE B); however, no published studies demonstrate that such therapy would prevent enterococcal IE. For patients with the conditions listed in Table 3 scheduled for an elective cystoscopy or other urinary tract manipulation who have an enterococcal urinary tract infection or coloniza- tion, antibiotic therapy to eradicate enterococci from the urine before the procedure may be reasonable (Class IIb, LOE B). If the urinary tract procedure is not elective, it may be reasonable that the empiric or specific antimicrobial regimen administered to the patient contain an agent active against enterococci (Class IIb, LOE B). Amoxicillin or ampicillin is the preferred agent for entero- coccal coverage for these patients. Vancomycin may be administered to patients unable to tolerate ampicillin. If infection is caused by a known or suspected strain of resistant enterococcus, consultation with an infectious diseases expert is recommended. Regimens for Procedures on Infected Skin, Skin Structure, or Musculoskeletal Tissue These infections are often polymicrobial, but only staphylococci and -hemolytic streptococci are likely to cause IE.

Regimens for Procedures on Infected Skin, Skin Structure, or Musculoskeletal Tissue These infections are often polymicrobial, but only staphylococci and -hemolytic streptococci are likely to cause IE. For patients with the conditions listed in Table 3 who undergo a surgical procedure that involves infected skin, skin structure, or musculo- skeletal tissue, it may be reasonable that the therapeutic regimen administered for treatment of the infection contain an agent active against staphylococci and -hemolytic streptococci, such as an antistaphylococcal penicillin or a cephalosporin (Table 5 for dosage; Class IIb, LOE C). Vancomycin or clindamycin may be administered to patients unable to tolerate a -lactam or who are known or suspected to have an infection caused by a methicillin- resistant strain of staphylococcus. A summary of the major changes in these updated recom- mendations for prevention of IE compared with previous AHA recommendations is shown in Table 6. Specific Situations and Circumstances Patients Already Receiving Antibiotics If a patient is already receiving long-term antibiotic therapy with an antibiotic that is also recommended for IE prophy- laxis for a dental procedure, it is prudent to select an antibiotic from a different class rather than to increase the dosage of the current antibiotic. For example, antibiotic regimens used to prevent the recurrence of acute rheumatic fever are administered in dosages lower than those recom- mended for the prevention of IE. Individuals who take an oral Table 6. Summary of Major Changes in Updated Document We concluded that bacteremia resulting from daily activities is much more likely to cause IE than bacteremia associated with a dental procedure. We concluded that only an extremely small number of cases of IE might be prevented by antibiotic prophylaxis even if prophylaxis is 100% effective.

We concluded that only an extremely small number of cases of IE might be prevented by antibiotic prophylaxis even if prophylaxis is 100% effective. Antibiotic prophylaxis is not recommended based solely on an increased lifetime risk of acquisition of IE. Limit recommendations for IE prophylaxis only to those conditions listed in Table 3. Antibiotic prophylaxis is no longer recommended for any other form of CHD, except for the conditions listed in Table 3. Antibiotic prophylaxis is reasonable for all dental procedures that involve manipulation of gingival tissues or periapical region of teeth or perforation of oral mucosa only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from IE (Table 3). Antibiotic prophylaxis is reasonable for procedures on respiratory tract or infected skin, skin structures, or musculoskeletal tissue only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from IE (Table 3). Antibiotic prophylaxis solely to prevent IE is not recommended for GU or GI tract procedures. Although these guidelines recommend changes in indications for IE prophylaxis with regard to selected dental procedures (see text), the writing group reaffirms that those medical procedures listed as not requiring IE prophylaxis in the 1997 statement remain unchanged and extends this view to vaginal delivery, hysterectomy, and tattooing. Additionally, the committee advises against body piercing for patients with conditions listed in Table 3 because of the possibility of bacteremia, while recognizing that there are minimal published data regarding the risk of bacteremia or endocarditis associated with body piercing. penicillin for secondary prevention of rheumatic fever or for other purposes are likely to have viridans group streptococci in their oral cavity that are relatively resistant to penicillin or amoxicillin.

penicillin for secondary prevention of rheumatic fever or for other purposes are likely to have viridans group streptococci in their oral cavity that are relatively resistant to penicillin or amoxicillin. In such cases, the provider should select either clindamycin, azithromycin, or clarithromycin for IE prophy- laxis for a dental procedure, but only for patients shown in Table 3. Because of possible cross-resistance of viridans group streptococci with cephalosporins, this class of antibi- otics should be avoided. If possible, it would be preferable to delay a dental procedure until at least 10 days after comple- tion of the antibiotic therapy. This may allow time for the usual oral flora to be reestablished. Patients receiving parenteral antibiotic therapy for IE may require dental procedures during antimicrobial therapy, particu- larly if subsequent cardiac valve replacement surgery is antici- pated. In these cases, the parenteral antibiotic therapy for IE should be continued and the timing of the dosage adjusted to be administered 30 to 60 minutes before the dental procedure. This parenteral antimicrobial therapy is administered in such high doses that the high concentration would overcome any possible low-level resistance developed among mouth flora (unlike the concentration that would occur after oral administration). Patients Who Receive Anticoagulants Intramuscular injections for IE prophylaxis should be avoided in patients who are receiving anticoagulant therapy (Class I, LOE A). In these circumstances, orally administered regi- mens should be given whenever possible. Intravenously administered antibiotics should be used for patients who are unable to tolerate or absorb oral medications. Patients Who Undergo Cardiac Surgery A careful preoperative dental evaluation is recommended so that required dental treatment may be completed whenever possible before cardiac valve surgery or replacement or repair of CHD. Such measures may decrease the incidence of late prosthetic valve endocarditis caused by viridans group streptococci.

Such measures may decrease the incidence of late prosthetic valve endocarditis caused by viridans group streptococci. Patients who undergo surgery for placement of prosthetic heart valves or prosthetic intravascular or intracardiac mate- rials are at risk for the development of infection.152 Because the morbidity and mortality of infection in these patients are high, perioperative prophylactic antibiotics are recommended (Class I, LOE B). Early-onset prosthetic valve endocarditis is most often caused by S aureus, coagulase-negative staphylo- cocci, or diphtheroids. No single antibiotic regimen is effec- tive against all these microorganisms. Prophylaxis at the time of cardiac surgery should be directed primarily against staphylococci and should be of short duration. A first- generation cephalosporin is most often used, but the choice of an antibiotic should be influenced by the antibiotic suscepti- bility patterns at each hospital. For example, a high preva- lence of infection by methicillin-resistant S aureus should prompt the consideration of the use of vancomycin for perioperative prophylaxis. The majority of nosocomial coagulase-negative staphylococci are methicillin-resistant. Nonetheless, surgical prophylaxis with a first-generation cephalosporin may be recommended for these patients (Class I, LOE A).107 In hospitals with a high prevalence of methicillin-resistant strains of S epidermidis, surgical prophylaxis with vancomycin may be reasonable but has not been shown to be superior to prophylaxis with a cephalosporin (Class IIb, LOE C). Prophylaxis should be initiated immediately before the operative procedure, repeated during prolonged procedures to maintain serum concentrations intraoperatively, and continued for no more than 48 hours postoperatively to minimize emergence of resistant micro- organisms (Class IIa, LOE B). The effects of cardiopulmonary bypass and compromised renal function on antibiotic concentra- tions in serum should be considered and dosages adjusted as necessary before and during the procedure.

The effects of cardiopulmonary bypass and compromised renal function on antibiotic concentra- tions in serum should be considered and dosages adjusted as necessary before and during the procedure. Other Considerations There is no evidence that coronary artery bypass graft surgery is associated with a long-term risk for infection. Therefore, antibi- otic prophylaxis for dental procedures is not needed for individ- uals who have undergone this surgery. Antibiotic prophylaxis for dental procedures is not recommended for patients with coronary artery stents (Class III, LOE C). The treatment and prevention of infection for these and other endovascular grafts and prosthetic devices are addressed in a separate AHA publi- cation.152 There are insufficient data to support specific recom- mendations for patients who have undergone heart transplanta- tion. Such patients are at risk of acquired valvular dysfunction, especially during episodes of rejection. Endocarditis that occurs in a heart transplant patient is associated with a high risk of adverse outcome (Table 3).153 Accordingly, the use of IE prophylaxis for dental procedures in cardiac transplant recipients who develop cardiac valvulopathy is reasonable, but the useful- ness is not well established (Class IIa, LOE C; Table 4). The use of prophylactic antibiotics to prevent infection of joint prosthe- ses during potentially bacteremia-inducing procedures is not within the scope of this document. Future Considerations Prospective placebo-controlled, double-blinded studies of anti- biotic prophylaxis of IE in patients who undergo a bacteremia- producing procedure would be necessary to evaluate accurately the efficacy of IE prophylaxis. Additional prospective case- control studies are needed. The AHA has made substantial revisions to previously published guidelines on IE prophylaxis. Given our current recommendations, we anticipate that signifi- cantly fewer patients will receive IE prophylaxis for a dental procedure. Studies are necessary to monitor the effects, if any, of these recommended changes in IE prophylaxis.

Studies are necessary to monitor the effects, if any, of these recommended changes in IE prophylaxis. The incidence of IE could change or stay the same. Because the incidence of IE is low, small changes in incidence may take years to detect. Accordingly, we urge that such studies be designed and insti- tuted promptly so that any change in incidence may be detected sooner rather than later. Subsequent revisions of the AHA guidelines on the preven-tion of IE will be based on the results of these studies and other published data. Acknowledgments The writing group thanks the following international experts on infec- tive endocarditis for their valuable comments: Drs Christa Gohlke- Ba rwolf, Roger Hall, Jae-Hoon Song, Catherine Kilmartin, Catherine Leport, Jose M. Miro , Christoph Naber, Graham Roberts, and Jan T.M. van der Meer. The writing group also thanks Dr George Meyer for his helpful comments regarding gastroenterology. Finally, the writing group would like to thank Lori Hinrichs for her superb assistance with the preparation of this manuscript.

Finally, the writing group would like to thank Lori Hinrichs for her superb assistance with the preparation of this manuscript. Wilson et al Prevention of Infective Endocarditis 1749 Disclosures Writing Group Disclosures Writing Group Member Employment Research Grant Other Research Support Speakers Bureau/ Honoraria Ownership Interest Consultant/ Advisory Board Other Walter Wilson Mayo Clinic None None None None None None Larry M. Baddour Mayo Clinic None None None None None None Robert S. Baltimore Yale University School of Medicine None None None None None None Ann Bolger University of California, San Francisco None None None None None None Robert O. Bonow Northwestern University Feinberg School of Medicine None None None None None None Jane C. Burns University of California, San Diego None None None None None None Christopher H. Cabell Duke University National Institutes of Health None None None Gloucester*; Shire*; Cubist*; Carbomedics*; GlaxoSmithKline*; Acusphere*; Endo*; Eli Lilly*; Watson*; Johnson & Johnson* None David T. Durack Becton Dickinson & Co (manufactures medical devices and diagnostics) None None None None Joint Commission Resources Board None Patricia Ferrieri University of Minnesota Medical School None None None None None None Timothy Gardner Christiana Care Health System None None None None None None Michael Gerber Cincinnati Children s Hospital Medical Center None None None None None None Michael Gewitz Maria Fareri Children s Hospital of Westchester, New York Medical College None None None None None None David Goff Wake Forest University School of Medicine None None None None Spriggs & Hollingsworth Law Firm; Scientific Evidence Consulting Firm; GlaxoSmithKline* None Matthew Levison Drexel University College of Medicine None None None None Merck* None Peter B. Lockhart Carolinas Medical Center None None None None None None Jane W. Newburger Boston Children s Heart Foundation None None None None None None Thomas Pallasch University of Southern California None None None None Consultation and expert witness testimony on records of patients with endocarditis None Anne H. Rowley Children s Memorial Hospital, Chicago None None None None None None Stanford T. Shulman Children s Memorial Hospital, Chicago None None None None None None Brian L. Strom University of Pennsylvania School of Medicine Pfizer* Merck*; Novartis*; Wyeth*; Pfizer* None None Abbott*; GlaxoSmithKline*; Eli Lilly*; Pfizer*; Sanofi Pasteur*; Johnson & Johnson*; Schering AG*; Tap Pharma*; Wyeth* None Masato Takahashi University of Southern California Bristol-Myers Squibb Medical Imaging* None None None None None Lloyd Y. Tani University of Utah School of Medicine None None None None None None Kathryn A. Taubert American Heart Association None None None None None None This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit.

A relationship is considered to be Significant if (1) the person receives $10 000 or more during any 12-month period, or 5% or more of the person s gross income; or (2) the person owns 5% or more of the voting stock or share of the entity or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be Modest if it is less than Significant under the preceding definition. *Modest. Significant. References 1. Dajani AS, Taubert KA, Wilson W, Bolger AF, Bayer A, Ferrieri P, Gewitz MH, Shulman ST, Nouri S, Newburger JW, Hutto C, Pallasch TJ, Gage TW, Levison ME, Peter G, Zuccaro G Jr. Prevention of bacterial endocarditis: recommendations by the American Heart Asso- ciation. JAMA. 1997;277:1794 1801. 2. Strom BL, Abrutyn E, Berlin JA, Kinman JL, Feldman RS, Stolley PD, Levison ME, Korzeniowski OM, Kaye D. Dental and cardiac risk factors for infective endocarditis: a population-based, case-control study. Ann Intern Med. 1998;129:761 769. 3. Durack DT. Prevention of infective endocarditis. N Engl J Med. 1995; 332:38 44. 4. Durack DT. Antibiotics for prevention of endocarditis during dentistry: time to scale back? Ann Intern Med. 1998;129:829 831. 5. Lockhart PB, Brennan MT, Fox PC, Norton HJ, Jernigan DB, Strausbaugh LJ. Decision-making on the use of antimicrobial pro- phylaxis for dental procedures: a survey of infectious disease consultants and review. Clin Infect Dis. 2002;34:1621 1626. 6. Jones TD, Baumgartner L, Bellows MT, Breese BB, Kuttner AG, McCarty M, Rammelkamp CH (Committee on Prevention of Rheumatic Fever and Bacterial Endocarditis, American Heart Association). Pre- vention of rheumatic fever and bacterial endocarditis through control of streptococcal infections. Circulation. 1955;11:317 320. 7.

Pre- vention of rheumatic fever and bacterial endocarditis through control of streptococcal infections. Circulation. 1955;11:317 320. 7. Rammelkamp CH Jr, Breese BB, Griffeath HI, Houser HB, Kaplan MH, Kuttner AG, McCarty M, Stollerman GH, Wannamaker LW (Committee on Prevention of Rheumatic Fever and Bacterial Endocarditis, American Heart Association). Prevention of rheumatic fever and bacterial endo- carditis through control of streptococcal infections. Circulation. 1957; 15:154 158. 8. Committee on Prevention of Rheumatic Fever and Bacterial Endo- carditis, American Heart Association. Prevention of rheumatic fever and bacterial endocarditis through control of streptococcal infections. Cir- culation. 1960;21:151 155. 9. Wannamaker LW, Denny FW, Diehl A, Jawetz E, Kirby WMM, Markowitz M, McCarty M, Mortimer EA, Paterson PY, Perry W, Ram- melkamp CH Jr, Stollerman GH (Committee on Prevention of Rheumatic Fever and Bacterial Endocarditis, American Heart Association). Prevention of bacterial endocarditis. Circulation. 1965;31:953 954. 10. Rheumatic Fever Committee and the Committee on Congenital Cardiac Defects, American Heart Association. Prevention of bacterial endo- carditis. Circulation. 1972;46:S3 S6. 11. Kaplan EL, Anthony BF, Bisno A, Durack D, Houser H, Millard HD, Sanford J, Shulman ST, Stollerman M, Taranta A, Wenger N (Committee on Rheumatic Fever and Bacterial Endocarditis, American Heart Association). Prevention of bacterial endocarditis. Circulation. 1977;56:139A 143A. 12. Shulman ST, Amren DP, Bisno AL, Dajani AS, Durack DT, Gerber MA, Kaplan EL, Millard HD, Sanders WE, Schwartz RH, Watanaku- nakorn C (Committee on Rheumatic Fever and Infective Endocarditis, American Heart Association). Prevention of bacterial endocarditis: a statement for health professionals by the Committee on Rheumatic Fever and Infective Endocarditis of the Council on Cardiovascular Disease in the Young. Circulation. 1984;70:1123A 1127A. 13. Dajani AS, Bisno AL, Chung KJ, Durack DT, Freed M, Gerber MA, Karchmer AW, Millard HD, Rahimtoola S, Shulman ST, Watanaku- nakorn C, Taubert KA.

Dajani AS, Bisno AL, Chung KJ, Durack DT, Freed M, Gerber MA, Karchmer AW, Millard HD, Rahimtoola S, Shulman ST, Watanaku- nakorn C, Taubert KA. Prevention of bacterial endocarditis: recommen- dations by the American Heart Association. JAMA. 1990;264: 2919 2922. 14. Selton-Suty C, Duval X, Brochet E, Doco-Lecompte T, Hoen B, Delahaye E, Leport C, Danchin N. New French recommendations for the prophylaxis of infectious endocarditis [in French]. Arch Mal Coeur Vaiss. 2004;97:626 631. 15. Gould FK, Elliott TS, Foweraker J, Fulford M, Perry JD, Robert GJ, Sandoe JA, Watkin RW. Guidelines for the prevention of endocarditis: report of the Working Party of the British Society for Antimicrobial Chemotherapy: authors response. J Antimicrob Chemother. 2006;57: 1035 1042. 16. Ashrafian H, Bogle RG. Antimicrobial prophylaxis for endocarditis: emotion or science? Heart. 2007;93:5 6. 17. Burnette-Curley D, Wells V, Viscount H, Munro CL, Fenno JC, Fives- Taylor P, Macrina FL. FimA, a major virulence factor associated with Streptococcus parasanguis endocarditis. Infect Immun. 1995;63: 4669 4674. 18. Viscount HB, Munro CL, Burnette-Curley D, Peterson DL, Macrina FL. Immunization with FimA protects against Streptococcus parasanguis endocarditis in rats. Infect Immun. 1997;65:994 1002. 19. Kitten T, Munro CL, Wang A, Macrina FL. Vaccination with FimA from Streptococcus parasanguis protects rats from endocarditis caused by other viridans streptococci. Infect Immun. 2002;70:422 425. 20. Durack DT, Beeson PB. Experimental bacterial endocarditis, II: survival of a bacteria in endocardial vegetations. Br J Exp Pathol. 1972;53:50 53. 21. Fowler VG, Scheld WM, Bayer AS. Endocarditis and intravascular infections. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practices of Infectious Diseases. Philadelphia, Pa: Elsevier Churchill Livingstone; 2005:975 1021. 22. Osler W. Gulstonian lectures on malignant endocarditis. lecture I, and lecture II Lancet. 1885;1:415 418, 459 464. 23. Okell CC, Elliott SD.

lecture I, and lecture II Lancet. 1885;1:415 418, 459 464. 23. Okell CC, Elliott SD. Bacteraemia and oral sepsis: with special reference to the aetiology of subacute endocarditis. Lancet. 1935;2:869 872. Reviewer Disclosures Reviewer Employment Research Grant Other Research Support Speakers Bureau/ Honoraria Expert Witness Ownership Interest Consultant/ Advisory Board Other Thomas Bashore Duke University Medical Center None None None None None None None Arnold Bayer University of California, Los Angeles Titan NIH Cubist June Baker Laird at McElroy, Deutsch, Mulvaney & Carpenter, LLP (Denver, Colo)* None Pfizer* None Donald Falace University of Kentucky None None None None None None None Michael Freed Boston Children s Hospital None None None None None None None Welton Gersony Children s Hospital of New York None None None None None None None Loren Hiratzka Bethesda North Hospital None None None None None None None Patrick O Gara Brigham & Women s Hospital None None None None None None None Lauren L. Patton University of North Carolina None None None None None None None Catherine L. Webb Northwestern University None None None None Amgen None None This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be Significant if (1) the person receives $10 000 or more during any 12-month period, or 5% or more of the person s gross income; or (2) the person owns 5% or more of the voting stock or share of the entity or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be Modest if it is less than Significant under the preceding definition. *Modest. Significant.

A relationship is considered to be Modest if it is less than Significant under the preceding definition. *Modest. Significant. Wilson et al Prevention of Infective Endocarditis 1751 24. Lockhart PB, Durack DT. Oral microflora as a cause of endocarditis and other distant site infections. Infect Dis Clin North Am. 1999;13: 833 850, vi. 25. Roberts GJ, Holzel HS, Sury MR, Simmons NA, Gardner P, Longhurst P. Dental bacteremia in children. Pediatr Cardiol. 1997;18:24 27. 26. Pallasch TJ, Slots J. Antibiotic prophylaxis and the medically com- promised patient. Periodontol 2000. 1996;10:107 138. 27. Lockhart PB. The risk for endocarditis in dental practice. Periodontol 2000. 2000;23:127 135. 28. Cobe HM. Transitory bacteremia. Oral Surg Oral Med Oral Pathol. 1954;7:609 615. 29. Sconyers JR, Crawford JJ, Moriarty JD. Relationship of bacteremia to toothbrushing in patients with periodontitis. J Am Dent Assoc. 1973;87: 616 622. 30. Forner L, Larsen T, Kilian M, Holmstrup P. Incidence of bacteremia after chewing, tooth brushing and scaling in individuals with periodontal inflammation. J Clin Periodontol. 2006;33:401 407. 31. Rise E, Smith JF, Bell J. Reduction of bacteremia after oral manipu- lations. Arch Otolaryngol. 1969;90:198 201. 32. Schlein RA, Kudlick EM, Reindorf CA, Gregory J, Royal GC. Tooth- brushing and transient bacteremia in patients undergoing orthodontic treatment. Am J Orthod Dentofacial Orthop. 1991;99:466 472. 33. Faden HS. Letter: dental procedures and bacteremia. Ann Intern Med. 1974;81:274. 34. Round H, Kirkpatrick HJR, Hails CG. Further investigations on bacte- riological infections of the mouth. Proc R Soc Med. 1936;29:1552 1556. 35. Felix JE, Rosen S, App GR. Detection of bacteremia after the use of an oral irrigation device in subjects with periodontitis. J Periodontol. 1971; 42:785 787. 36. O Leary TJ, Shafer WG, Swenson HM, Nesler DC, Van Dorn PR.

O Leary TJ, Shafer WG, Swenson HM, Nesler DC, Van Dorn PR. Possible penetration of crevicular tissue from oral hygiene procedures, I: use of oral irrigating devices. J Periodontol. 1970;41:158 162. 37. Socransky SS, Haffajee AD, Smith GL, Dzink JL. Difficulties encountered in the search for the etiologic agents of destructive peri- odontal diseases. J Clin Periodontol. 1987;14:588 593. 38. Tanner A, Maiden MF, Paster BJ, Dewhirst FE. The impact of 16S ribosomal RNA-based phylogeny on the taxonomy of oral bacteria. Periodontol 2000. 1994;5:26 51. 39. Paster BJ, Boches SK, Galvin JL, Ericson RE, Lau CN, Levanos VA, Sahasrabudhe A, Dewhirst FE. Bacterial diversity in human subgingival plaque. J Bacteriol. 2001;183:3770 3783. 40. Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE. Defining the normal bacterial flora of the oral cavity. J Clin Microbiol. 2005;43: 5721 5732. 41. Pallasch TJ. Antibiotic prophylaxis: problems in paradise. Dent Clin North Am. 2003;47:665 679. 42. Hillman JD, Socransky SS, Shivers M. The relationships between strep- tococcal species and periodontopathic bacteria in human dental plaque. Arch Oral Biol. 1985;30:791 795. 43. Roberts GJ, Jaffray EC, Spratt DA, Petrie A, Greville C, Wilson M, Lucas VS. Duration, prevalence and intensity of bacteraemia after dental extractions in children. Heart. 2006;92:1274 1277. 44. Lucas VS, Lytra V, Hassan T, Tatham H, Wilson M, Roberts GJ. Com- parison of lysis filtration and an automated blood culture system (BACTEC) for detection, quantification, and identification of odon- togenic bacteremia in children. J Clin Microbiol. 2002;40:3416 3420. 45. Lockhart PB, Schmidtke MA. Antibiotic considerations in medically compromised patients. Dent Clin North Am. 1994;38:381 402. 46. Overholser CD, Moreillon P, Glauser MP. Experimental endocarditis following dental extractions in rats with periodontitis [published cor- rection appears in J Oral Maxillofac Surg. 1989;47:215]. J Oral Max- illofac Surg. 1988;46:857 861. 47.

Experimental endocarditis following dental extractions in rats with periodontitis [published cor- rection appears in J Oral Maxillofac Surg. 1989;47:215]. J Oral Max- illofac Surg. 1988;46:857 861. 47. Baltch AL, Schaffer C, Hammer MC, Sutphen NT, Smith RP, Conroy J, Shayegani M. Bacteremia following dental cleaning in patients with and without penicillin prophylaxis. Am Heart J. 1982;104:1335 1339. 48. Baltch AL, Pressman HL, Schaffer C, Smith RP, Hammer MC, Shayegani M, Michelsen P. Bacteremia in patients undergoing oral procedures: study following parenteral antimicrobial prophylaxis as rec- ommended by the American Heart Association, 1977. Arch Intern Med. 1988;148:1084 1088. 49. Coffin F, Thompson RE. Factors influencing bacteraemia following dental extraction. Lancet. 1956;271:654 656. 50. Heimdahl A, Hall G, Hedberg M, Sandberg H, Soder PO, Tuner K, Nord CE. Detection and quantitation by lysis-filtration of bacteremia after dif- ferent oral surgical procedures. J Clin Microbiol. 1990;28:2205 2209. 51. Lucartorto FM, Franker CK, Maza J. Postscaling bacteremia in HIV- associated gingivitis and periodontitis. Oral Surg Oral Med Oral Pathol. 1992;73:550 554. 52. Lockhart PB. An analysis of bacteremias during dental extractions: a double-blind, placebo-controlled study of chlorhexidine. Arch Intern Med. 1996;156:513 520. 53. Lockhart PB, Brennan MT, Kent ML, Norton HJ, Weinrib DA. Impact of amoxicillin prophylaxis on the incidence, nature, and duration of bacteremia in children after intubation and dental procedures. Circu- lation. 2004;109:2878 2884. 54. Lazansky JP, Robinson L, Rodofsky L. Factors influencing the incidence of bacteremias following surgical procedures in the oral cavity. J Dent Res. 1949;28:533 543. 55. Bender IB, Montgomery S. Nonsurgical endodontic procedures for the patient at risk for infective endocarditis and other systemic disorders. J Endod. 1986;12:400 407. 56. Conner HD, Haberman S, Collings CK, Winford TE. Bacteremias fol- lowing periodontal scaling in patients with healthy appearing gingiva. J Periodontol. 1967;38:466 472. 57. McEntegart MG, Porterfield JS.

Bacteremias fol- lowing periodontal scaling in patients with healthy appearing gingiva. J Periodontol. 1967;38:466 472. 57. McEntegart MG, Porterfield JS. Bacteraemia following dental extractions. Lancet. 1949;2:596 598. 58. Robinson L, Kraus FW, Lazansky JP, Wheeler RE, Gordon S, Johnson V. Bacteremias of dental origin, II: a study of the factors influencing occurrence and detection. Oral Surg Oral Med Oral Pathol. 1950;3: 923 936. 59. Eldirini AH. Effectiveness of epinephrine in local anesthetic solutions on the bacteremia following dental extraction. J Oral Ther Pharmacol. 1968;4:317 326. 60. Elliott RH, Dunbar JM. Streptococcal bacteraemia in children following dental extractions. Arch Dis Child. 1968;43:451 454. 61. Vargas B, Collings CK, Polter L, Haberman S. Effects of certain factors on bacteremias resulting from gingival resection. J Periodontal. 1959; 30:196 207. 62. Roberts GJ. Dentists are innocent! Everyday bacteremia is the real culprit: a review and assessment of the evidence that dental surgical procedures are a principal cause of bacterial endocarditis in children. Pediatr Cardiol. 1999;20:317 325. 63. Hockett RN, Loesche WJ, Sodeman TM. Bacteraemia in asymptomatic human subjects. Arch Oral Biol. 1977;22:91 98. 64. Thayer W. Studies on bacterial (infective) endocarditis. Hopkins Hosp Rep. 1926;22:1 185. 65. Okabe K, Nakagawa K, Yamamoto E. Factors affecting the occurrence of bacteremia associated with tooth extraction. Int J Oral Maxillofac Surg. 1995;24:239 242. 66. Hall G, Hedstrom SA, Heimdahl A, Nord CE. Prophylactic adminis- tration of penicillins for endocarditis does not reduce the incidence of postextraction bacteremia. Clin Infect Dis. 1993;17:188 194. 67. Lineberger LT, De Marco TJ. Evaluation of transient bacteremia fol- lowing routine periodontal procedures. J Periodontol. 1973;44:757 762. 68. Witzenberger T, O Leary TJ, Gillette WB. Effect of a local germicide on the occurrence of bacteremia during subgingival scaling. J Periodontol. 1982;53:172 179. 69.

Effect of a local germicide on the occurrence of bacteremia during subgingival scaling. J Periodontol. 1982;53:172 179. 69. Rogosa M, Hampp EG, Nevin TA, Wagner HN Jr, Driscoll EJ, Baer PN. Blood sampling and cultural studies in the detection of postoperative bacteremias. J Am Dent Assoc. 1960;60:171 180. 70. Bandt CL, Korn NA, Schaffer EM. Bacteremias from ultrasonic and hand instrumentation. J Periodontol. 1964;35:214 215. 71. De Leo AA, Schoenknecht FD, Anderson MW, Peterson JC. The incidence of bacteremia following oral prophylaxis on pediatric patients. Oral Surg Oral Med Oral Pathol. 1974;37:36 45. 72. Barco CT. Prevention of infective endocarditis: a review of the medical and dental literature. J Periodontol. 1991;62:510 523. 73. Bayliss R, Clarke C, Oakley C, Somerville W, Whitfield AG. The teeth and infective endocarditis. Br Heart J. 1983;50:506 512. 74. Hirsh HL, Vivino JJ, Merril A, Dowling HF. Effect of prophylactically administered penicillin on incidence of bacteremia following extraction of teeth. Arch Intern Med. 1948;81:868 878. 75. Shanson DC, Akash S, Harris M, Tadayon M. Erythromycin stearate, 1.5 g, for the oral prophylaxis of streptococcal bacteraemia in patients undergoing dental extraction: efficacy and tolerance. J Antimicrob Che- mother. 1985;15:83 90. 76. Roberts GJ, Radford P, Holt R. Prophylaxis of dental bacteraemia with oral amoxycillin in children. Br Dent J. 1987;162:179 182. 77. Hall G, Heimdahl A, Nord CE. Effects of prophylactic administration of cefaclor on transient bacteremia after dental extraction. Eur J Clin Microbiol Infect Dis. 1995;15:646 649. 78. Hall G, Heimdahl A, Nord CE. Bacteremia after oral surgery and antibiotic prophylaxis for endocarditis. Clin Infect Dis. 1999;29:1 8; quiz 9 10. 79. Macfarlane TW, Ferguson MM, Mulgrew CJ. Post-extraction bacter- aemia: role of antiseptics and antibiotics. Br Dent J. 1984;156:179 181. 80.

Post-extraction bacter- aemia: role of antiseptics and antibiotics. Br Dent J. 1984;156:179 181. 80. Oliver R, Roberts GJ, Hooper L. Penicillins for the prophylaxis of bacterial endocarditis in dentistry. Cochrane Database Syst Rev. 2004: CD003813. 81. Guntheroth WG. How important are dental procedures as a cause of infective endocarditis? Am J Cardiol. 1984;54:797 801. 82. Everett ED, Hirschmann JV. Transient bacteremia and endocarditis prophylaxis: a review. Medicine (Baltimore). 1977;56:61 77. 83. Horstkotte D, Rosin H, Friedrichs W, Loogen F. Contribution for choosing the optimal prophylaxis of bacterial endocarditis. Eur Heart J. 1987;8(supp J):379 381. 84. Imperiale TF, Horwitz RI. Does prophylaxis prevent postdental infective endocarditis? A controlled evaluation of protective efficacy. Am J Med. 1990;88:131 136. 85. van der Meer JT, Thompson J, Valkenburg HA, Michel MF. Epidemi- ology of bacterial endocarditis in The Netherlands, II: antecedent pro- cedures and use of prophylaxis. Arch Intern Med. 1992;152:1869 1873. 86. Van der Meer JT, Van Wijk W, Thompson J, Vandenbroucke JP, Valkenburg HA, Michel MF. Efficacy of antibiotic prophylaxis for prevention of native-valve endocarditis. Lancet. 1992;339:135 139. 87. van der Meer JT, van Wijk W, Thompson J, Valkenburg HA, Michel MF. Awareness of need and actual use of prophylaxis: lack of patient compliance in the prevention of bacterial endocarditis. J Antimicrob Chemother. 1992;29:187 194. 88. Duval X, Alla F, Hoen B, Danielou F, Larrieu S, Delahaye F, Leport C, Briancon S. Estimated risk of endocarditis in adults with predisposing cardiac conditions undergoing dental procedures with or without anti- biotic prophylaxis. Clin Infect Dis. 2006;42:e102 e107. 89. Starkebaum M, Durack D, Beeson P. The incubation period of sub- acute bacterial endocarditis. Yale J Biol Med. 1977;50:49 58. 90. Steckelberg JM, Wilson WR. Risk factors for infective endocarditis. Infect Dis Clin North Am. 1993;7:9 19. 91. Pallasch TJ, Wahl MJ.

Infect Dis Clin North Am. 1993;7:9 19. 91. Pallasch TJ, Wahl MJ. Focal infection: new age or ancient history? Endodontic Topics. 2003;4:32 45. 92. Idsoe O, Guthe T, Willcox RR, de Weck AL. Nature and extent of penicillin side-reactions, with particular reference to fatalities from ana- phylactic shock. Bull World Health Organ. 1968;38:159 188. 93. Ahlstedt S. Penicillin allergy: can the incidence be reduced? Allergy. 1984;39:151 164. 94. Agha Z, Lofgren RP, VanRuiswyk JV. Is antibiotic prophylaxis for bac- terial endocarditis cost-effective? Med Decis Making. 2005;25:308 320. 95. Kelkar PS, Li JT. Cephalosporin allergy. N Engl J Med. 2001;345: 804 809. 96. Guay DR, Patterson DR, Seipman N, Craft JC. Overview of the toler- ability profile of clarithromycin in preclinical and clinical trials. Drug Saf. 1993;8:350 364. 97. Mazur N, Greenberger PA, Regalado J. Clindamycin hypersensitivity appears to be rare. Ann Allergy Asthma Immunol. 1999;82:443 445. 98. Bombassaro AM, Wetmore SJ, John MA. Clostridium difficile colitis following antibiotic prophylaxis for dental procedures. J Can Dent Assoc. 2001;67:20 22. 99. Tleyjeh IM, Steckelberg JM, Murad HS, Anavekar NS, Ghomrawi HM, Mirzoyev Z, Moustafa SE, Hoskin TL, Mandrekar JN, Wilson WR, Baddour LM. Temporal trends in infective endocarditis: a population-based study in Olmsted County, Minnesota. JAMA. 2005;293:3022 3028. 100. Griffin MR, Wilson WR, Edwards WD, O Fallon WM, Kurland LT. Infective endocarditis: Olmsted County, Minnesota, 1950 through 1981. JAMA. 1985;254:1199 1202. 101. Durack DT, Petersdorf RG. Changes in the epidemiology of endocarditis. Paper presented at: Infective Endocarditis: An American Heart Association Symposium; held May 14 15, 1976. In: AHA Monograph #52, 1977. 102. Delahaye F, Goulet V, Lacassin F, et al. Characteristics of infective endo- carditis in France in 1991: a 1-year survey. Eur Heart J. 1995;16:394 401. 103.

Characteristics of infective endo- carditis in France in 1991: a 1-year survey. Eur Heart J. 1995;16:394 401. 103. Hoen B, Alla F, Selton-Suty C, Beguinot I, Bouvet A, Briancon S, Casalta JP, Danchin N, Delahaye F, Etienne J, Le Moing V, Leport C, Mainardi JL, Ruimy R, Vandenesch F; Association pour l Etude et la Prevention de l Endocardite Infectieuse (AEPEI) Study Group. Changing profile of infective endocarditis: results of a 1-year survey in France. JAMA. 2002;288:75 81. 104. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345:1318 1330. 105. Gersony WM, Hayes CJ, Driscoll DJ, Keane JF, Kidd L, O Fallon WM, Pieroni DR, Wolfe RR, Weidman WH. Bacterial endocarditis in patients with aortic stenosis, pulmonary stenosis, or ventricular septal defect. Circulation. 1993;87(suppl):I-121 I-126. 106. Wilson WR, Jaumin PM, Danielson GK, Giuliani ER, Washington JA II, Geraci JE. Prosthetic valve endocarditis. Ann Intern Med. 1975;82:751 756. 107. Baddour LM, Wilson WR. Infections of prosthetic valves and other cardio- vascular devices. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett s Principles and Practice of Infectious Diseases. Philadelphia, Pa: Elsevier Churchill Livingstone; 2005:1022 1044. 108. Baddour LM, Wilson WR, Bayer AS, Fowler VG Jr, Bolger AF, Levison ME, Ferrieri P, Gerber MA, Tani LY, Gewitz MH, Tong DC, Steckelberg JM, Baltimore RS, Shulman ST, Burns JC, Falace DA, Newburger JW, Pallasch TJ, Takahashi M, Taubert KA; Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease; Council on Cardiovascular Disease in the Young; Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia; American Heart Association; Infectious Diseases Society of America.

Baddour LM, Wilson WR, Bayer AS, Fowler VG Jr, Bolger AF, Levison ME, Ferrieri P, Gerber MA, Tani LY, Gewitz MH, Tong DC, Steckelberg JM, Baltimore RS, Shulman ST, Burns JC, Falace DA, Newburger JW, Pallasch TJ, Takahashi M, Taubert KA; Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease; Council on Cardiovascular Disease in the Young; Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia; American Heart Association; Infectious Diseases Society of America. Infective endo- carditis: diagnosis, antimicrobial therapy, and management of compli- cations: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Car- diovascular Disease in the Young, and the Councils on Clinical Car- diology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America [published correction appears in Circulation. 2005;112:2373]. Circulation. 2005;111:e394 e434. 109. Wilson WR, Danielson GK, Giuliani ER, Geraci JE. Prosthetic valve endocarditis. Mayo Clin Proc. 1982;57:155 161. 110. Wilson WR, Geraci JE, Wilkowske CJ, Washington JA II. Short-term intramuscular therapy with procaine penicillin plus streptomycin for infective endocarditis due to viridans streptococci. Circulation. 1978; 57:1158 1161. 111. Anderson DJ, Olaison L, McDonald JR, Miro JM, Hoen B, Selton-Suty C, Doco-Lecompte T, Abrutyn E, Habib G, Eykyn S, Pappas PA, Fowler VG, Sexton DJ, Almela M, Corey GR, Cabell CH. Enterococcal pros- thetic valve infective endocarditis: report of 45 episodes from the Inter- national Collaboration on Endocarditis-merged database. Eur J Clin Microbiol Infect Dis. 2005;24:665 670. 112. Chu VH, Cabell CH, Abrutyn E, Corey GR, Hoen B, Miro JM, Olaison L, Stryjewski ME, Pappas P, Anstrom KJ, Eykyn S, Habib G, Benito N, Fowler VG Jr; International Collaboration on Endocarditis Merged Database Study Group.

Chu VH, Cabell CH, Abrutyn E, Corey GR, Hoen B, Miro JM, Olaison L, Stryjewski ME, Pappas P, Anstrom KJ, Eykyn S, Habib G, Benito N, Fowler VG Jr; International Collaboration on Endocarditis Merged Database Study Group. Native valve endocarditis due to coagulase-negative staphylococci: report of 99 episodes from the International Collaboration on Endocarditis Merged Database. Clin Infect Dis. 2004;39:1527 1530. 113. Lalani T, Kanafani ZA, Chu VH, Moore L, Corey GR, Pappas P, Woods CW, Cabell CH, Hoen B, Selton-Suty C, Doco-Lecompte T, Chirouze C, Raoult D, Miro JM, Mestres CA, Olaison L, Eykyn S, Abrutyn E, Fowler VG Jr; The International Collaboration on Endocarditis Merged Database Study Group. Prosthetic valve endocarditis due to coagulase-negative staph- ylococci: findings from the International Collaboration on Endocarditis Merged Database. Eur J Clin Microbiol Infect Dis. 2006;25:365 368. 114. McDonald JR, Olaison L, Anderson DJ, Hoen B, Miro JM, Eykyn S, Abrutyn E, Fowler VG Jr, Habib G, Selton-Suty C, Pappas PA, Cabell CH, Corey GR, Marco F, Sexton DJ. Enterococcal endocarditis: 107 cases from the International Collaboration on Endocarditis Merged Database. Am J Med. 2005;118:759 766. 115. Sexton DJ, Tenenbaum MJ, Wilson WR, Steckelberg JM, Tice AD, Gilbert D, Dismukes W, Drew RH, Durack DT; Endocarditis Treatment Consortium Group. Ceftriaxone once daily for four weeks compared with ceftriaxone plus gentamicin once daily for two weeks for treatment of endocarditis due to penicillin-susceptible streptococci. Clin Infect Dis. 1998;27:1470 1474. 116. Francioli P, Etienne J, Hoigne R, Thys JP, Gerber A. Treatment of streptococcal endocarditis with a single daily dose of ceftriaxone sodium for 4 weeks: efficacy and outpatient treatment feasibility. JAMA. 1992; 267:264 267. 117. Wilson WR, Wilkowske CJ, Wright AJ, Sande MA, Geraci JE. Treatment of streptomycin-susceptible and streptomycin-resistant enterococcal endocarditis. Ann Intern Med. 1984;100:816 823. 118.

Treatment of streptomycin-susceptible and streptomycin-resistant enterococcal endocarditis. Ann Intern Med. 1984;100:816 823. 118. Mansur AJ, Dal Bo CM, Fukushima JT, Issa VS, Grinberg M, Pomer- antzeff PM. Relapses, recurrences, valve replacements, and mortality Wilson et al Prevention of Infective Endocarditis 1753 during the long-term follow-up after infective endocarditis. Am Heart J. 2001;141:78 86. 119. Baddour LM. Twelve-year review of recurrent native-valve infective endocarditis: a disease of the modern antibiotic era. Rev Infect Dis. 1988;10:1163 1170. 120. Chu VH, Sexton DJ, Cabell CH, Reller LB, Pappas PA, Singh RK, Fowler VG Jr, Corey GR, Aksoy O, Woods CW. Repeat infective endocarditis: differentiating relapse from reinfection. Clin Infect Dis. 2005;41:406 409. 121. Welton DE, Young JB, Gentry WO, Raizner AE, Alexander JK, Chahine RA, Miller RR. Recurrent infective endocarditis: analysis of predisposing factors and clinical features. Am J Med. 1979;66:932 938. 122. Levison ME, Kaye D, Mandell GL, Hook EW. Characteristics of patients with multiple episodes of bacterial endocarditis. JAMA. 1970; 211:1355 1357. 123. Renzulli A, Carozza A, Romano G, De Feo M, Della Corte A, Gregorio R, Cotrufo M. Recurrent infective endocarditis: a multivariate analysis of 21 years of experience. Ann Thorac Surg. 2001;72:39 43. 124. Erbel R, Liu F, Ge J, Kupferwasser I. Identification of high-risk sub- groups in infective endocarditis and the role of echocardiography. Eur Heart J. 1995;16:588 602. 125. Kaplan EL, Rich H, Gersony W, Manning J. A collaborative study of infective endocarditis in the 1970s: emphasis on infections in patients who have undergone cardiovascular surgery. Circulation. 1979;59:327 335. 126. Coward K, Tucker N, Darville T. Infective endocarditis in Arkansan children from 1990 through 2002. Pediatr Infect Dis J. 2003;22: 1048 1052. 127. Saiman L, Prince A, Gersony WM. Pediatric infective endocarditis in the modern era. J Pediatr. 1993;122:847 853. 128. Dodo H, Child JS.

Pediatric infective endocarditis in the modern era. J Pediatr. 1993;122:847 853. 128. Dodo H, Child JS. Infective endocarditis in congenital heart disease. Cardiol Clin. 1996;14:383 392. 129. Martin JM, Neches WH, Wald ER. Infective endocarditis: 35 years of experience at a children s hospital. Clin Infect Dis. 1997;24:669 675. 130. Parras F, Bouza E, Romero J, Buzon L, Quero M, Brito J, Vellibre D. Infectious endocarditis in children. Pediatr Cardiol. 1990;11:77 81. 131. Takeda S, Nakanishi T, Nakazawa M. A 28-year trend of infective endocarditis associated with congenital heart diseases: a single institute experience. Pediatr Int. 2005;47:392 396. 132. Ferrieri P, Gewitz MH, Gerber MA, Newburger JW, Dajani AS, Shulman ST, Wilson W, Bolger AF, Bayer A, Levison ME, Pallasch TJ, Gage TW, Taubert KA; Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the American Heart Association Council on Cardiovascular Disease in the Young. Unique features of infective endocarditis in childhood. Circulation. 2002;105:2115 2126. 133. Ishiwada N, Niwa K, Tateno S, Yoshinaga M, Terai M, Nakazawa M; for The Japanese Society of Pediatric Cardiology and Cardiac Surgery Joint Working Groups for Guidelines for Prophylaxis, Diagnosis and Management of Infective Endocarditis in Patients With Congenital Heart Disease. Causative organism influences clinical profile and outcome of infective endocarditis in pediatric patients and adults with congenital heart disease. Circ J. 2005;69:1266 1270. 134. Han YM, Gu X, Titus JL, Rickers C, Bass JL, Urness M, Amplatz K. New self-expanding patent foramen ovale occlusion device. Catheter Cardiovasc Interv. 1999;47:370 376. 135. Prabhu RM, Piper KE, Baddour LM, Steckelberg JM, Wilson WR, Patel R. Antimicrobial susceptibility patterns among viridans group strepto- coccal isolates from infective endocarditis patients from 1971 to 1986 and 1994 to 2002. Antimicrob Agents Chemother. 2004;48:4463 4465. 136. Doern GV, Ferraro MJ, Brueggemann AB, Ruoff KL.

2004;48:4463 4465. 136. Doern GV, Ferraro MJ, Brueggemann AB, Ruoff KL. Emergence of high rates of antimicrobial resistance among viridans group streptococci in the United States. Antimicrob Agents Chemother. 1996;40:891 894. 137. Diekema DJ, Beach ML, Pfaller MA, Jones RN; SENTRY Participants Group. Antimicrobial resistance in viridans group streptococci among patients with and without the diagnosis of cancer in the USA, Canada and Latin America. Clin Microbiol Infect. 2001;7:152 157. 138. Groppo FC, Castro FM, Pacheco AB, Motta RH, Filho TR, Ramacciato JC, Florio FM, Meechan JG. Antimicrobial resistance of Staphylococcus aureus and oral streptococci strains from high-risk endocarditis patients. Gen Dent. 2005;53:410 413. 139. Teng LJ, Hsueh PR, Chen YC, Ho SW, Luk KT. Antimicrobial suscep- tibility of viridans group streptococci in Taiwan with an emphasis on the high rates of resistance to penicillin and macrolides in Streptococcus oralis. J Antimicrob Chemother. 1998;41:621 627. 140. Tuohy M, Washington JA. Antimicrobial susceptibility of viridans group streptococci. Diagn Microbiol Infect Dis. 1997;29:277 280. 141. Seppala H, Haanpera M, Al-Juhaish M, Jarvinen H, Jalava J, Huovinen P. Antimicrobial susceptibility patterns and macrolide resistance genes of viridans group streptococci from normal flora. J Antimicrob Che- mother. 2003;52:636 644. 142. Marron A, Carratala J, Alcaide F, Fernandez-Sevilla A, Gudiol F. High rates of resistance to cephalosporins among viridans-group streptococci causing bacteraemia in neutropenic cancer patients. J Antimicrob Che- mother. 2001;47:87 91. 143. Wu JJ, Lin KY, Hsueh PR, Liu JW, Pan HI, Sheu SM. High incidence of erythromycin-resistant streptococci in Taiwan. Antimicrob Agents Chemother. 1997;41:844 846. 144. King A, Bathgate T, Phillips I. Erythromycin susceptibility of viridans streptococci from the normal throat flora of patients treated with azithromycin or clarithromycin. Clin Microbiol Infect. 2002;8:85 92. 145.

King A, Bathgate T, Phillips I. Erythromycin susceptibility of viridans streptococci from the normal throat flora of patients treated with azithromycin or clarithromycin. Clin Microbiol Infect. 2002;8:85 92. 145. Strom BL, Abrutyn E, Berlin JA, Kinman JL, Feldman RS, Stolley PD, Levison ME, Korzeniowski OM, Kaye D. Risk factors for infective endocarditis: oral hygiene and nondental exposures. Circulation. 2000; 102:2842 2848. 146. Fridkin SK, Gaynes RP. Antimicrobial resistance in intensive care units. Clin Chest Med. 1999;20:303 316, viii. 147. Shay DK, Maloney SA, Montecalvo M, Banerjee S, Wormser GP, Arduino MJ, Bland LA, Jarvis WR. Epidemiology and mortality risk of vancomycin-resistant enterococcal bloodstream infections. J Infect Dis. 1995;172:993 1000. 148. Harbarth S, Rutschmann O, Sudre P, Pittet D. Impact of methicillin resistance on the outcome of patients with bacteremia caused by Staph- ylococcus aureus. Arch Intern Med. 1998;158:182 189. 149. Soufir L, Timsit JF, Mahe C, Carlet J, Regnier B, Chevret S. Attrib- utable morbidity and mortality of catheter-related septicemia in critically ill patients: a matched, risk-adjusted, cohort study. Infect Control Hosp Epidemiol. 1999;20:396 401. 150. Lucas GM, Lechtzin N, Puryear DW, Yau LL, Flexner CW, Moore RD. Vancomycin-resistant and vancomycin-susceptible enterococcal bac- teremia: comparison of clinical features and outcomes. Clin Infect Dis. 1998;26:1127 1133. 151. Pfaller MA, Jones RN, Doern GV, Sader HS, Kugler KC, Beach ML; for the SENTRY Participants Group. Survey of blood stream infections attributable to gram-positive cocci: frequency of occurrence and anti- microbial susceptibility of isolates collected in 1997 in the United States, Canada, and Latin America from the SENTRY Antimicrobial Sur- veillance Program. Diagn Microbiol Infect Dis. 1999;33:283 297. 152.

Survey of blood stream infections attributable to gram-positive cocci: frequency of occurrence and anti- microbial susceptibility of isolates collected in 1997 in the United States, Canada, and Latin America from the SENTRY Antimicrobial Sur- veillance Program. Diagn Microbiol Infect Dis. 1999;33:283 297. 152. Baddour LM, Bettmann MA, Bolger AF, Epstein AE, Ferrieri P, Gerber MA, Gewitz MH, Jacobs AK, Levison ME, Newburger JW, Pallasch TJ, Wilson WR, Baltimore RS, Falace DA, Shulman ST, Tani LY, Taubert KA; American Heart Association. Nonvalvular cardiovascular device- related infections. Circulation. 2003;108:2015 2031. 153. Sherman-Weber S, Axelrod P, Suh B, Rubin S, Beltramo D, Manacchio J, Furukawa S, Weber T, Eisen H, Samuel R. Infective endocarditis following orthotopic heart transplantation: 10 cases and a review of the literature. Transpl Infect Dis. 2004;6:165 170.

Cardiovascular disease: risk assessment and reduction, including lipid modification Clinical guideline NICE 2023. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and- conditions#notice-of-rights). Last updated 10 February 2023 Your responsibility The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals and practitioners are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or the people using their service. It is not mandatory to apply the recommendations, and the guideline does not override the responsibility to make decisions appropriate to the circumstances of the individual, in consultation with them and their families and carers or guardian. All problems (adverse events) related to a medicine or medical device used for treatment or in a procedure should be reported to the Medicines and Healthcare products Regulatory Agency using the Yellow Card Scheme. Local commissioners and providers of healthcare have a responsibility to enable the guideline to be applied when individual professionals and people using services wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with complying with those duties. Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible. Contents Overview 4 Who is it for?

Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible. Contents Overview 4 Who is it for? 4 1.1 Identifying and assessing cardiovascular disease (CVD) risk 7 1.2 Aspirin for primary prevention of CVD 11 1.3 Lifestyle modifications for the primary and secondary prevention of CVD 11 1.4 Lipid modification therapy for the primary and secondary prevention of CVD 15 Terms used in this guideline 25 Implementation: getting started 26 Measuring non-high-density lipoprotein cholesterol when lipid profiling for the primary prevention of cardiovascular disease 26 Reduction of the primary prevention threshold from 20% to 10% CVD risk as calculated by Atorvastatin for the primary and secondary prevention of CVD 28 Further resources 29 Recommendations for research 30 1 Simplifying risk assessment 30 2 Cost effectiveness using individual patient-level data 30 3 Statin therapy in older people 31 4 Lipid modification therapy in people with type 1 diabetes 31 5 Comparative effectiveness and risks of alternative doses of atorvastatin 31 Appendix A: Grouping of statins 33 Finding more information and committee details 36 Update information 37 This guideline replaces CG67 and TA94. This guideline partially replaces CG87. This guideline is the basis of QS100, QS5, QS208 and QS209. Overview This guideline covers the assessment and care of adults who are at risk of or who have cardiovascular disease (CVD), such as heart disease and stroke. It aims to help healthcare professionals identify people who are at risk of cardiovascular problems including people with type 1 or type 2 diabetes, or chronic kidney disease. It describes the lifestyle changes people can make and how statins can be used to reduce their risk. Who is it for?

It describes the lifestyle changes people can make and how statins can be used to reduce their risk. Who is it for? Healthcare professionals People who are at risk of CVD or who have had CVD Introduction This guideline updates and replaces NICE guideline CG67 and NICE technology appraisal guidance 94. The recommendations are labelled according to when they were originally published (see update information for details). Cardiovascular disease (CVD) describes disease of the heart and blood vessels caused by the process of atherosclerosis. It is the leading cause of death in England and Wales, accounting for almost one-third of deaths according to UK National Statistics. In 2010, 180,000 people died from CVD around 80,000 of these deaths were caused by coronary heart disease and 49,000 were caused by strokes. Of the 180,000 deaths, 46,000 occurred before people were aged 75 years, and 70% of those were in men. Death rates from CVD peaked in the 1970s and 1980s but have more than halved since then. Rates have fallen more rapidly in older age groups compared with younger ones, with an approximately 50% reduction in the 55- to 64-year age group compared with a 20% reduction in men aged 35 to 44 years. Despite evidence that mortality from CVD is falling, morbidity appears to be rising. CVD has significant cost implications and was estimated to cost the NHS in England almost 6,940 million in 2003, rising to 7,880 million in 2010. CVD shows strong age dependence and predominantly affects people older than 50 years. Risk factors for CVD include non-modifiable factors such as age, sex, family history of CVD, ethnic background and modifiable risk factors such as smoking, raised blood pressure and cholesterol.

Risk factors for CVD include non-modifiable factors such as age, sex, family history of CVD, ethnic background and modifiable risk factors such as smoking, raised blood pressure and cholesterol. CVD is strongly associated with low income and social deprivation and shows a North South divide, with higher rates in the north of England. This guideline includes recommendations on risk assessment for CVD and on the use of lipid-lowering drugs. The original guideline is updated in part to allow consideration of new evidence on risk assessment tools and to reflect changes in price and availability of generic statins. NICE has produced guidance on other modifiable risk factors for CVD and this guideline should be used in conjunction with it. In this update the guideline development group recommend the use of non-high-density lipoprotein (non-HDL) cholesterol rather than low-density lipoprotein (LDL) cholesterol. Non-HDL cholesterol is total cholesterol minus HDL cholesterol. LDL cholesterol is not directly measured but requires a calculation using a fasting sample and for triglyceride levels to be less than 4.5 mmol/litre, whereas the measurement of non-HDL cholesterol does not. For the purpose of this guideline, statins are grouped into 3 different intensity categories according to the percentage reduction in low-density lipoprotein cholesterol they produce: low intensity if the reduction is 20% to 30% medium intensity if the reduction is 31% to 40% high intensity if the reduction is above 40%. Please see appendix A for further details. This grouping was agreed by guideline development group consensus, informed by analyses in the literature. See also the full guideline for a discussion of this grouping. Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.

Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. 1.1 Identifying and assessing cardiovascular disease (CVD) risk Identifying people for full formal risk assessment 1.1.1 For the primary prevention of CVD in primary care, use a systematic strategy to identify people who are likely to be at high risk. [2008, 1.1.2 Prioritise people on the basis of an estimate of their CVD risk before a full formal risk assessment. Estimate their CVD risk using CVD risk factors already recorded in primary care electronic medical records. [2008] 1.1.3 People older than 40 should have their estimate of CVD risk reviewed on an ongoing basis. [2008] 1.1.4 Prioritise people for a full formal risk assessment if their estimated 10-year risk of CVD is 10% or more. [2008, amended 2014] 1.1.5 Discuss the process of risk assessment with the person identified as being at risk, including the option of declining any formal risk 1.1.6 Do not use opportunistic assessment as the main strategy in primary care to identify CVD risk in unselected people. [2008] Full formal risk assessment 1.1.7 Be aware that all CVD risk assessment tools can provide only an approximate value for CVD risk. Interpretation of CVD risk scores should always reflect informed clinical judgement. [2008] 1.1.8 Use the QRISK2 risk assessment tool to assess CVD risk for the primary prevention of CVD in people up to and including age 84 years.

[2008] 1.1.8 Use the QRISK2 risk assessment tool to assess CVD risk for the primary prevention of CVD in people up to and including age 84 years. [2014] 1.1.9 Do not use a risk assessment tool to assess CVD risk in people with type 1 diabetes. See recommendations 1.3.23, 1.3.24 and 1.3.25 for advice on treatment with statins for people with type 1 diabetes. [2014] 1.1.10 Use the QRISK2 risk assessment tool to assess CVD risk in people with 1.1.11 Do not use a risk assessment tool to assess CVD risk in people with an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2 and/or albuminuria. These people are at increased risk of CVD. See the recommendation on advice on treatment with statins for people with chronic kidney disease (CKD). [2014] People on renal replacement therapy are outside the scope of this guideline. 1.1.12 Complete as many fields of the risk assessment tool as possible. [2014] 1.1.13 Routinely record ethnicity, body mass index (BMI) and family history of premature CVD in medical records. [2008] 1.1.14 Consider socioeconomic status as an additional factor that contributes to CVD risk. [2008] 1.1.15 Do not use a risk assessment tool for people with pre-existing CVD. 1.1.16 Do not use a risk assessment tool for people who are at high risk of developing CVD because of familial hypercholesterolaemia (see NICE's guideline on familial hypercholesterolaemia) or other inherited disorders of lipid metabolism. [2008, amended 2014] 1.1.17 When using the risk score to inform drug treatment decisions, particularly if it is near to the threshold for treatment, take into account other factors that: may predispose the person to premature CVD and may not be included in calculated risk scores.

[2008, amended 2014] 1.1.17 When using the risk score to inform drug treatment decisions, particularly if it is near to the threshold for treatment, take into account other factors that: may predispose the person to premature CVD and may not be included in calculated risk scores. [2008, amended 2014] 1.1.18 Recognise that standard CVD risk scores will underestimate risk in people who have additional risk because of underlying medical conditions or treatments. These groups include: people treated for HIV people with serious mental health problems people taking medicines that can cause dyslipidaemia such as antipsychotic medication, corticosteroids or immunosuppressant drugs people with autoimmune disorders such as systemic lupus erythematosus, and other systemic inflammatory disorders. [2008, amended 2014] 1.1.19 Recognise that CVD risk will be underestimated in people who are already taking antihypertensive or lipid modification therapy, or who have recently stopped smoking. Use clinical judgement to decide on further treatment of risk factors in people who are below the CVD risk threshold for treatment. [2008, amended 2014] 1.1.20 Severe obesity (BMI greater than 40 kg/m2 ) increases CVD risk. Take this into account when using risk scores to inform treatment decisions in this group (see NICE's guideline on obesity: identification, assessment and 1.1.21 Consider people aged 85 or older to be at increased risk of CVD because of age alone, particularly people who smoke or have raised blood Communication about risk assessment and treatment 1.1.22 NICE has produced guidance on the components of good patient experience in adult NHS services. These include recommendations on the communication of risk. Follow the recommendations in NICE's guideline on patient experience in adult NHS services. See also NICE's guideline on shared decision making. [2014] 1.1.23 Use everyday, jargon-free language to communicate information on risk. If technical terms are used, explain them clearly.

[2014] 1.1.23 Use everyday, jargon-free language to communicate information on risk. If technical terms are used, explain them clearly. [2008] 1.1.24 Set aside adequate time during the consultation to provide information on risk assessment and to allow any questions to be answered. Further consultation may be required. [2008] 1.1.25 Document the discussion relating to the consultation on risk assessment and the person's decision. [2008] 1.1.26 Offer people information about their absolute risk of CVD and about the absolute benefits and harms of an intervention over a 10-year period. This information should be in a form that: presents individualised risk and benefit scenarios and presents the absolute risk of events numerically and uses appropriate diagrams and text. [2008] 1.1.27 To encourage the person to participate in reducing their CVD risk: find out what, if anything, the person has already been told about their CVD risk and how they feel about it explore the person's beliefs about what determines future health (this may affect their attitude to changing risk) assess their readiness to make changes to their lifestyle (diet, physical activity, smoking and alcohol consumption), to undergo investigations and to take long-term medication assess their confidence in making changes to their lifestyle, undergoing investigations and taking medication inform them of potential future management based on current evidence and best practice involve them in developing a shared management plan check with them that they have understood what has been discussed. [2008, 1.1.28 If the person's CVD risk is at a level where intervention is recommended but they decline the offer of treatment, advise them that their CVD risk should be reassessed again in the future. Record their choice in their medical notes. [2008, amended 2014] 1.2 Aspirin for primary prevention of CVD 1.2.1 Do not routinely offer aspirin for primary prevention of CVD.

[2008, amended 2014] 1.2 Aspirin for primary prevention of CVD 1.2.1 Do not routinely offer aspirin for primary prevention of CVD. [2023] For guidance on using aspirin to prevent venous thromboembolism in over 16s in hospital, see NICE's guideline on venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. 1.3 Lifestyle modifications for the primary and secondary prevention of CVD Cardioprotective diet 1.3.1 Advise people at high risk of or with CVD to eat a diet in which total fat intake is 30% or less of total energy intake, saturated fats are 7% or less of total energy intake, intake of dietary cholesterol is less than 300 mg/ day and where possible saturated fats are replaced by mono-unsaturated and polyunsaturated fats. Further information and advice can be found on the NHS Eat well webpage. [2014] 1.3.2 Advise people at high risk of or with CVD to: reduce their saturated fat intake. increase their mono-unsaturated fat intake with olive oil, rapeseed oil or spreads based on these oils and to use them in food preparation. Further information and advice on healthy cooking methods can be found on the NHS Eat well webpage. [2014] 1.3.3 Advise people at high risk of or with CVD to do all of the following: choose wholegrain varieties of starchy food reduce their intake of sugar and food products containing refined sugars including fructose eat at least 5 portions of fruit and vegetables per day eat at least 2 portions of fish per week, including a portion of oily fish eat at least 4 to 5 portions of unsalted nuts, seeds and legumes per week. Further information and advice can be found on the NHS Eat well webpage.

Further information and advice can be found on the NHS Eat well webpage. 1.3.4 Advise pregnant women to limit their oily fish to no more than 2 portions per week and to avoid marlin, shark and swordfish. Further information and advice on oily fish consumption can be found on the NHS Eat well 1.3.5 Take account of a person's individual circumstances for example, drug therapy, comorbidities and other lifestyle modifications when giving dietary advice. [2014] 1.3.6 Advise and support people at high risk of or with CVD to achieve a healthy diet in line with NICE's guideline on behaviour change: general Physical activity 1.3.7 Advise people at high risk of or with CVD to do the following every week: at least 150 minutes of moderate intensity aerobic activity or 75 minutes of vigorous intensity aerobic activity or a mix of moderate and vigorous aerobic activity in line with national guidance for the general population (see the UK Chief Medical Officers' physical activity guidelines for more information). [2008, amended 2014] 1.3.8 Advise people to do muscle-strengthening activities on 2 or more days a week that work all major muscle groups (legs, hips, back, abdomen, chest, shoulders and arms) in line with national guidance for the general population (see the UK Chief Medical Officers' physical activity guidelines for more information). [2014] 1.3.9 Encourage people who are unable to perform moderate-intensity physical activity because of comorbidity, medical conditions or personal circumstances to exercise at their maximum safe capacity. [2008, 1.3.10 Advice about physical activity should take into account the person's needs, preferences and circumstances.

[2008, 1.3.10 Advice about physical activity should take into account the person's needs, preferences and circumstances. Agree goals and provide the person with written information about the benefits of activity and local opportunities to be active, in line with NICE's guidelines on walking and cycling, physical activity: brief advice for adults and exercise referral Combined interventions (diet and physical activity) 1.3.11 Give advice on diet and physical activity in line with national recommendations (see the NHS Eat well webpage). [2008] Weight management 1.3.12 Offer people at high risk of or with CVD who are overweight or obese appropriate advice and support to work towards achieving and maintaining a healthy weight, in line with NICE's guideline on obesity: identification, assessment and management. [2008] Alcohol consumption 1.3.13 For advice on alcohol consumption, including binge drinking, see the UK chief medical officers' guidelines on low risk drinking. [2008] Smoking cessation 1.3.14 Advise all people who smoke to stop, in line with NICE's guideline on tobacco: preventing uptake, promoting quitting and treating dependence. 1.3.15 Offer people who want to stop smoking support and advice, and referral to an intensive support service (for example, the NHS Stop Smoking 1.3.16 If a person is unable or unwilling to accept a referral to an intensive support service, offer them pharmacotherapy in line with NICE's guideline on stop smoking interventions and services and NICE's technology appraisal guidance on varenicline for smoking cessation. Plant stanols and sterols 1.3.17 Do not advise any of the following to take plant stanols or sterols for the prevention of CVD: people who are being treated for primary prevention people who are being treated for secondary prevention people with CKD people with type 1 diabetes people with type 2 diabetes.

Plant stanols and sterols 1.3.17 Do not advise any of the following to take plant stanols or sterols for the prevention of CVD: people who are being treated for primary prevention people who are being treated for secondary prevention people with CKD people with type 1 diabetes people with type 2 diabetes. [2014] 1.4 Lipid modification therapy for the primary and secondary prevention of CVD 1.4.1 Be aware that when deciding on lipid modification therapy for the prevention of CVD, drugs are preferred for which there is evidence in clinical trials of a beneficial effect on CVD morbidity and mortality. 1.4.2 When a decision is made to prescribe a statin use a statin of high intensity and low acquisition cost. [2014] See appendix A for statin classification. Initial lipid measurement and referral for specialist review 1.4.3 Measure both total and high-density lipoprotein (HDL) cholesterol to achieve the best estimate of CVD risk. [2008] 1.4.4 Before starting lipid modification therapy for the primary prevention of CVD, take at least 1 lipid sample to measure a full lipid profile. This should include measurement of total cholesterol, HDL cholesterol, non-HDL cholesterol and triglyceride concentrations. A fasting sample is not For information about implementing this recommendation, see the implementation: getting started section. 1.4.5 Use the clinical findings, lipid profile and family history to judge the likelihood of a familial lipid disorder rather than the use of strict lipid cut-off values alone. [2014] 1.4.6 Exclude possible common secondary causes of dyslipidaemia (such as excess alcohol, uncontrolled diabetes, hypothyroidism, liver disease and nephrotic syndrome) before referring for specialist review.

[2014] 1.4.6 Exclude possible common secondary causes of dyslipidaemia (such as excess alcohol, uncontrolled diabetes, hypothyroidism, liver disease and nephrotic syndrome) before referring for specialist review. [2014] 1.4.7 Consider the possibility of familial hypercholesterolaemia and investigate as described in NICE's guideline on familial hypercholesterolaemia if they have: a total cholesterol concentration more than 7.5 mmol/litre and a family history of premature coronary heart disease. [2014] 1.4.8 Arrange for specialist assessment of people with a total cholesterol concentration of more than 9.0 mmol/litre or a non-HDL cholesterol concentration of more than 7.5 mmol/litre even in the absence of a first-degree family history of premature coronary heart disease. [2014] 1.4.9 Refer for urgent specialist review if a person has a triglyceride concentration of more than 20 mmol/litre that is not a result of excess alcohol or poor glycaemic control. [2014] 1.4.10 In people with a triglyceride concentration between 10 and 20 mmol/litre: repeat the triglyceride measurement with a fasting test (after an interval of 5 days, but within 2 weeks) and review for potential secondary causes of hyperlipidaemia and seek specialist advice if the triglyceride concentration remains above 10 mmol/ 1.4.11 In people with a triglyceride concentration between 4.5 and 9.9 mmol/ litre: be aware that the CVD risk may be underestimated by risk assessment tools and optimise the management of other CVD risk factors present and seek specialist advice if non-HDL cholesterol concentration is more than Statins for the prevention of CVD Recommendations in this section update and replace those in statins for the prevention of cardiovascular events (NICE technology appraisal guidance 94). There is a NICE patient decision aid to support discussions about statin therapy to reduce the risk of coronary heart disease and stroke.

There is a NICE patient decision aid to support discussions about statin therapy to reduce the risk of coronary heart disease and stroke. 1.4.12 The decision whether to start statin therapy should be made after an informed discussion between the clinician and the person about the risks and benefits of statin treatment, taking into account additional factors such as potential benefits from lifestyle modifications, informed patient preference, comorbidities, polypharmacy, general frailty and life 1.4.13 Before starting statin treatment perform baseline blood tests and clinical assessment, and treat comorbidities and secondary causes of dyslipidaemia. Include all of the following in the assessment: smoking status alcohol consumption blood pressure (see NICE's guideline on hypertension) BMI or other measure of obesity (see NICE's guideline on obesity: identification, assessment and management) total cholesterol, non-HDL cholesterol, HDL cholesterol and triglycerides renal function and eGFR transaminase level (alanine aminotransferase or aspartate aminotransferase) thyroid-stimulating hormone. [2014] Primary prevention 1.4.14 Before offering statin treatment for primary prevention, discuss the benefits of lifestyle modification and optimise the management of all other modifiable CVD risk factors if possible. [2014] 1.4.15 Recognise that people may need support to change their lifestyle. To help them do this, refer them to programmes such as exercise referral schemes. (See NICE's guidelines on behaviour change: individual approaches and physical activity: exercise referral schemes.) [2014] 1.4.16 Offer people the opportunity to have their risk of CVD assessed again after they have tried to change their lifestyle. [2014] 1.4.17 If lifestyle modification is ineffective or inappropriate offer statin treatment after risk assessment. [2014] 1.4.18 Offer atorvastatin 20 mg for the primary prevention of CVD to people who have a 10% or greater 10-year risk of developing CVD. Estimate the level of risk using the QRISK2 assessment tool.

Estimate the level of risk using the QRISK2 assessment tool. [2014] For information about implementing this recommendation, see implementation: getting started. 1.4.19 For people 85 years or older consider atorvastatin 20 mg as statins may be of benefit in reducing the risk of non-fatal myocardial infarction. Be aware of factors that may make treatment inappropriate (see Secondary prevention 1.4.20 Start statin treatment in people with CVD with atorvastatin 80 mg. Use a lower dose of atorvastatin if any of the following apply: potential drug interactions high risk of adverse effects patient preference. [2014] In July 2014, this was an off-label use of atorvastatin. See NICE's information on prescribing medicines. For information about implementing this recommendation, see the implementation: getting started section. 1.4.21 Do not delay statin treatment in secondary prevention to manage modifiable risk factors. [2014] 1.4.22 If a person has acute coronary syndrome, do not delay statin treatment. Take a lipid sample on admission and about 3 months after the start of Primary prevention for people with type 1 diabetes 1.4.23 Consider statin treatment for the primary prevention of CVD in all adults with type 1 diabetes. [2014] 1.4.24 Offer statin treatment for the primary prevention of CVD to adults with type 1 diabetes who: are older than 40 years or have had diabetes for more than 10 years or have established nephropathy or have other CVD risk factors. [2014] 1.4.25 Start treatment for adults with type 1 diabetes with atorvastatin 20 mg. Primary prevention for people with type 2 diabetes 1.4.26 Offer atorvastatin 20 mg for the primary prevention of CVD to people with type 2 diabetes who have a 10% or greater 10-year risk of developing CVD.

[2014] 1.4.25 Start treatment for adults with type 1 diabetes with atorvastatin 20 mg. Primary prevention for people with type 2 diabetes 1.4.26 Offer atorvastatin 20 mg for the primary prevention of CVD to people with type 2 diabetes who have a 10% or greater 10-year risk of developing CVD. Estimate the level of risk using the QRISK2 assessment People with CKD 1.4.27 Offer atorvastatin 20 mg for the primary or secondary prevention of CVD to people with CKD. Increase the dose if a greater than 40% reduction in non-HDL cholesterol is not achieved (see recommendation 1.3.28) and eGFR is 30 ml/min/1.73 m2 or more. Agree the use of higher doses with a renal specialist if eGFR is less than 30 ml/ See NICE's guideline on chronic kidney disease for CKD classification. People on renal replacement therapy are outside the scope of this guideline. Follow-up of people started on statin treatment 1.4.28 Measure total cholesterol, HDL cholesterol and non-HDL cholesterol in all people who have been started on high-intensity statin treatment (both primary and secondary prevention, including atorvastatin 20 mg for primary prevention) at 3 months of treatment and aim for a greater than 40% reduction in non-HDL cholesterol. If a greater than 40% reduction in non-HDL cholesterol is not achieved: discuss adherence and timing of dose optimise adherence to diet and lifestyle measures consider increasing the dose if started on less than atorvastatin 80 mg and the person is judged to be at higher risk because of comorbidities, risk score or using clinical judgement. [2014] 1.4.29 Provide annual medication reviews for people taking statins. Use these reviews to discuss medicines adherence and lifestyle modification and address CVD risk factors. Consider an annual non-fasting blood test for non-HDL cholesterol to inform the discussion.

Consider an annual non-fasting blood test for non-HDL cholesterol to inform the discussion. [2014] 1.4.30 Discuss with people who are stable on a low- or middle-intensity statin the likely benefits and potential risks of changing to a high-intensity statin when they have a medication review and agree with the person whether a change is needed. [2014] For information about implementing this recommendation, see the implementation: getting started section. Advice and monitoring for adverse effects 1.4.31 Advise people who are being treated with a statin: that other drugs, some foods (for example, grapefruit juice) and some supplements may interfere with statins and to always consult the patient information leaflet, a pharmacist or prescriber for advice when starting other drugs or thinking about taking supplements. [2014] 1.4.32 Remind the person to restart the statin if they stopped taking it because of drug interactions or to treat intercurrent illnesses. [2014] 1.4.33 Before offering a statin, ask the person if they have had persistent generalised unexplained muscle pain, whether associated or not with previous lipid-lowering therapy. If they have, measure creatine kinase levels. If creatine kinase levels are more than 5 times the upper limit of normal, re-measure creatine kinase after 7 days. If creatine kinase levels are still 5 times the upper limit of normal, do not start statin treatment. If creatine kinase levels are raised but less than 5 times the upper limit of normal, start statin treatment at a lower dose. [2014] 1.4.34 Advise people who are being treated with a statin to seek medical advice if they develop muscle symptoms (pain, tenderness or weakness). If this occurs, measure creatine kinase.

[2014] 1.4.34 Advise people who are being treated with a statin to seek medical advice if they develop muscle symptoms (pain, tenderness or weakness). If this occurs, measure creatine kinase. [2008] 1.4.35 If people report muscle pain or weakness while taking a statin, explore other possible causes of muscle pain or weakness and raised creatine kinase if they have previously tolerated statin therapy for more than 1.4.36 Do not measure creatine kinase levels in asymptomatic people who are being treated with a statin. [2008] 1.4.37 Measure baseline liver transaminase enzymes (alanine aminotransferase or aspartate aminotransferase) before starting a statin. Measure liver transaminase within 3 months of starting treatment and at 12 months, but not again unless clinically indicated. [2008] 1.4.38 Do not routinely exclude from statin therapy people who have liver transaminase levels that are raised but are less than 3 times the upper limit of normal. [2008] 1.4.39 Do not stop statins because of an increase in blood glucose level or HbA1c. (See the recommendations on assessing for risk of diabetes mellitus in NICE's guideline on preventing type 2 diabetes.) [2014] 1.4.40 Statins are contraindicated in pregnancy: Advise women of childbearing potential of the potential teratogenic risk of statins and to stop taking them if pregnancy is a possibility. Advise women planning pregnancy to stop taking statins 3 months before they attempt to conceive and to not restart them until breastfeeding is finished. Intolerance of statins 1.4.41 If a person is not able to tolerate a high-intensity statin aim to treat with the maximum tolerated dose. [2014] 1.4.42 Tell the person that any statin at any dose reduces CVD risk.

[2014] 1.4.42 Tell the person that any statin at any dose reduces CVD risk. If someone reports adverse effects when taking high-intensity statin discuss the following possible strategies with them: stopping the statin and trying again when the symptoms have resolved to check if the symptoms are related to the statin reducing the dose within the same intensity group changing the statin to a lower intensity group. [2014] 1.4.43 Seek specialist advice about options for treating people at high risk of CVD such as those with CKD, type 1 diabetes, type 2 diabetes or genetic dyslipidaemias, and those with CVD, who are intolerant to 3 different statins. Advice can be sought for example, by telephone, virtual clinic or Adherence to statin therapy 1.4.44 Do not offer coenzyme Q10 or vitamin D to increase adherence to statin Fibrates for preventing CVD 1.4.45 Do not routinely offer fibrates for the prevention of CVD to any of the following: people who are being treated for primary prevention people who are being treated for secondary prevention people with CKD people with type 1 diabetes people with type 2 diabetes. [2014] Nicotinic acid for preventing CVD 1.4.46 Do not offer nicotinic acid (niacin) for the prevention of CVD to any of the following: people who are being treated for primary prevention people who are being treated for secondary prevention people with CKD people with type 1 diabetes people with type 2 diabetes. [2014] Bile acid sequestrants (anion exchange resins) for preventing CVD 1.4.47 Do not offer a bile acid sequestrant (anion exchange resin) for the prevention of CVD to any of the following: people who are being treated for primary prevention people who are being treated for secondary prevention people with CKD people with type 1 diabetes people with type 2 diabetes.

[2014] Bile acid sequestrants (anion exchange resins) for preventing CVD 1.4.47 Do not offer a bile acid sequestrant (anion exchange resin) for the prevention of CVD to any of the following: people who are being treated for primary prevention people who are being treated for secondary prevention people with CKD people with type 1 diabetes people with type 2 diabetes. [2014] Omega-3 fatty acid compounds for preventing CVD 1.4.48 Do not offer omega-3 fatty acid compounds for the prevention of CVD to any of the following: people who are being treated for primary prevention people who are being treated for secondary prevention people with CKD people with type 1 diabetes people with type 2 diabetes. Icosapent ethyl is an exception to this if used as described in NICE's technology appraisal guidance on icosapent ethyl with statin therapy for reducing the risk of cardiovascular events in people with raised triglycerides. 1.4.49 Tell people that there is no evidence that use of omega-3 fatty acid compounds help prevent CVD, except use of icosapent ethyl as described in NICE's technology appraisal guidance on icosapent ethyl with statin therapy. [2014] Combination therapy for preventing CVD 1.4.50 For the primary or secondary prevention of CVD, do not offer the combination of a statin with: a bile acid sequestrant (anion exchange resin), a fibrate or nicotinic acid, or an omega 3 fatty acid compound, except icosapent ethyl as described in NICE's technology appraisal guidance on icosapent ethyl with statin therapy. Ezetimibe 1.4.51 People with primary hypercholesterolaemia should be considered for ezetimibe treatment in line with NICE's technology appraisal guidance on ezetimibe for treating primary heterozygous-familial and non-familial Other treatment options For other treatment options, see the NICE technology appraisal guidance on our topic page on lipid disorders.

Ezetimibe 1.4.51 People with primary hypercholesterolaemia should be considered for ezetimibe treatment in line with NICE's technology appraisal guidance on ezetimibe for treating primary heterozygous-familial and non-familial Other treatment options For other treatment options, see the NICE technology appraisal guidance on our topic page on lipid disorders. Terms used in this guideline High-intensity statin The following doses for statins are high intensity, based on the percentage reduction in low-density lipoprotein (LDL) cholesterol they can produce: atorvastatin: 20 mg to 80 mg rosuvastatin: 10 mg to 40 mg simvastatin: 80 mg. Implementation: getting started This section highlights some important changes to practice that may result from implementing this guideline identified at publication in July 2014. With input from stakeholders, experts and health professionals, 3 areas have been identified that may have a big impact on practice or could be challenging to implement. However, other changes to practice may be needed to fully implement the guideline. Measuring non-high-density lipoprotein cholesterol when lipid profiling for the primary prevention of cardiovascular disease Potential impact of implementation Non-high-density lipoprotein (non-HDL) cholesterol is seen to be a better cardiovascular disease (CVD) risk indicator than low-density lipoprotein (LDL) cholesterol. It is more accurate, more practical and cost effective. A fasting blood sample is not needed. This is more convenient for patients and may reduce the need for additional blood samples. Those requesting lipid profiles for their patients such as GPs, practice nurses and community pharmacists may need to change their practice. Laboratories may also need to change their reporting procedures. Challenges for implementation The United Kingdom National External Quality Assessment Service (UKNEQAS) estimated that less than 10% of laboratories included non-HDL cholesterol in their reports; however, this was primarily due to lack of demand.

Challenges for implementation The United Kingdom National External Quality Assessment Service (UKNEQAS) estimated that less than 10% of laboratories included non-HDL cholesterol in their reports; however, this was primarily due to lack of demand. Healthcare workers may need educating in what the non-HDL cholesterol test means, how to interpret the laboratory results, and how it compares with the previously used LDL cholesterol test. Support for implementation The Association of Clinical Biochemistry and Laboratory Medicine disseminated the updated guidance to their members specifically clinical scientists at the laboratories to request that they routinely include non-HDL cholesterol in their lipid profile reports. No additional equipment is needed for the non-HDL cholesterol test, other than a change to the software used when producing the report, and no extra time is needed to produce the lipid profile. Local organisations may wish to contact the laboratory they use to ensure it has this information. Lab Tests Online UK information on lipid profiling was updated to include details of the non-HDL cholesterol test. The information on this site explains what the test is, why it is carried out, what it involves and how to interpret the results. The website is a resource for both professionals and the public. Reduction of the primary prevention threshold from 20% to 10% CVD risk as calculated by QRISK2 Potential impact of implementation It is expected that there will be a reduction in the number of deaths and hospital-related admissions due to CVD events. Because the price of statins has fallen, using statins to reduce the risk of CVD at a lower threshold than NICE previously recommended is cost effective. Primary healthcare professionals may need to change their practice.

Because the price of statins has fallen, using statins to reduce the risk of CVD at a lower threshold than NICE previously recommended is cost effective. Primary healthcare professionals may need to change their practice. Challenges for implementation The number of people eligible to take statins for the primary prevention of CVD will increase because of the reduction in the treatment threshold from a 20% to a 10% 10-year risk of a CVD event. The challenge is to ensure that statin treatment is presented as a patient choice in addition to lifestyle modification to avoid unnecessarily 'medicalising' this group of people. To help patients make an informed decision, healthcare professionals will need an effective way of briefly but clearly communicating the pros and cons of the various options available. Support for implementation The guideline does not propose that statins should be used instead of the lifestyle adjustments that people at risk need to make. It encourages GPs to fully explore with their patients all the options promoted by the guidance, including lifestyle changes, blood pressure control, avoidance of diabetes and cholesterol (lipid) lowering. There is a NICE patient decision aid to support primary healthcare professionals in discussing the pros and cons of statin therapy with their patients so they can make an informed choice. Expert opinion suggests that around 20% of these people will choose not to take statins after discussions with their healthcare professional. Health practitioners may wish to refer to the lifestyle modification information in NICE's guideline on behaviour change: individual approaches. Atorvastatin for the primary and secondary prevention of CVD Potential impact of implementation Since the 2008 guideline on lipid modification was published, atorvastatin has come off- patent and is available at a reduced cost, therefore making it more cost effective.

Atorvastatin for the primary and secondary prevention of CVD Potential impact of implementation Since the 2008 guideline on lipid modification was published, atorvastatin has come off- patent and is available at a reduced cost, therefore making it more cost effective. Atorvastatin is more potent than other non-generic statins and has a lower risk of adverse interactions with other drugs. There is also greater compatibility with other cardiovascular and lipid modifying therapies. In addition, atorvastatin does not have to be taken at night, which may increase convenience. Challenges for implementation The rationale for recommending atorvastatin over other statins may not be well understood, both when starting treatment for people with a 10% CVD risk or greater and when prescribing statins for people with existing CVD. Prescribers may be uncertain about switching existing patients to atorvastatin from other statins, and may perceive there to be an impact on their workload in doing so. Support for implementation A meta-analysis of studies with statins was conducted after statins were classified into high-, medium- and low-efficacy groups based on their efficacy in lowering LDL cholesterol levels. High-efficacy statins at low acquisition cost (for example, atorvastatin 20 mg or greater) were more effective than moderate-intensity statins (simvastatin 20 mg or atorvastatin 10 mg) in reducing cardiovascular outcomes. This increment in therapy was cost effective, with high-intensity statin therapy reducing CVD events by an extra 9 to 12 per thousand fatal and non-fatal heart attacks and stroke events in this comparison. People admitted for acute coronary syndromes are likely to have been prescribed atorvastatin 80 mg on the basis of recommendations made in the 2008 guideline. Therefore, only people with chronic CVD would need to be considered for conversion to high-dose, high-intensity statin (atorvastatin 80 mg).

Therefore, only people with chronic CVD would need to be considered for conversion to high-dose, high-intensity statin (atorvastatin 80 mg). There is no time restriction on implementing recommendation 1.3.30 with existing patients. There is no anticipated increase in workload as discussion could take place at the time of their next annual review. Further resources There are further NICE resources that may help to support implementation. The UK National Screening Committee has agreed to reflect the 10% risk threshold in The NHS Health Check programme in line with the NICE recommendations. NICE produces indicators annually for use in the Quality and Outcomes Framework (QOF) for the UK. The process for this and the NICE menu can be found on NICE's Quality and Outcomes Framework indicator webpage. Uptake data about guideline recommendations and quality standard measures are available. Recommendations for research The guideline development group has made the following recommendations for research. The guideline development group's full set of research recommendations is in the full guideline. 1 Simplifying risk assessment What is the effectiveness of age alone and other routinely available risk factors compared with the formal structured multifactorial risk assessment to identify people at high risk of developing cardiovascular disease (CVD)? Why this is important Current risk assessment tools rely on a complex set of data derived from demographic, lifestyle, physiological and biochemical parameters. The principal determinant of CVD risk is age, and this may be sufficient to identify high-risk populations. However, focusing on age alone may result in people being missed who are at higher risk as a result of other factors that do not require access to intensive resources, such as smoking status, family history and deprivation. It is important therefore to assess age against validated simplified and complex CVD risk tools when predicting people at high risk.

It is important therefore to assess age against validated simplified and complex CVD risk tools when predicting people at high risk. 2 Cost effectiveness using individual patient-level data What is the improvement in the cost-effectiveness metrics for statin therapy in reducing CVD that can be obtained when using a complete individual patient-based outcomes meta-analysis data set compared with using published outcomes data? Why this is important This guideline development process uses published summary data from trials in a meta-analysis to inform the clinical efficacy of statins. This use of aggregate data has limitations. The use of individual patient data would allow use of time to event statistics and allow investigation of interaction with baseline risk. Such an approach can be used to validate the current approach and would provide useful information on limitations of use of summary data. 3 Statin therapy in older people What is the effectiveness of statin therapy in older people? Why this is important The UK population is ageing and atherosclerosis is an age-associated process. Few trials assessing cardiovascular outcomes have recruited many people older than 80 years yet the important effect of age on CVD risk suggests that all people in this group should be offered statin therapy. However, there is no evidence to validate the CVD benefits and side effects of statin therapy such as effect on muscle and renal function in this age group. Controversy also exists about the efficacy of statins in preventing or promoting other chronic diseases of ageing such as dementia, Parkinson's disease, or age-related macular degeneration. 4 Lipid modification therapy in people with type 1 diabetes What is the effectiveness of statins and/or other low-density lipoprotein (LDL) cholesterol-lowering treatment in people with type 1 diabetes?

4 Lipid modification therapy in people with type 1 diabetes What is the effectiveness of statins and/or other low-density lipoprotein (LDL) cholesterol-lowering treatment in people with type 1 diabetes? Why this is important People with type 1 diabetes have increased CVD risk derived from age, sex, glycaemia, blood pressure, renal function and lipid levels as identified in epidemiological studies. Long-term glycaemic control is associated with better outcomes but no trial has investigated the efficacy of statin therapy or other LDL-cholesterol-lowering therapies exclusively in people with type 1 diabetes. 5 Comparative effectiveness and risks of alternative doses of atorvastatin What is the clinical effectiveness and rate of adverse events of statin therapy using atorvastatin 20 mg per day compared with atorvastatin 40 mg per day and atorvastatin 80 mg per day in people without established CVD? Why this is important This guideline has established that atorvastatin 20 mg is clinically and cost effective for the primary prevention of CVD and should be recommended for those at 10% risk of cardiovascular events as assessed using the QRISK2 calculator. However, this analysis looked at the effectiveness of treatment shown by 'high-intensity' statins as a group, as it was not possible to establish the relative effectiveness of atorvastatin 20 mg, 40 mg and 80 mg using trial data. Trial data with clinical outcomes exists for atorvastatin 80 mg against atorvastatin 10 mg only. The rates of adverse events resulting from different doses of atorvastatin in routine clinical practice are also uncertain and would need to be considered in combination with effectiveness in assessing the relative costs and benefits of different doses of atorvastatin.

The rates of adverse events resulting from different doses of atorvastatin in routine clinical practice are also uncertain and would need to be considered in combination with effectiveness in assessing the relative costs and benefits of different doses of atorvastatin. Appendix A: Grouping of statins For the purpose of this guideline, statins are grouped into 3 different intensity categories according to the percentage reduction in low-density lipoprotein cholesterol: a 20% to 30% reduction is low intensity a 31% to 40% reduction is medium intensity a reduction of more than 40% is high intensity. This grouping was agreed by guideline development group consensus, informed by analyses in the literature. See the full guideline for a discussion of this grouping. Grouping of statins used in this guideline: reduction in low-density lipoprotein (LDL) cholesterol by daily dose Fluvastatin: 20 mg/day, 21% reduction 40 mg/day, 27% reduction 80 mg/day, 33% reduction Pravastatin: 10 mg/day, 20% reduction 20 mg/day, 24% reduction 40 mg/day, 29% reduction Simvastatin: 10 mg/day, 27% reduction 20 mg/day, 32% reduction 40 mg/day, 37% reduction 80 mg/day, 42% reduction Atorvastatin: 10 mg/day, 37% reduction 20 mg/day, 43% reduction 40 mg/day, 49% reduction 80 mg/day, 55% reduction Rosuvastatin: 5 mg/day, 38% reduction 10 mg/day, 43% reduction 20 mg/day, 48% reduction 40 mg/day, 53% reduction MHRA advice: there is an increased risk of myopathy associated with high dose (80 mg) simvastatin. The 80 mg dose should be considered only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks. This information is from Law MR, Wald NJ, Rudnicka AR (2003) Quantifying effect of statins on low-density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 326: 1423.

This information is from Law MR, Wald NJ, Rudnicka AR (2003) Quantifying effect of statins on low-density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 326: 1423. Finding more information and committee details To find NICE guidance on related topics, including guidance in development, see the NICE topic page on cardiovascular conditions. For full details of the evidence and the guideline committee's discussions, see the full guideline. You can also find information about how the guideline was developed, including details of the committee. NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice. Update information February 2023: We have added a new recommendation on aspirin for primary prevention of CVD. This is based on a 2023 surveillance decision. September 2016: Recommendation 1.4.28 was amended to clarify what was meant by high-intensity statin treatment, and that the recommendation applies to both primary and secondary prevention. The term 'high-intensity statin' was also added to the terms used in this guideline section and linked to throughout. January 2015: New section on implementation: getting started added. July 2014: This guideline updated and replaced NICE guideline CG67 (published September 2008). It also updated and replaced recommendations relating to statin therapy for people at increased risk of developing cardiovascular disease or those with established cardiovascular disease in statins for the prevention of cardiovascular events (NICE technology appraisal guidance 94, 2006). Recommendations marked [2014] last had an evidence review in 2014. Recommendations marked [2008] or [2008, amended 2014] last had an evidence review in 2008. In some cases, minor changes were made to the wording to bring the language and style up to date, without changing the meaning.

In some cases, minor changes were made to the wording to bring the language and style up to date, without changing the meaning. We also made some changes without an evidence review: The age range was removed from recommendation 1.1.1 for clarity. The threshold for treatment in recommendations 1.1.4, 1.1.17 and 1.1.19 has been changed because of new health economics results. Recommendation 1.1.15 was amended to include all cardiovascular diseases. In recommendation 1.1.16, the bullet point about type 2 diabetes was deleted because the committee made separate specific recommendations for this subgroup. The list of underlying medical conditions in recommendation 1.1.18 has been updated. In recommendation 1.1.21, the age value has been changed to 85, as this is the upper limit of the QRISK2 assessment tools. The part on treatment has been deleted, as recommendations on treatment are listed in section 1.4. In recommendation 1.1.27, the words 'long-term' have been added to emphasise the need to discuss people's views about taking medication long term. Recommendation 1.1.28 has been amended to highlight the importance of the person's involvement in decision making and that their choices are adequately recorded. Recommendations 1.3.7 and 1.3.9 were updated because the chief medical officer issued changes to recommendations on physical activity in 2011. In recommendation 1.4.22, the reference to fasting was deleted because the committee considered that a fasting sample is not necessary if non-high-density lipoprotein (HDL) cholesterol is measured (see recommendation 1.4.4). They also wished to highlight the importance of taking a lipid sample also on admission. These recommendations are marked [2008, amended 2014]. Minor changes since publication July 2022: Recommendations 1.4.48 to 1.4.50 have been updated in line with NICE's technical appraisal guidance on icosapent ethyl with statin therapy for reducing the risk of cardiovascular events in people with raised triglycerides.

Minor changes since publication July 2022: Recommendations 1.4.48 to 1.4.50 have been updated in line with NICE's technical appraisal guidance on icosapent ethyl with statin therapy for reducing the risk of cardiovascular events in people with raised triglycerides. April 2022: Changed heading for recommendations 1.4.3 to 1.4.11 to clarify that these cover initial lipid measurement and referral for specialist review. January 2022: Minor changes to redirect NICE Pathways links. November 2021: We added a link to NICE's shared decision making guideline in recommendation 1.1.22. October 2021: We added a link to other treatment options in NICE's technology appraisal guidance on lipid disorders (see end of recommendations section). November 2020: The link in recommendations 1.3.7 and 1.3.8 was replaced with a link to the 2019 UK Chief Medical Officers' physical activity guideline. Footnotes were incorporated into the text and the table in appendix A redrawn in line with accessibility guidance. June 2020: The recommendation on alcohol consumption was updated to bring it in line with the UK chief medical officers' guidelines on low-risk drinking. Links were added to the patient decision aid on taking a statin to reduce the risk of coronary heart disease and stroke. August 2018: A link to the NICE guideline on physical activity: exercise referral schemes was added to recommendation 1.4.15. February 2018: In recommendation 1.1.20, a link was updated to go to the NICE guideline on obesity. In recommendation 1.3.10, links were updated to go to the NICE guidelines on walking and cycling, physical activity, and exercise referral schemes to promote physical activity. In recommendation 1.3.12, a link was updated to go to the NICE guideline on obesity. In recommendation 1.4.13, a link was updated to go to the NICE guideline on obesity.

In recommendation 1.4.13, a link was updated to go to the NICE guideline on obesity. July 2016: Amended recommendation 1.3.2 to clarify the advice on saturated and monounsaturated fat. December 2015: Changes to update information and recommendation labelling after publication of the updated NICE guideline on type 2 diabetes in adults. August 2015: Changes to recommendation labelling and update information following publication of updated NICE guidelines on chronic kidney disease and type 1 diabetes in adults. Accreditation

Antithrombotic Therapy for VTE Disease CHEST Guideline and Expert Panel Report Clive Kearon, MD, PhD; Elie A. Akl, MD, MPH, PhD; Joseph Ornelas, PhD; Allen Blaivas, DO, FCCP; David Jimenez, MD, PhD, FCCP; Henri Bounameaux, MD; Menno Huisman, MD, PhD; Christopher S. King, MD, FCCP; Timothy A. Morris, MD, FCCP; Namita Sood, MD, FCCP; Scott M. Stevens, MD; Janine R. E. Vintch, MD, FCCP; Philip Wells, MD; Scott C. Woller, MD; and COL Lisa Moores, MD, FCCP BACKGROUND: We update recommendations on 12 topics that were in the 9th edition of these guidelines, and address 3 new topics. METHODS: We generate strong (Grade 1) and weak (Grade 2) recommendations based on high- (Grade A), moderate- (Grade B), and low- (Grade C) quality evidence. RESULTS: For VTE and no cancer, as long-term anticoagulant therapy, we suggest dabigatran (Grade 2B), rivaroxaban (Grade 2B), apixaban (Grade 2B), or edoxaban (Grade 2B) over vitamin K antagonist (VKA) therapy, and suggest VKA therapy over low-molecular-weight heparin (LMWH; Grade 2C). For VTE and cancer, we suggest LMWH over VKA (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). We have not changed recommendations for who should stop anticoagulation at 3 months or receive extended therapy. For VTE treated with anticoagulants, we recommend against an inferior vena cava lter (Grade 1B). For DVT, we suggest not using compression stockings routinely to prevent PTS (Grade 2B). For subsegmental pulmonary embolism and no proximal DVT, we suggest clinical surveillance over anticoagulation with a low risk of recurrent VTE (Grade 2C), and anticoagulation over clinical surveillance with a high risk (Grade 2C). We suggest thrombolytic therapy for pulmonary embolism with hypotension (Grade 2B), and systemic therapy over catheter-directed thrombolysis (Grade 2C).

We suggest thrombolytic therapy for pulmonary embolism with hypotension (Grade 2B), and systemic therapy over catheter-directed thrombolysis (Grade 2C). For recurrent VTE on a non-LMWH anticoagulant, we suggest LMWH (Grade 2C); for recurrent VTE on LMWH, we suggest increasing the LMWH dose (Grade 2C). CONCLUSIONS: Of 54 recommendations included in the 30 statements, 20 were strong and none was based on high-quality evidence, highlighting the need for further research.

CONCLUSIONS: Of 54 recommendations included in the 30 statements, 20 were strong and none was based on high-quality evidence, highlighting the need for further research. KEY WORDS: antithrombotic therapy; evidence-based medicine; GRADE approach; venous thromboembolism FOR EDITORIAL COMMENT SEE PAGE 293 ABBREVIATIONS: AT9 = 9th Edition of the Antithrombotic Guideline; AT10 = 10th Edition of the Antithrombotic Guideline; CHEST = American College of Chest Physicians; CDT = catheter-directed thrombolysis; COI = con ict of interest; CTEPH = chronic thrombo- embolic pulmonary hypertension; CTPA = CT pulmonary angiogram; GOC = Guidelines Oversight Committee; INR = International Normalized Ratio; IVC = inferior vena cava; LMWH = low-molecular- weight heparin; NOAC = non-vitamin K oral anticoagulant; PE = pulmonary embolism; PTS = postthrombotic syndrome; RCT = ran- domized controlled trial; UEDVT = upper extremity deep vein thrombosis; US = ultrasound; VKA = vitamin K antagonist AFFILIATIONS: From McMaster University (Drs Kearon and Akl), Hamilton, ON; American University of Beirut (Dr Akl), Beirut, Lebanon; CHEST (Dr Ornelas), Glenview, IL; VA New Jersey Health Care System (Dr Blaivas), Newark, NJ; Hospital Ram n y Cajal and Instituto Ram n y Cajal de Investigaci n Sanitaria, Universidad de Alcala (Dr Jimenez), Madrid, Spain; University of Geneva (Dr Bou- nameaux), Geneva, Switzerland; Leiden University Medical Center (Dr Huisman), Leiden, Netherlands; Virginia Commonwealth University (Dr King), Falls Church, VA; University of California (Dr Morris), San Diego, CA; The Ohio State University (D. Sood), Columbus, OH; Intermountain Medical Center and the University of Utah (Drs Stevens and Woller), Murray, UT; Harbor-UCLA Medical Center (Dr Vintch), Torrance, CA; The University of Ottawa and Ottawa Hospital Research Institute (Dr Wells), Ottawa, ON; Uniformed Services University of the Health Sciences (Dr Moores), Bethesda, MD.

KEY WORDS: antithrombotic therapy; evidence-based medicine; GRADE approach; venous thromboembolism FOR EDITORIAL COMMENT SEE PAGE 293 ABBREVIATIONS: AT9 = 9th Edition of the Antithrombotic Guideline; AT10 = 10th Edition of the Antithrombotic Guideline; CHEST = American College of Chest Physicians; CDT = catheter-directed thrombolysis; COI = con ict of interest; CTEPH = chronic thrombo- embolic pulmonary hypertension; CTPA = CT pulmonary angiogram; GOC = Guidelines Oversight Committee; INR = International Normalized Ratio; IVC = inferior vena cava; LMWH = low-molecular- weight heparin; NOAC = non-vitamin K oral anticoagulant; PE = pulmonary embolism; PTS = postthrombotic syndrome; RCT = ran- domized controlled trial; UEDVT = upper extremity deep vein thrombosis; US = ultrasound; VKA = vitamin K antagonist AFFILIATIONS: From McMaster University (Drs Kearon and Akl), Hamilton, ON; American University of Beirut (Dr Akl), Beirut, Lebanon; CHEST (Dr Ornelas), Glenview, IL; VA New Jersey Health Care System (Dr Blaivas), Newark, NJ; Hospital Ram n y Cajal and Instituto Ram n y Cajal de Investigaci n Sanitaria, Universidad de Alcala (Dr Jimenez), Madrid, Spain; University of Geneva (Dr Bou- nameaux), Geneva, Switzerland; Leiden University Medical Center (Dr Huisman), Leiden, Netherlands; Virginia Commonwealth University (Dr King), Falls Church, VA; University of California (Dr Morris), San Diego, CA; The Ohio State University (D. Sood), Columbus, OH; Intermountain Medical Center and the University of Utah (Drs Stevens and Woller), Murray, UT; Harbor-UCLA Medical Center (Dr Vintch), Torrance, CA; The University of Ottawa and Ottawa Hospital Research Institute (Dr Wells), Ottawa, ON; Uniformed Services University of the Health Sciences (Dr Moores), Bethesda, MD. [ Evidence-Based Medicine ] Note on Shaded Text: In this guideline, shaded text with an asterisk (shading appears in PDF only) indicates recommendations that are newly added or have been changed since the publication of Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis (9th edition): American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

[ Evidence-Based Medicine ] Note on Shaded Text: In this guideline, shaded text with an asterisk (shading appears in PDF only) indicates recommendations that are newly added or have been changed since the publication of Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis (9th edition): American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Recommendations that remain unchanged since that edition are not shaded. The order of our presentation of the non-vitamin K oral anticoagulants (dabigatran, rivaroxaban, apixaban, edoxaban) is based on the chronology of publication of the phase 3 trials in VTE treatment and should not be interpreted as the guideline panel s order of preference for the use of these agents. Summary of Recommendations Choice of Long-Term (First 3 Months) and Extended (No Scheduled Stop Date) Anticoagulant 1. In patients with proximal DVT or pulmonary embolism (PE), we recommend long-term (3 months) anticoagulant therapy over no such therapy (Grade 1B). *2. In patients with DVT of the leg or PE and no cancer, as long-term ( rst 3 months) anticoagulant therapy, we suggest dabigatran, rivaroxaban, apix- aban, or edoxaban over vitamin K antagonist (VKA) therapy (all Grade 2B). For patients with DVT of the leg or PE and no cancer who are not treated with dabigatran, rivaroxaban, apixaban, or edoxaban, we suggest VKA therapy over low-molecular weight heparin (LMWH) (Grade 2C). Remarks: Initial parenteral anticoagulation is given before dabigatran and edoxaban, is not given before rivaroxaban and apixaban, and is overlapped with VKA therapy. See text for factors that in uence choice of therapy. *3. In patients with DVT of the leg or PE and cancer ( cancer-associated thrombosis ), as long-term ( rst 3 months) anticoagulant therapy, we suggest LMWH over VKA therapy (Grade 2B), dabigatran (Grade or edoxaban (Grade 2C).

In patients with DVT of the leg or PE and cancer ( cancer-associated thrombosis ), as long-term ( rst 3 months) anticoagulant therapy, we suggest LMWH over VKA therapy (Grade 2B), dabigatran (Grade or edoxaban (Grade 2C). Remarks: Initial parenteral anticoagulation is given before dabigatran and edoxaban, is not given before rivaroxaban and apixaban, and is overlapped with VKA therapy. See text for factors that in uence choice of therapy. *4. In patients with DVT of the leg or PE who receive extended therapy, we suggest that there is no need to change the choice of anticoagulant after the rst 3 months (Grade 2C). Remarks: It may be appropriate for the choice of anticoagulant to change in response to changes in the patient s circumstances or preferences during long-term or extended phases of treatment. Duration of Anticoagulant Therapy 5. In patients with a proximal DVT of the leg or PE provoked by surgery, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B), (ii) treatment of a longer time-limited period (eg, 6, 12, or 24 months) (Grade 1B), or (iii) extended therapy (no scheduled stop date) (Grade 1B). 6. In patients with a proximal DVT of the leg or PE provoked by a nonsurgical transient risk factor, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B) and (ii) treatment of a longer time-limited period (eg, 6, 12, or 24 months) (Grade 1B). We suggest treatment with anticoagulation for 3 months over extended therapy if there is a low or moderate bleeding risk (Grade 2B), and recommend treatment for 3 months over extended therapy if there is a high risk of bleeding (Grade 1B).

We suggest treatment with anticoagulation for 3 months over extended therapy if there is a low or moderate bleeding risk (Grade 2B), and recommend treatment for 3 months over extended therapy if there is a high risk of bleeding (Grade 1B). Remarks: In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually). DISCLAIMER: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://www.chestnet. org/Guidelines-and-Resources/Guidelines-and-Consensus-Statements/ CHEST-Guidelines. FUNDING/SUPPORT: This guideline was supported solely by internal funds from The American College of Chest Physicians. ENDORSEMENTS: This guideline is endorsed by the American Asso- ciation for Clinical Chemistry, the American College of Clinical Pharmacy, the International Society for Thrombosis and Haemostasis, and the American Society of Health-System Pharmacists. CORRESPONDENCE TO: Elie A. Akl, MD, MPH, PhD, Department of Internal Medicine, Faculty of Medicine, American University of Beirut, PO Box 11-0236, Riad-El-Solh Beirut 1107 2020, Lebanon; e-mail: Copyright 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. 316 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] 7.

316 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] 7. In patients with an isolated distal DVT of the leg provoked by surgery or by a nonsurgical transient risk factor, we suggest treatment with anticoagulation for 3 months over treatment of a shorter period (Grade 2C), we recommend treatment with anticoagulation for 3 months over treatment of a longer time-limited period (eg, 6, 12, or 24 months) (Grade 1B), and we recommend treatment with anticoagulation for 3 months over extended therapy (no scheduled stop date) (Grade 1B). Remarks: Duration of treatment of patients with isolated distal DVT refers to patients in whom a decision has been made to treat with anticoagulant therapy; however, it is anticipated that not all patients who are diagnosed with isolated distal DVT will be prescribed anticoagulants. 8. In patients with an unprovoked DVT of the leg (isolated distal or proximal) or PE, we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B), and we recommend treatment with anticoagulation for 3 months over treatment of a longer time-limited period (eg, 6, 12, or 24 months) (Grade 1B). Remarks: After 3 months of treatment, patients with unprovoked DVT of the leg or PE should be evaluated for the risk-bene t ratio of extended therapy. Duration of treatment of patients with isolated distal DVT refers to patients in whom a decision has been made to treat with anticoagulant therapy; however, it is anticipated that not all patients who are diagnosed with isolated distal DVT will be prescribed anticoagulants. 9.

Duration of treatment of patients with isolated distal DVT refers to patients in whom a decision has been made to treat with anticoagulant therapy; however, it is anticipated that not all patients who are diagnosed with isolated distal DVT will be prescribed anticoagulants. 9. In patients with a rst VTE that is an unprovoked proximal DVT of the leg or PE and who have a (i) low or moderate bleeding risk (see text), we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B), and (ii) high bleeding risk (see text), we recommend 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 1B). Remarks: Patient sex and D-dimer level measured a month after stopping anticoagulant therapy may in uence the decision to stop or extend anticoagulant therapy (see text). In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually). 10. In patients with a second unprovoked VTE and who have a (i) low bleeding risk (see text), we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months (Grade 1B); (ii) moderate bleeding risk (see text), we suggest extended anticoagulanttherapy over 3 months of therapy (Grade 2B); or (iii) high bleeding risk (see text), we suggest 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 2B). Remarks: In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually). 11.

Remarks: In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually). 11. In patients with DVT of the leg or PE and active cancer ( cancer-associated thrombosis ) and who (i) do not have a high bleeding risk, we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 1B), or (ii) have a high bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B). Remarks: In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually). Aspirin for Extended Treatment of VTE *12. In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, we suggest aspirin over no aspirin to prevent recurrent VTE (Grade 2B). Remarks: Because aspirin is expected to be much less effective at preventing recurrent VTE than anticoagulants, we do not consider aspirin a reasonable alternative to anticoagulant therapy in patients who want extended therapy. However, if a patient has decided to stop anticoagulants, prevention of recurrent VTE is one of the bene ts of aspirin that needs to be balanced against aspirin s risk of bleeding and inconvenience. Use of aspirin should also be reevaluated when patients stop anticoagulant therapy because aspirin may have been stopped when anticoagulants were started. Whether and How to Anticoagulate Isolated Distal DVT 13.

Use of aspirin should also be reevaluated when patients stop anticoagulant therapy because aspirin may have been stopped when anticoagulants were started. Whether and How to Anticoagulate Isolated Distal DVT 13. In patients with acute isolated distal DVT of the leg and (i) without severe symptoms or risk factors for extension (see text), we suggest serial imaging of the deep veins for 2 weeks over anticoagulation (Grade 2C) or (ii) with severe symptoms or risk factors for extension (see text), we suggest anticoagulation over serial imaging of the deep veins (Grade 2C). Remarks: Patients at high risk for bleeding are more likely to bene t from serial imaging. Patients who place a high value on avoiding the inconvenience of repeat imaging and a low value on the inconvenience of treatment and on the potential for bleeding are likely to choose initial anticoagulation over serial imaging. 14. In patients with acute isolated distal DVT of the leg who are managed with anticoagulation, we recommend using the same anticoagulation as for patients with acute proximal DVT (Grade 1B). 15. In patients with acute isolated distal DVT of the leg who are managed with serial imaging, we (i) recommend no anticoagulation if the thrombus does not extend (Grade 1B), (ii) suggest anticoagulation if the thrombus extends but remains con ned to the distal veins (Grade 2C), and (iii) recommend anticoagulation if the thrombus extends into the proximal veins (Grade 1B). Catheter-Directed Thrombolysis for Acute DVT of the Leg 16. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over CDT (Grade 2C).

In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over CDT (Grade 2C). Remarks: Patients who are most likely to bene t from CDT (see text), who attach a high value to prevention of postthrombotic syndrome (PTS), and a lower value to the initial complexity, cost, and risk of bleeding with CDT, are likely to choose CDT over anticoagulation alone. Role of Inferior Vena Cava Filter in Addition to Anticoagulation for Acute DVT or PE 17. In patients with acute DVT or PE who are treated with anticoagulants, we recommend against the use of an inferior vena cava (IVC) lter (Grade 1B). Compression Stocking to Prevent PTS *18. In patients with acute DVT of the leg, we sug- gest not using compression stockings routinely to prevent PTS (Grade 2B). Remarks: This recommendation focuses on prevention of the chronic complication of PTS and not on the treatment of symptoms. For patients with acute or chronic symptoms, a trial of graduated compression stockings is often justi ed. Whether to Anticoagulate Subsegmental PE *19. In patients with subsegmental PE (no involve- ment of more proximal pulmonary arteries) and no proximal DVT in the legs who have a (i) low risk for recurrent VTE (see text), we suggest clinical surveillance over anticoagulation (Grade 2C) or (ii) high risk for recurrent VTE (see text), we suggest anticoagulation over clinical surveillance (Grade 2C). Remarks: Ultrasound (US) imaging of the deep veins of both legs should be done to exclude proximal DVT. Clinical surveillance can be supplemented by serial US imaging of the proximal deep veins of both legs to detect evolving DVT (see text). Patients and physicians are more likely to opt for clinical surveillance over anticoagulation if there is good cardiopulmonary reserve or a high risk of bleeding.

Patients and physicians are more likely to opt for clinical surveillance over anticoagulation if there is good cardiopulmonary reserve or a high risk of bleeding. Treatment of Acute PE Out of the Hospital *20. In patients with low-risk PE and whose home circumstances are adequate, we suggest treatment at home or early discharge over standard discharge (eg, after the rst 5 days of treatment) (Grade 2B). Systemic Thrombolytic Therapy for PE 21. In patients with acute PE associated with hypotension (eg, systolic BP <90 mm Hg) who do not have a high bleeding risk, we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B). *22. In most patients with acute PE not associated with hypotension, we recommend against systemically administered thrombolytic therapy (Grade 1B). *23. In selected patients with acute PE who deteri- orate after starting anticoagulant therapy but have yet to develop hypotension and who have a low bleeding risk, we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2C). Remarks: Patients with PE and without hypotension who have severe symptoms or marked cardiopulmonary impairment should be monitored closely for deterioration. Development of hypotension suggests that 318 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] thrombolytic therapy has become indicated. Cardiopulmonary deterioration (eg, symptoms, vital signs, tissue perfusion, gas exchange, cardiac biomarkers) that has not progressed to hypotension may also alter the risk-bene t assessment in favor of thrombolytic therapy in patients initially treated with anticoagulation alone. Catheter-Based Thrombus Removal for the Initial Treatment of PE *24. In patients with acute PE who are treated with a thrombolytic agent, we suggest systemic thrombo- lytic therapy using a peripheral vein over CDT (Grade 2C).

In patients with acute PE who are treated with a thrombolytic agent, we suggest systemic thrombo- lytic therapy using a peripheral vein over CDT (Grade 2C). Remarks: Patients who have a higher risk of bleeding with systemic thrombolytic therapy and who have access to the expertise and resources required to do CDT are likely to choose CDT over systemic thrombolytic therapy. *25. In patients with acute PE associated with hypotension and who have (i) a high bleeding risk, (ii) failed systemic thrombolysis, or (iii) shock that is likely to cause death before systemic thrombolysis can take effect (eg, within hours), if appropriate expertise and resources are available, we suggest catheter- assisted thrombus removal over no such intervention (Grade 2C). Remarks: Catheter-assisted thrombus removal refers to mechanical interventions, with or without catheter directed thrombolysis. Pulmonary Thromboendarterectomy for the Treatment of Chronic Thromboembolic Pulmonary Hypertension *26. In selected patients with chronic thromboem- bolic pulmonary hypertension (CTEPH) who are identi ed by an experienced thromboendarter- ectomy team, we suggest pulmonary thromboen- darterectomy over no pulmonary thromboendarterectomy (Grade 2C). Remarks: Patients with CTEPH should be evaluated by a team with expertise in treatment of pulmonary hypertension. Pulmonary thromboendarterectomy is often lifesaving and life-transforming. Patients with CTEPH who are not candidates for pulmonary thromboendarterectomy may bene t from other mechanical and pharmacological interventions designed to lower pulmonary arterial pressure. Thrombolytic Therapy in Patients With Upper Extremity DVT 27. In patients with acute upper extremity DVT (UEDVT) that involves the axillary or more proximal veins, we suggest anticoagulant therapy alone over thrombolysis (Grade 2C).

In patients with acute upper extremity DVT (UEDVT) that involves the axillary or more proximal veins, we suggest anticoagulant therapy alone over thrombolysis (Grade 2C). Remarks: Patients who (i) are most likely to bene t from thrombolysis (see text); (ii) have access to CDT; (iii) attach a high value to prevention of PTS; and (iv) attach a lower value to the initial complexity, cost, and risk of bleeding with thrombolytic therapy are likely to choose thrombolytic therapy over anticoagulation alone. 28. In patients with UEDVT who undergo thrombolysis, we recommend the same intensity and duration of anticoagulant therapy as in patients with UEDVT who do not undergo thrombolysis (Grade 1B). Management of Recurrent VTE on Anticoagulant Therapy *29. In patients who have recurrent VTE on VKA therapy (in the therapeutic range) or on dabigatran, rivaroxaban, apixaban, or edoxaban (and are believed to be compliant), we suggest switching to treatment with LMWH at least temporarily (Grade 2C). Remarks: Recurrent VTE while on therapeutic-dose anticoagulant therapy is unusual and should prompt the following assessments: (1) reevaluation of whether there truly was a recurrent VTE; (2) evaluation of compliance with anticoagulant therapy; and (3) consideration of an underlying malignancy. A temporary switch to LMWH will usually be for at least 1 month. *30. In patients who have recurrent VTE on long- term LMWH (and are believed to be compliant), we suggest increasing the dose of LMWH by about one-quarter to one-third (Grade 2C). Remarks: Recurrent VTE while on therapeutic-dose anticoagulant therapy is unusual and should prompt the following assessments: (1) reevaluation of whether there truly was a recurrent VTE; (2) evaluation of compliance with anticoagulant therapy; and (3) consideration of an underlying malignancy.

Remarks: Recurrent VTE while on therapeutic-dose anticoagulant therapy is unusual and should prompt the following assessments: (1) reevaluation of whether there truly was a recurrent VTE; (2) evaluation of compliance with anticoagulant therapy; and (3) consideration of an underlying malignancy. CHEST has been developing and publishing guidelines for the treatment of DVT and PE, collectively referred to as VTE, for more than 30 years. CHEST published the last (9th) edition of these guidelines in February 2012 Since then, a substantial amount of new evidence relating to the treatment of VTE has been published, particularly in relation the use of non-vitamin K oral anticoagulants (NOACs). Moreover, several VTE treatment questions that were not addressed in the last edition have been highlighted. This article focuses on new developments and ongoing controversies in the treatment of VTE, updating recommendations for 12 topics that were included in AT9, and providing recommendations for 3 new topics. The target users of this guideline are clinicians. Methods Composition and Selection of Topic Panel Members The Guidelines Oversight Committee (GOC) at CHEST appointed the editor for the guideline update. Then, the editor nominated the project executive committee, the chair, and the remaining panelists (see Acknowledgments section). The GOC approved all panelists after review of their quali cations and con ict of interest (COI) disclosures. The 15 panelists include general internists, thrombosis specialists, pulmonologists, hematologists, and methodologists. Throughout guideline development, panelists were required to disclose any potential nancial or intellectual con icts of interest by topic.2 Financial and intellectual con icts of interest were classi ed as primary (more serious) or secondary (less serious) (e-Table 1). Panelists with primary COIs were required to abstain from voting on related topic areas, but could participate in discussions provided they refrained from strong advocacy.

Panelists with primary COIs were required to abstain from voting on related topic areas, but could participate in discussions provided they refrained from strong advocacy. Selection of Topics and Key Questions First, we listed all of the topic areas from AT9 and added potential new topics proposed by the panel members. Next, all panel members voted on whether each topic should be included in the update. Finally, the full panel reviewed the results of the vote and decided on the nal list. The panel selected a total of 15 topics: 12 update topics from AT9 and 3 new topics. For each topic, we developed standardized questions in the Population, Intervention, Comparator, Outcome format (e-Table 2). Systematic Search Systematic methods were used to search for evidence for each question. When available, the National Library of Medicine s medical subject headings keyword nomenclature was used. We searched MEDLINE via PubMed for original studies and the Cochrane Library for systematic reviews. For update topics, we searched the literature from January 2005 to July 2014. For new topics, we searched the literature from 1946 (Medline inception) to July 2014. All searches were limited to English-language publications. We augmented searches by checking reference lists of published articles and personal les, and with ongoing surveillance of the literature by panel members (e-Figures 1-4). When we identi ed systematic reviews, we assessed their quality according to the Assessment of Multiple Systematic Reviews tool.3 We used those that were of highest quality and up to date as the source of evidence. In the absence of a satisfactory systematic review, we did our own evidence synthesis using the primary studies identi ed in AT9 and in the updated search.

In the absence of a satisfactory systematic review, we did our own evidence synthesis using the primary studies identi ed in AT9 and in the updated search. If the panel judged that the identi ed randomized controlled trials (RCTs) were inadequate, we expanded the search to include prospective cohort studies. Study Selection, Data Abstraction, and Data Analysis The criteria for selecting the evidence were based on the Population, Intervention, Comparator, Outcome elements of the standardized questions and the study design (e-Table 2). We followed standard processes (duplicate independent work with agreement checking and disagreement resolution) for title and abstract screening, full text screening, data abstraction, and risk of bias assessment. We abstracted data on the characteristics of: study design, participants, intervention, control, outcomes, funding, and COI. We assessed risk of bias using the Cochrane Risk of Bias Tool in randomized trials4 and an adapted tool for observational studies5 (e-Table 3). When existing systematic reviews were not available or were inadequate, we performed meta-analyses when appropriate. For each outcome of interest, we calculated the risk ratios of individual studies then pooled them and assessed statistical heterogeneity using the I2 statistic. We used a xed-effects model when pooling data from two trials, or when one of the included trials was large relative to the others. Otherwise, we used a random-effects model. We used Review Manager software (version 5.2) to perform the meta-analyses and construct forest plots. We calculated absolute effects by applying pooled relative risks to baseline risks, ideally estimated from valid prognostic observational data or, in the absence of the latter, from control group risks. When credible data from prognostic observational studies were not available, we used risk estimates from control groups of RCTs included in the meta-analyses (e-Figures 5 and 6).

When credible data from prognostic observational studies were not available, we used risk estimates from control groups of RCTs included in the meta-analyses (e-Figures 5 and 6). Assessing Quality of Evidence Based on the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, quality of evidence (also known as certainty of evidence) is de ned as the extent to which our con dence in the effect estimate is adequate to support a recommendation.6,7 The quality of evidence is categorized as high (A level), moderate (B level), or low (includes very low) (C level).6,7 The rating of the quality of evidence re ects the strengths and limitations of the body of evidence and was based on the study design, risk of bias, imprecision, inconsistency, indirectness of results, and likelihood of publication bias, in addition to factors speci c to observational Using GRADEpro software (version 3.6), we generated tables to summarize the judgments of the quality of the evidence and the relative and absolute effects.13 The GRADE tables include Summary of Findings tables presented in the main text, and a more detailed version called Evidence Pro les presented in the online supplement. The evidence pro les also explicitly link recommendations to the supporting evidence. Drafting of Recommendations Following the GRADE approach, the strength of a recommendation is de ned as the extent to which we can be con dent that the desirable effects of an intervention outweigh its undesirable effects. The strength of recommendation was categorized as strong (grade 1) or 320 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] weak/conditional (grade 2).

The strength of recommendation was categorized as strong (grade 1) or 320 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] weak/conditional (grade 2). In determining the strength of the recommendation, the panel considered the balance of desirable and undesirable consequences (typically tradeoff between recurrent VTE and bleeding events), quality of evidence, resource implications, and patients average values and preferences for different outcomes and The chair drafted the recommendations after the entire panel had reviewed the evidence and discussed the recommendation. Recommendations were then revised over a series of conference calls and through e-mail exchanges with the entire panel. A major aim was to ensure recommendations were speci c and unambiguous. Methods for Achieving Consensus We used a modi ed Delphi technique17,18 to achieve consensus on each recommendation. This technique aims to minimize group interaction bias and to maintain anonymity among respondents. Using an online survey (www.surveymonkey.com), panelists without a primary COI voted their level of agreement with each recommendation (including quality of evidence and strength of recommendation) based on a 5-point scale derived from the GRADE grid (strongly agree, weakly agree, neutral, weakly disagree, strongly Each panelist could also provide open-ended feedback on each recommendation with suggested wording edits or general remarks. To achieve consensus and be included in the nal manuscript, each recommendation had to have at least 80% agreement (strong or weak) with a response rate of at least 75% of eligible panel members. All recommendations achieved consensus in the rst round. We then used an iterative approach that involved review by, and approval from, all panel members for the writing of this manuscript.

We then used an iterative approach that involved review by, and approval from, all panel members for the writing of this manuscript. Peer Review External reviewers who were not members of the expert panel reviewed the guideline before it was published. These reviewers included content experts, a methodological expert, and a practicing clinician. The nal manuscript was reviewed and approved by the CHEST GOC, the CHEST Board of Regents, and the CHEST journal. Choice of Long-Term (First 3 Months) and Extended (No Scheduled Stop Date) Anticoagulant Summary of the Evidence Phases of Anticoagulant Therapy for VTE: The need for anticoagulant therapy in patients with proximal DVT or PE is presented in AT9.1 The minimum duration of anticoagulant therapy for DVT or PE is usually 3 months; this period of treatment is referred to as long-term therapy. 1 A decision to treat patients for longer than 3 months, which we refer to as extended anticoagulant therapy, usually implies that anticoagulant therapy will be continued inde nitely.1 1. In patients with proximal DVT or pulmonary embolism (PE), we recommend long-term (3 months) anticoagulant therapy over no such therapy (Grade 1B). Choice of Anticoagulant for Acute and Long-Term (First 3 Months) Therapy AT9 recommendations on choice of anticoagulant therapy were based on comparisons of VKA with LMWH that were performed in the preceding two and with two of the NOACs (dabigatran,20 ) that had recently been published.

Choice of Anticoagulant for Acute and Long-Term (First 3 Months) Therapy AT9 recommendations on choice of anticoagulant therapy were based on comparisons of VKA with LMWH that were performed in the preceding two and with two of the NOACs (dabigatran,20 ) that had recently been published. Although we judged that there was no convincing evidence that the ef cacy of LMWH compared with VKA differed between VTE patients without and with cancer, there are, nevertheless, reasons to make different suggestions for the preferred anticoagulant in patients without and with cancer.1 We suggested VKA therapy over LMWH in patients without cancer for the following reasons: injections are burdensome; LMWH is expensive; there are low rates of recurrence with VKA in patients with VTE without cancer; and VKA may be as effective as LMWH in patients without cancer. We suggested LMWH over VKA in patients with cancer for the following reasons: there is moderate-quality evidence that LMWH was more effective than VKA in patients with cancer; there is a substantial rate of recurrent VTE in patients with VTE and cancer who are treated with VKA; it is often harder to keep patients with cancer who are on VKA in the therapeutic range; LMWH is reliable in patients who have dif culty with oral therapy (eg, vomiting); and LMWH is easier to withhold or adjust than VKA if invasive interventions are required or thrombocytopenia develops. One new randomized trial compared LMWH (tinzaparin) with warfarin for the rst 6 months of treatment in 900 cancer patients with VTE.22 The ndings of this study are consistent with evidence in AT9 that LMWH is more effective than VKA for long- term treatment of VTE, but that there is no difference in major bleeding or death (Table 1, e-Table 4).

One new randomized trial compared LMWH (tinzaparin) with warfarin for the rst 6 months of treatment in 900 cancer patients with VTE.22 The ndings of this study are consistent with evidence in AT9 that LMWH is more effective than VKA for long- term treatment of VTE, but that there is no difference in major bleeding or death (Table 1, e-Table 4). Consequently, we still suggest VKA over LMWH in patients without cancer, and LMWH over VKA in patients with cancer, and we have not changed our assessment of the quality of evidence for either of these recommendations (Table 1, e-Table 4). We suggested VKA therapy or LMWH over the NOACs in AT9 because only two randomized trials had compared a NOAC (dabigatran,20 ) with VKA therapy, and none had compared a NOAC with long-term LMWH. In addition, at that time, there was little experience using a NOAC for treatment of VTE and a scarcity of long-term follow-up data to support their ef cacy and safety. Since then, four new TABLE 1 ] Summary of Findings: LMWH vs VKA for Long-Term Treatment of VTEa Outcomes No.

Since then, four new TABLE 1 ] Summary of Findings: LMWH vs VKA for Long-Term Treatment of VTEa Outcomes No. of Participants (Studies) Follow-up Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with VKA Risk Difference with LMWH (95% CI) All-cause mortality Moderatec because of risk of bias Noncancerd (from 2 fewer to 2 more) Nonmetastatic Cancerd (from 5 fewer to 6 more) Metastatic Cancerd (from 28 fewer to 35 more) Recurrent VTE Moderatee because of risk of bias Lowf (from 5 fewer to 15 fewer) Moderatef (from 14 fewer to 39 fewer) Highf (from 34 fewer to 98 fewer) Major bleeding Moderateg,h because of imprecision Lowi (from 9 fewer to 6 more) Highi (from 35 fewer to 26 more) The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CATCH Comparison of Acute Treatments in Cancer Haemostasis; GRADE Grades of Recommendations, Assessment, Development, and Evaluation; LITE Long-term Innovations in Treatment program; LMWH low-molecular-weight heparin; RIETE Registro Informatizado de Enfermedad Tromboembolica; RR risk ratio; UFH unfractionated heparin; VKA vitamin K antagonist. GRADE Working Group grades of evidence: High quality: Further research is very unlikely to change our con dence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our con dence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our con dence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Very low quality: We are very uncertain about the estimate. a The initial parenteral anticoagulation was similar in both arms for all except 1 study (Hull et al174 ) in which patients randomized to LMWH received initially the same LWMH, whereas patients randomized to VKA initially received UFH. b The relative effect (RR; 95% CI) of LMWH vs VKA was assessed, and compared, in the subgroup of trials that enrolled patients without (Hull et al174 [LITE], Lopez-Beret et al177 ) and with (Deitcher et al173 [ONCENOX], Hull et al174 [LITE], Lee et al170 [CLOT], Lee et al22 [CATCH], Lopez-Beret et al,177 Meyer et al178 ) cancer: Recurrent VTE: cancer RR 0.59 (0.44-0.78) vs no cancer RR 0.99 (0.46-2.13); P .21 for subgroup difference. Major bleeding: cancer RR 0.96 (0.65-1.42) vs no cancer RR 0.43 (0.17 -1.17); P .14 for subgroup difference. All-cause mortality: cancer RR 1.00 (0.88-1.33) vs no cancer RR 1.85 (0.59-5.77); P .29 for subgroup difference. c One study did not report deaths, which is unusual and could re ect selective reporting of outcomes. d Low corresponds to patients without cancer and patients with nonmetastatic cancer. High corresponds to patients with metastatic cancer. These control event rates were derived from the Computerized Registry of Patients with Venous Thromboembolism (RIETE) registry, an ongoing prospective registry of consecutive patients with acute VTE) (Prandoni et al180 ). e None of the studies was blinded, whereas the diagnosis of recurrent VTE has a subjective component and there could be a lower threshold for diagnosis of recurrent VTE in VKA- treated patients because switching the treatment of such patients to LMWH is widely practiced. At the same time, there is reluctance to diagnose recurrent VTE in patients who are already on LMWH because there is no attractive alternative treatment option.

At the same time, there is reluctance to diagnose recurrent VTE in patients who are already on LMWH because there is no attractive alternative treatment option. f Risk of recurrent VTE: Low corresponds to patients without cancer (3% estimate taken from recent large RCTs of acute treatment), intermediate to patients with local or recently resected cancer (appears to be consistent with Prandoni [particularly if low risk is increased to 4%]), and high to patients with locally advanced or distant metastatic cancer (Prandoni et al181 ). g CI includes both no effect and harm with LMWH. h 95% CIs for the risk ratio for major bleeding includes a potentially clinically important increase or decrease with LMWH, and may also vary with the dose of LMWH used during the extended phase of therapy i Risk of bleeding: Low corresponds to patients without risk factor for bleeding (ie, > 75 years, cancer, metastatic disease; chronic renal or hepatic failure; platelet count <80,0000; requires antiplatelet therapy; history of bleeding without a reversible cause) (Prandoni et al,180 Byeth et al182 ). Bibliography: Deitcher et al173 (ONCENOX), Hull et al174 (LITE), Hull et al175 (LITE Home), Lee et al170 (CLOT), Lopaciuk et al,176 Lopez-Beret et al,177 Meyer et al,178 Romera et al,179 Lee et al22 (CATCH) 322 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] randomized trials have compared a NOAC (with23,24 or initial heparin therapy) with VKA therapy (with initial heparin therapy) for the acute and long- term treatment of VTE.23-26 The ndings of these studies have been analyzed in a number of systematic including a network meta-analysis.35 In addition, there is now extensive clinical experience using NOACs in patients with VTE and atrial brillation.

Bibliography: Deitcher et al173 (ONCENOX), Hull et al174 (LITE), Hull et al175 (LITE Home), Lee et al170 (CLOT), Lopaciuk et al,176 Lopez-Beret et al,177 Meyer et al,178 Romera et al,179 Lee et al22 (CATCH) 322 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] randomized trials have compared a NOAC (with23,24 or initial heparin therapy) with VKA therapy (with initial heparin therapy) for the acute and long- term treatment of VTE.23-26 The ndings of these studies have been analyzed in a number of systematic including a network meta-analysis.35 In addition, there is now extensive clinical experience using NOACs in patients with VTE and atrial brillation. For the comparison of each of the NOACs with VKA in the initial and long-term treatment of VTE, current evidence for ef cacy is moderate or high quality, for safety (risk of bleeding) is moderate or high quality, and overall is moderate or high quality (Tables 2-5, e-Tables 5-8).

For the comparison of each of the NOACs with VKA in the initial and long-term treatment of VTE, current evidence for ef cacy is moderate or high quality, for safety (risk of bleeding) is moderate or high quality, and overall is moderate or high quality (Tables 2-5, e-Tables 5-8). In the 10th Edition of the Antithrombotic Guideline (AT10), the panel s overall assessment of the relative ef cacy and risk of bleeding with different anticoagulant agents is that: (1) the risk reduction for recurrent VTE with all of the NOACs appears to be similar to the risk reduction with VKA,35 including in patients with ; (2) in patients with VTE and cancer, the risk reduction for recurrent VTE appears to be greater with LMWH than with VKA therapy1,36,40 ; (3) the risk reduction for recurrent VTE with the NOACs compared to LMWH has not been assessed but, based on indirect comparisons, LMWH may be more effective that the NOACs in patients with VTE and cancer36 ; (4) the risk reduction for recurrent VTE with different NOACs has not been directly compared but, based on indirect comparisons, appears to be similar to all of the NOACs35 ; (5) the risk of bleeding with the NOACs, and particularly intracranial bleeding, is less with the NOACs than with ; (6) based on patients with atrial brillation, GI bleeding may be higher with dabigatran, rivaroxaban, and edoxaban than with VKA therapy, although this has not been seen in patients with ; (7) based on indirect comparisons, the risk of bleeding may be lower with apixaban than with the ; and (8) despite the lack of speci c reversal agents for the NOACs, the risk that a major bleed will be fatal appears to be no higher for the NOACs than for VKA therapy.33,34,45 Based on less bleeding with NOACs and greater convenience for patients and health- care providers, we now suggest that a NOAC is used in preference to VKA for the initial and long-term treatment of VTE in patients without cancer.

In the 10th Edition of the Antithrombotic Guideline (AT10), the panel s overall assessment of the relative ef cacy and risk of bleeding with different anticoagulant agents is that: (1) the risk reduction for recurrent VTE with all of the NOACs appears to be similar to the risk reduction with VKA,35 including in patients with ; (2) in patients with VTE and cancer, the risk reduction for recurrent VTE appears to be greater with LMWH than with VKA therapy1,36,40 ; (3) the risk reduction for recurrent VTE with the NOACs compared to LMWH has not been assessed but, based on indirect comparisons, LMWH may be more effective that the NOACs in patients with VTE and cancer36 ; (4) the risk reduction for recurrent VTE with different NOACs has not been directly compared but, based on indirect comparisons, appears to be similar to all of the NOACs35 ; (5) the risk of bleeding with the NOACs, and particularly intracranial bleeding, is less with the NOACs than with ; (6) based on patients with atrial brillation, GI bleeding may be higher with dabigatran, rivaroxaban, and edoxaban than with VKA therapy, although this has not been seen in patients with ; (7) based on indirect comparisons, the risk of bleeding may be lower with apixaban than with the ; and (8) despite the lack of speci c reversal agents for the NOACs, the risk that a major bleed will be fatal appears to be no higher for the NOACs than for VKA therapy.33,34,45 Based on less bleeding with NOACs and greater convenience for patients and health- care providers, we now suggest that a NOAC is used in preference to VKA for the initial and long-term treatment of VTE in patients without cancer. Factors that may in uence which anticoagulant is chosen for initial and long-term treatment of VTE are summarized in Table 6.

Factors that may in uence which anticoagulant is chosen for initial and long-term treatment of VTE are summarized in Table 6. This decision is also expected to be sensitive to patient preferences. The order of our presentation of the NOACs (dabigatran, rivaroxaban, apixaban, edoxaban) is based on the chronology of publication of the phase 3 trials in VTE treatment and should not be interpreted as the guideline panel s order of preference for the use of these agents. TABLE 2 ] Summary of Findings: Dabigatran vs VKA for Long-Term Treatment of VTEa,b Outcomes No. of Participants (Studies) Follow-up Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with VKA Risk Difference with Dabigatran (95% CI) All-cause mortality Moderatec because of imprecision (from 6 fewer to 9 more) Recurrent VTE 5,107 Moderatec because of imprecision (from 5 fewer to 13 more) Major bleeding 5,107 Moderatec because of imprecision (from 10 fewer to 2 more) The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). RE-COVER I Ef cacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism; RE-COVER II Phase III Study Testing Ef cacy & Safety of Oral Dabigatran Etexilate vs Warfarin for 6 m Treatment for Acute Symptomatic Venous Thromboembolism. See Table 1 legend for expansion of other abbreviations and GRADE Working Group grades of evidence. a Patients with acute VTE treated initially with LMWH or UFH. b Dabigatran 150 mg twice daily vs warfarin. c CI includes values suggesting no effect and values suggesting either bene t or harm.

c CI includes values suggesting no effect and values suggesting either bene t or harm. d Pooled analysis of Schulman et al20 (RE-COVER I) and Schulman et al24 (RE-COVER II) performed by Schulman et al.24 *2. In patients with DVT of the leg or PE and no cancer, as long-term ( rst 3 months) anticoagulant therapy, we suggest dabigatran, rivaroxaban, apix- aban, or edoxaban over vitamin K antagonist (VKA) therapy (all Grade 2B). For patients with DVT of the leg or PE and no cancer who are not treated with dabigatran, rivaroxaban, apixaban, or edoxaban, we suggest VKA therapy over LMWH (Grade 2C). Remarks: Initial parenteral anticoagulation is given before dabigatran and edoxaban, is not given before rivaroxaban and apixaban, and is overlapped with VKA therapy. See text for factors that in uence choice of therapy. In patients with VTE and cancer ( cancer-associated thrombosis ), as noted earlier in this section, we still suggest LMWH over VKA. In patients with VTE and cancer who are not treated with LMWH, we do not have TABLE 3 ] Summary of Findings: Rivaroxaban vs LMWH and VKA for Acute and Long-Term Treatment of VTEa,b Outcomes No. of Participants (Studies) Follow-up Quality of the Evidence (GRADE) Relative Effect Anticipated absolute effects Risk with LMWH and VKA Risk difference with Rivaroxaban (95% CI) All-cause mortality Moderatec because of imprecision (from 6 fewer to 6 more) Recurrent VTE 8,281 Moderatec because of imprecision (from 7 fewer to 5 more) Major bleeding 8,246 High (from 3 fewer to 11 fewer) The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes.

of Participants (Studies) Follow-up Quality of the Evidence (GRADE) Relative Effect Anticipated absolute effects Risk with LMWH and VKA Risk difference with Rivaroxaban (95% CI) All-cause mortality Moderatec because of imprecision (from 6 fewer to 6 more) Recurrent VTE 8,281 Moderatec because of imprecision (from 7 fewer to 5 more) Major bleeding 8,246 High (from 3 fewer to 11 fewer) The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). EINSTEIN-DVT Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep Vein Thrombosis; EINSTEIN-PE Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism. See Table 1 legend for expansion of other abbreviations and GRADE Working Group grades of evidence. a Included patients had acute, symptomatic, objectively veri ed proximal DVT of the legs or PE (unprovoked, 73%; cancer, 5%; previous VTE, 19%). b Rivaroxaban 20 mg daily for 6 or 12 mo after initial long-term therapy. c CI includes values suggesting no effect and values suggesting either bene t or harm. d Pooled analysis of Bauersachs et al21 (EINSTEIN-DVT) and Buller et al26 (EINSTEIN-PE) performed by Prins et al.183 Bibliography: Prins et al183 TABLE 4 ] Summary of Findings: Apixaban vs LMWH and VKA for Acute and Long-Term Treatment of VTEa,b Outcomes No.

d Pooled analysis of Bauersachs et al21 (EINSTEIN-DVT) and Buller et al26 (EINSTEIN-PE) performed by Prins et al.183 Bibliography: Prins et al183 TABLE 4 ] Summary of Findings: Apixaban vs LMWH and VKA for Acute and Long-Term Treatment of VTEa,b Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with LMWH and VKA Risk Difference with Apixaban (95% CI) All-cause mortality Moderatec because of imprecision (from 9 fewer to 4 more) Recurrent VTE 5,244 Moderatec because of imprecision (from 11 fewer to 5 more) Major bleeding 5,365 High (from 8 fewer to 15 fewer) The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AMPLIFY Apixiban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy; PE pulmonary embolism. See Table 1 legend for expansion of other abbreviations and GRADE Working Group grades of evidence. a Apixaban 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 mo. b Subcutaneous enoxaparin, followed by warfarin. c CI includes values suggesting no effect and values suggesting either bene t or harm. Bibliography: Agnelli et al25 (AMPLIFY) 324 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] a preference for either an NOAC or VKA. In the absence of direct comparisons between NOACs, and no convincing indirect evidence that one NOAC is superior to another, we do not have a preference for one NOAC over another NOAC.

In the absence of direct comparisons between NOACs, and no convincing indirect evidence that one NOAC is superior to another, we do not have a preference for one NOAC over another NOAC. Factors that may in uence which anticoagulant is chosen for initial and long-term treatment of VTE are summarized in Table 6. This decision is also expected to be sensitive to patient preferences. *3. In patients with DVT of the leg or PE and cancer ( cancer-associated thrombosis ), as long-term ( rst 3 months) anticoagulant therapy, we suggest LMWH over VKA therapy (Grade 2B), dabigatran (Grade or edoxaban (Grade 2C). Remarks: Initial parenteral anticoagulation is given before dabigatran and edoxaban, is not given before rivaroxaban and apixaban, and is overlapped with VKA therapy. See text for factors that in uence choice of therapy. Choice of anticoagulant for extended therapy (after 3 months and no scheduled stop date) When AT9 was written, other than a comparison of low- and standard-intensity anticoagulant therapy,46 there were no comparisons of different types of extended therapy. Since AT9, dabigatran has been compared with VKA therapy for extended treatment of VTE and found to be similarly effective but associated with less bleeding Extended treatment with markedly reduces recurrent VTE without being associated with much bleeding (Tables 8-10, e-Tables 10-12).49,50 These studies provide moderate quality evidence that dabigatran is as effective and as safe as VKA for extended treatment of VTE (Table 7, e-Table 9) and provide moderate quality evidence that each of the NOACs are effective at preventing recurrent VTE without being associated with a high risk of bleeding (Tables 8-10, e-Tables 10-12). In AT9, we suggested that if a decision was made to use extended treatment of VTE, the same anticoagulant should be used as was used for the initial treatment period.

In AT9, we suggested that if a decision was made to use extended treatment of VTE, the same anticoagulant should be used as was used for the initial treatment period. Our intention then was to indicate that there was no obligation to switch from one anticoagulant to a different one after 3 or 6 months of treatment (eg, from LMWH to VKA in patients with VTE and cancer). We have revised the wording of this recommendation to make it clearer that we neither encourage nor discourage use of the same anticoagulant for initial and extended therapy. Although we anticipate that the anticoagulant that was used for initial treatment will often also be used for the extended therapy, if there are reasons to change the type of anticoagulant, this should be done. We also note that whereas apixaban 5 mg twice daily is used for long-term treatment, apixaban 2.5 mg twice daily is used for extended therapy.48 TABLE 5 ] Summary of Findings: Edoxaban vs VKA for Acute and Long-Term Treatment of VTEa,b Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with VKA Risk Difference with Edoxaban (95% CI) All-cause mortality Moderatec because of imprecision (from 6 fewer to 10 more) Recurrent VTE 8,240 Moderatec,d because of imprecision (from 15 fewer to 7 more) Major bleeding 8,240 Moderated because of imprecision (from 6 fewer to 3 more) The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). See Table 1 and 4 legends for expansion of abbreviations and GRADE Working Group grades of evidence.

See Table 1 and 4 legends for expansion of abbreviations and GRADE Working Group grades of evidence. a Patients with acute VTE who had initially received heparin. b Edoxaban 60 mg once daily, or 30 mg once daily if patients with creatinine clearance of 30 to 50 mL/min or a body weight below 60 kg. c CI includes values suggesting no effect and values suggesting either bene t or harm. d Death, with PE not ruled out. Bibliography: Buller et al23 (Hokusai-VTE study) *4. In patients with DVT of the leg or PE who receive extended therapy, we suggest that there is no need to change the choice of anticoagulant after the rst 3 months (Grade 2C). Remarks: It may be appropriate for the choice of anticoagulant to change in response to changes in the patient s circumstances or preferences during the long- term or extended phases of treatment.

Remarks: It may be appropriate for the choice of anticoagulant to change in response to changes in the patient s circumstances or preferences during the long- term or extended phases of treatment. Duration of Anticoagulant Therapy Summary of the Evidence AT9 recommendations on how long VTE should be treated were based on comparisons of four durations of than 3 months but still a time-limited course of therapy (usually 6 or 12 months); or (4) extended (also termed inde nite ; no scheduled stopping date) therapy.1 These four options were assessed in four subgroups of VTE patients with different estimated risks of recurrence after stopping anticoagulant therapy: (1) VTE provoked by surgery (a major transient risk factor; 3% recurrence ; (2) VTE provoked by a nonsurgical transient risk factor (eg, estrogen therapy, pregnancy, leg injury, ight of >8 h; 15% recurrence at 5 years)51 ; (3) unprovoked (also termed idiopathic ) VTE; not meeting criteria for provoked by a transient risk factor or by cancer (30% recurrence at 5 years)52,53 ; and (4) VTE associated with cancer (also termed cancer- associated thrombosis ; 15% annualized risk of recurrence; recurrence at 5 years not estimated because of high mortality from cancer).54,55 Recurrence risk was further strati ed by estimating the risk of recurrence after: (1) an isolated distal DVT was half that after a proximal DVT or PE56,57 and (2) a second unprovoked TABLE 6 ] Factors That May In uence Which Anticoagulant Is Chosen for Initial and Long-Term Treatment of VTE Factor Preferred Anticoagulant Qualifying Remarks Cancer LMWH More so if: just diagnosed, extensive VTE, metastatic cancer, very symptomatic; vomiting; on cancer chemotherapy. Parenteral therapy to be avoided Rivaroxaban; apixaban VKA, dabigatran, and edoxaban require initial parenteral therapy.