The relative strength of C-reactive protein and lipid levels as determinants of ischemic stroke compared with coronary heart disease in women. Cost-Effectiveness and Population Impact of Statins for Primary Prevention in Adults Aged 75 Years or Older in the United States Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial. Baseline characteristics of patients participating in the Bezafibrate Infarction Prevention (BIP) Study. Effect of postmenopausal hormone therapy on coronary heart disease events after percutaneous transluminal coronary angioplasty. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Design and Baseline Characteristics of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial--lipid-lowering arm (ASCOT-LLA). Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Semi-parametric risk prediction models for recurrent cardiovascular events in the LIPID study Design of the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with type 2 diabetes. Risk Factors and Secondary Prevention in Women with Heart Disease: The Heart and Estrogen/progestin Replacement Study Implementation of case management to reduce cardiovascular disease risk in the Stanford and San Mateo Heart to Heart randomized controlled trial: study protocol and baseline characteristics Intensive lipid lowering with atorvastatin in patients with stable coronary disease. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators. Prevention of Coronary and Stroke Events with Atorvastatin in Hypertensive Patients who have Average or Lower-than-Average Cholesterol Concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial— Lipid Lowering Arm (ASCOT-LLA): A Multicentre Randomised Controlled Trial Serum Non-High-Density Lipoprotein Cholesterol and Risk of Cardiovascular Disease in Community Dwellers with Chronic Kidney Disease: the Hisayama Study Aspirin, Statins, or Both Drugs for the Primary Prevention of Coronary Heart Disease Events in Men: A CostUtility Analysis Treatment with Atorvastatin to the National Cholesterol Educational Program Goal Versus 'Usual' Care in Secondary Coronary Heart Disease Prevention
OBJECTIVES We sought to determine the relative strength of high-sensitivity C-reactive protein ( hs-CRP ) and lipid levels as markers for future ischemic stroke compared with coronary heart disease ( CHD ) in women . BACKGROUND Although hs-CRP and lipid levels are established risk determinants for vascular disease , the relative strength of these biomarkers for ischemic stroke compared with CHD is uncertain . METHODS Among 15,632 initially healthy women who were followed for a 10-year period , we compared  hs-CRP , total cholesterol ( TC ) , low-density lipoprotein cholesterol ( LDL-C ) , non-high-density lipoprotein cholesterol ( non-HDL-C ) , high-density lipoprotein cholesterol ( HDL-C ) , apolipoproteins A-I and B100 , and lipid ratios  as determinants of ischemic stroke compared with CHD . RESULTS After adjustment for age , smoking status , blood pressure , diabetes , and obesity , the hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) for the third versus the first tertile for future ischemic stroke compared with CHD were , respectively , 1.91 ( 95 % CI 1.13 to 3.21 ) and 2.26 ( 95 % CI 1.64 to 3.12 ) for TC , 1.29 ( 95 % CI 0.83 to 2.02 ) and 2.09 ( 95 % CI 1.53 to 2.85 ) for LDL-C , 0.57 ( 95 % CI 0.36 to 0.92 ) and 0.38 ( 95 % CI 0.27 to 0.52 ) for HDL-C , 1.72 ( 95 % CI 1.03 to 2.86 ) and 2.93 ( 95 % CI 2.04 to 4.21 ) for non-HDL-C , and 2.76 ( 95 % CI 1.51 to 5.05 ) and 1.66 ( 95 % CI 1.17 to 2.34 ) for hs-CRP . Of the lipid ratios , that of TC to HDL-C had the largest HR for both future ischemic stroke and CHD ( HR 1.95 [ 95 % CI 1.16 to 3.26 ] and 4.20 [ 95 % CI 2.79 to 6.32 ] , respectively ) . CONCLUSIONS In this large prospect i ve cohort of initially healthy women , lipid levels are significant risk determinants for ischemic stroke , but with a magnitude of effect smaller than that observed for CHD . High-sensitivity CRP associates more closely with ischemic stroke than with CHD . Concomitant evaluation of lipid levels and hs-CRP may improve risk assessment for stroke as well as CHD . ( The Women 's Health Study ; http://www . clinical trials.gov/ct/show/NCT00000479/ ; NCT00000479 ) Editors ' Notes Context Clinical guidelines provide conflicting recommendations about whether to prescribe statins in persons aged 75 years or older for primary prevention of unwanted cardiovascular outcomes . Contribution This study used information from clinical trials to model the tradeoffs between benefits and harms and found that using  statins  in all persons aged 75 to 94 years would prevent new myocardial infa rct ions and deaths from coronary heart disease at an acceptable cost . Caution Small increases in the frequency or severity of harms would negate the benefits . Implication Additional research is warranted to better underst and the tradeoffs between benefits and harms in this age group . Statins are commonly used in adults aged 75 years or older ( 1 ) . Despite their widespread use , evidence for their effectiveness for primary prevention in elderly adults is unclear , and guidelines for their use in this population are inconsistent . The recently published American College of Cardiology/American Heart Association ( ACC/AHA ) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults gave limited recommendations for statin use for primary prevention in adults aged 75 years or older ( 2 ) , noting that few data were available to indicate an atherosclerotic cardiovascular disease event reduction benefit in primary prevention among individuals > 75 years of age who do not have clinical year atherosclerotic cardiovascular disease , and suggesting that comorbid conditions , safety , and priorities of care are recommended for joint provider and patient decision making . The American Medical Directors Association , a professional group of long-term care providers , recommended that statins not be routinely prescribed in adults aged 70 years or older as part of the American Board of Internal Medicine Choosing Wisely campaign ( 3 ) . This recommendation was based on the lack of an association between high cholesterol levels and outcomes in older adults as well as the potential for an increased risk for statin-related adverse events , including cognitive impairment , falls , neuropathy , and muscle damage ( 3 ) . The variation in these treatment recommendations reflects uncertainty about the balance between the benefits and risks of statin use in older adults compared with younger adults as well as the more limited evidence base in this population . Adults aged 75 years or older have been underrepresented in trials of statins for primary prevention , so the effectiveness of statins is less clear in this population . Results from observational studies suggest that the associations between low-density lipoprotein ( LDL ) cholesterol levels and outcomes are attenuated in older adults ( 47 ) . Although the baseline risk for cardiovascular disease is increased in older adults , their life expectancy is shorter and their risks for competing mortality are greater . Finally , there has been concern about geriatric-specific adverse effects , especially functional limitation due to muscle pain , weakness , and mild cognitive impairment ( 816 ) . In the presence of uncertainty about the riskbenefit tradeoff , computer simulations can provide estimates of the potential benefits of various treatment strategies as well as the costs and potential risk for harms . We evaluated the population benefit and cost-effectiveness of statins in persons aged 75 years or older without a history of cardiovascular disease in the United States . This investigation was conducted using the Cardiovascular Disease Policy Model ( CVDPM ) , a Markov model of the U.S. population ( 17 ) . We simulated the impact of statins for primary prevention based on treatment of the high-risk groups identified by the ACC/AHA guidelines , the associated costs , and potential harms that could offset the potential cardiovascular benefits in the U.S. population of adults aged 75 to 94 years over the next 10 years . Methods The Model The CVDPM is an established state-transition ( Markov ) model of the incidence , prevalence , mortality , and cost of CHD and stroke in U.S. residents aged 35 to 94 years ( 17 ) . The present study was limited to adults aged 75 to 94 years . The model comprises 3 components . First , the demographic-epidemiologic submodel estimates the incidence of coronary heart disease ( CHD ) ( cardiac arrest , myocardial infa rct ion [ MI ] , angina , or CHD death ) , ischemic stroke , and death from other causes on the basis of age , sex , systolic blood pressure , smoking , high-density lipoprotein and LDL cholesterol levels , diabetes , body mass index , and statin use . Second , the bridge submodel characterizes the initial CHD or stroke event and related events in the subsequent 30 days . Third , the disease-history submodel predicts the number of subsequent CHD and stroke events , revascularization procedures , and deaths among patients with cardiovascular disease , stratified according to age , sex , and history of cardiovascular disease events . In addition , persons may exit the model at any stage through a non-CHD , nonstroke mortality function , allowing for competing risk . Modifiable components of the model include population distributions , risk factor levels , risk factor coefficients , event rates , case-fatality rates , costs , and disability adjustments ( 17 ) . Costs for stroke requiring hospitalization , CHD , and acute stroke rehabilitation were estimated using California hospital data ( 18 ) and were deflated using costcharge ratios and the ratio of the U.S. national average costs to the California average ( 19 , 20 ) . Age- and sex-specific background health care costs were estimated using national data ( 21 ) . All model costs were inflated to 2014 costs by using the medical component of the Consumer Price Index ( 22 ) . All disability weights associated with the CHD and stroke event states were based on the Global Burden of Disease Study ( 23 , 24 ) . Additional details are provided in the Appendix . Simulation Inputs We modeled the effect of statins on LDL cholesterol level based on PROSPER ( Prospect i ve Study of Pravastatin in the Elderly at Risk of Vascular Disease ) , a r and omized , placebo-controlled trial of 5804 men and women aged 70 to 82 years ( 25 ) . In that trial , the mean reduction in LDL cholesterol level was 34 % for participants with an average initial level of 147 mg/dL , consistent with the estimated effect of a moderate-dose statin in the 2013 ACC/AHA guideline ( 2 ) . We included 3 estimates for the effectiveness of a decrease in LDL cholesterol level on events . The primary estimates were derived by extrapolating the age-stratified effect sizes of a 1.0-mmol/L reduction in LDL cholesterol level from the Cholesterol Treatment Trialists ' meta- analysis ( 26 ) . We fit a regression line to the 3 age strata reported in that analysis ( 60 years , > 60 to 70 years , and > 70 years ) to estimate the effect sizes at ages 80 and 90 years . In a sensitivity analysis , we used a high estimate based on the age-pooled estimate of effect of a 1.0-mmol/L reduction in LDL cholesterol level on major coronary events in the meta- analysis . We used a low estimate based on the effect size from PROSPER for primary prevention ( 25 ) . Statin costs were derived from the National Average Drug Acquisition Cost ( NADAC ) data base ( 27 ) . Our primary cost estimate ( $ 5.59 for a 30-day supply ) was the average of the NADAC costs for the 4 moderate-dose statins that are available in generic form : atorvastatin , 10 mg ; simvastatin , 20 mg ; pravastatin , 40 mg ; and lovastatin , 40 mg . This cost estimate was $ 5.00 when indexed to 2010 dollars based on the medical component of the Consumer Price Index ( 22 ) . In addition , we used a low cost estimate of $ 4 per month , based on the price of generic statins from multiple discount retailers ( such as Walmart , Target , and Walgreens ) . For a high cost estimate , we used $ 30 for a 30-day supply ; the low and high cost estimates have been used similarly in other contemporary cost-effectiveness analyses ( 28 , 29 ) . Adults aged 65 years or older use a median of 4 medications ; therefore , we estimated the cost of an additional 0.25 physician visit per year for statin use , assuming that medication management could be covered in 1 visit ( 30 , 31 ) . We estimated 1 lipid panel per year for monitoring ( 32 ) . Event rates for myopathy and hemorrhagic stroke were estimated as 0.001 per statin-year of use , based on the ACC/AHA guideline statement ( 2 ) . Although many major and minor adverse effects have been reported to be associated with statin use , we focused on 2 that are important to geriatric population s and that have generated concern in the scientific literature : functional limitation due to muscle pain and weakness , and mild cognitive impairment ( 816 ) . Both are prevalent in older adults and can have a substantial effect on quality of life and the ability to live independently . A recent review of late-life activity limitations in the United States reported data on participants in 5 nationally representative surveys . The prevalence of limitations in activities of daily living was 27 % in adults aged 75 to 84 years and 45 % in those aged 85 years or older ( 33 ) . The population -weighted average of these estimates is 32 % for adults aged 75 to 94 years . Widely varying prevalence estimates for mild cognitive impairment have been reported due to the differential measures of this condition and the differences between population s. A recent review reported prevalence of mild cognitive impairment of 19 % to 28 % in studies of older U.S. adults ; we used the average of the 4 U.S. studies , which was 25 % ( 34 ) . Disability-adjusted life-years for the corresponding states were calculated as 1 minus the disability weights reported in the Global Burden of Disease Study ( 24 ) . Because the statin-associated relative risk for these adverse effects is uncertain , we assumed no elevated risk for these adverse effects in our base-case scenario . The goal of this investigation was not to evaluate the strength of the literature regarding the presence of these adverse OBJECTIVE Diabetes , a major health problem worldwide , increases the risk of cardiovascular disease and its associated mortality : The Long-Term Intervention with Pravastatin in Ischemic Disease ( LIPID ) trial showed that cholesterol-lowering treatment with pravastatin reduced mortality and coronary heart disease ( CHD ) events in 9014 patients aged 31 - 75 years with CHD and total cholesterol 4.0 - 7.0 mmol/l . We measured the effects of pravastatin therapy , 40 mg/day over 6.0 years , on the risk of CHD death or nonfatal myocardial infa rct ion and other cardiovascular outcomes in 1,077 LIPID patients with diabetes and 940 patients with impaired fasting glucose ( IFG ) . RESULTS In patients allocated to placebo , the risk of a major CHD event was 61 % higher in patients with diabetes and 23 % higher in the IFG group than in patients with normal fasting glucose , and the risk of any cardiovascular event was 37 % higher in the diabetic group and 19 % higher in the IFG group . Pravastatin therapy reduced the risk of a major CHD event overall from 15.9 to 12.3 % ( relative risk reduction [ RRR ] 24 % , P < 0.001 ) and from 23.4 to 19.6 % in the diabetic group ( 19 % , P = 0.11 ) ; in the diabetic group , the reduction was not significantly different from the reductions in the other groups . Pravastatin reduced the risk of any cardiovascular event from 52.7 to 45.2 % ( 21 % , P < 0.008 ) in patients with diabetes and from 45.7 to 37.1 % ( 26 % , P = 0.003 ) in the IFG group . Pravastatin reduced the risk of stroke from 9.9 to 6.3 % in the diabetic group ( RRR 39 % , CI 7 - 61 % , P = 0.02 ) and from 5.4 to 3.4 % in the IFG group ( RRR 42 % , CI -9 to 69 % , P = 0.09 ) . Pravastatin did not reduce the incidence of diabetes . Over 6 years , pravastatin therapy prevented one major CHD event ( CHD death or nonfatal myocardial infa rct ion ) in 23 patients with IFG and 18 patients with diabetes . A meta- analysis of other major trials confirmed the high absolute risks of diabetes and IFG and the absolute benefits of statin therapy in these patients . CONCLUSIONS Cholesterol-lowering treatment with pravastatin therapy prevents cardiovascular events , including stroke , in patients with diabetes or IFG and established CHD Low high density lipoprotein ( HDL ) cholesterol , elevated triglycerides , or a combination of both , carries an increased risk of coronary heart disease ( CHD ) . The benefit of therapy that increases serum HDL cholesterol concentrations and lowers triglyceride concentrations on the reduced incidence of myocardial infa rct ions and mortality has not been unequivocally demonstrated in healthy persons or patients with CHD . The Bezafibrate Infa rct ion Prevention ( BIP ) study r and omized men and women , with CHD and with total serum cholesterol 180 - 250 mg . dl-1 , low density lipoprotein ( LDL ) cholesterol < or = 180 mg . dl-1 ( < or = 160 mg . dl-1 below age 50 years ) , HDL cholesterol < or = 45 mg . dl-1 and triglycerides < or = 300 mg . dl-1 , to bezafibrate retard ( 400 mg once daily ) or placebo . In addition to its effect on the lipids , this drug significantly lower plasma fibrinogen . The demographic , clinical and biochemical characteristics and existing cardiovascular therapy at baseline of 3122 patients r and omized onto the study are presented here . A comparison is made with other on-going or recently published secondary prevention studies of lipid modification in CHD patients Despite several observational studies , 1–3 no clinical trial has evaluated the effect of hormone therapy on percutaneous transluminal coronary angioplasty ( PTCA ) outcomes in matched population s r and omized to hormones or placebo . We compared the incidence of  coronary heart disease ( CHD ) events after PTCA among women who previously had been r and omly assigned to hormone therapy and placebo in the Heart and Estrogen/progestin Replacement Study ( HERS ) .  The design , methods , and primary results of HERS have been previously published . 4,5 Briefl y , HERS participants were postmenopausal women aged 80 years with established CHD who had not had a hysterectomy . Inclusion criteria were prior myocardial infa rct ion , coronary artery bypass graft surgery ( CABG ) , PTCA , or angiographic evidence of a 50 % diameter narrowing of 1 major coronary artery . Exclusion criteria were a recent CHD event , New York Heart Association class IV or severe class III congestive heart failure , serum triglyceride levels 300 mg/ dl , recent use of any hormone therapy , uncontrolled hypertension or diabetes , a disease ( other than CHD ) judged likely to be fatal within 4 years , or prior intolerance to hormone therapy . At the initiation of the HERS , participants were r and omly assigned to receive a single identical tablet containing either conjugated equine estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg or placebo . During the HERS , 357 patients underwent PCTA and constituted the study population . These patients were followed subsequently to ascertain their rate for subsequent CHD events . Demographic characteristics , health history , CHD risk factors , medication use , educational level , and quality of life were assessed at baseline . Baseline levels of fasting total cholesterol , low-density lipoprotein cholesterol , high-density lipoprotein cholesterol , triglycerides , and lipoprotein ( a ) were determined by the Lipoprotein Analytical Laboratory at Johns Hopkins Hospital ( Baltimore , Maryl and ) . Follow-up time for this analysis began at the time of the initial PTCA and concluded at the closeout of the HERS . All suspected outcome events were classifi ed independently by 2 physician review ers who were unaware of treatment assignment . Discordant classifi cations were resolved in discussion s between the review ers CONTEXT Observational studies have found lower rates of coronary heart disease ( CHD ) in postmenopausal women who take estrogen than in women who do not , but this potential benefit has not been confirmed in clinical trials . OBJECTIVE To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease . DESIGN R and omized , blinded , placebo-controlled secondary prevention trial . SETTING Outpatient and community setting s at 20 US clinical centers . PARTICIPANTS A total of 2763 women with coronary disease , younger than 80 years , and postmenopausal with an intact uterus . Mean age was 66.7 years . INTERVENTION Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily ( n = 1380 ) or a placebo of identical appearance ( n = 1383 ) . Follow-up averaged 4.1 years ; 82 % of those assigned to hormone treatment were taking it at the end of 1 year , and 75 % at the end of 3 years . MAIN OUTCOME MEASURES The primary outcome was the occurrence of nonfatal myocardial infa rct ion ( MI ) or CHD death . Secondary cardiovascular outcomes included coronary revascularization , unstable angina , congestive heart failure , resuscitated cardiac arrest , stroke or transient ischemic attack , and peripheral arterial disease . All-cause mortality was also considered . RESULTS Overall , there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes : 172 women in the hormone group and 176 women in the placebo group had MI or CHD death ( relative hazard [ RH ] , 0.99 ; 95 % confidence interval [ CI ] , 0.80 - 1.22 ) . The lack of an overall effect occurred despite a net 11 % lower low-density lipoprotein cholesterol level and 10 % higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group ( each P<.001 ) . Within the overall null effect , there was a statistically significant time trend , with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5 . More women in the hormone group than in the placebo group experienced venous thromboembolic events ( 34 vs 12 ; RH , 2.89 ; 95 % CI , 1.50 - 5.58 ) and gallbladder disease ( 84 vs 62 ; RH , 1.38 ; 95 % CI , 1.00 - 1.92 ) . There were no significant differences in several other end points for which power was limited , including fracture , cancer , and total mortality ( 131 vs 123 deaths ; RH , 1.08 ; 95 % CI , 0.84 - 1.38 ) . CONCLUSIONS During an average follow-up of 4.1 years , treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease . The treatment did increase the rate of thromboembolic events and gallbladder disease . Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events , we do not recommend starting this treatment for the purpose of secondary prevention of CHD . However , given the favorable pattern of CHD events after several years of therapy , it could be appropriate for women already receiving this treatment to continue Evidence suggests that statin therapy reduces the risk of stroke in patients with coronary heart disease ( CHD ) , but its benefit for patients with cerebrovascular disease and no history of CHD remains uncertain . The Stroke Prevention by Aggressive Reduction in Cholesterol Levels ( SPARCL ) Study is a prospect i ve , multi-centre , double-blind , r and omised , placebo-controlled trial design ed to evaluate the effects of atorvastatin 80 mg/day in patients who previously experienced a stroke or transient ischaemic attack , but who have no known CHD . A total of 4,732 patients have been enrolled , and the data collection phase of the study is expected to be completed by October 2004 . SPARCL is the first study primarily design ed to prospect ively evaluate the effect of statin treatment  in secondary stroke prevention CONTEXT Studies have demonstrated that statins administered to individuals with risk factors for coronary heart disease ( CHD ) reduce CHD events . However , many of these studies were too small to assess all-cause mortality or outcomes in important subgroups . OBJECTIVE To determine whether pravastatin compared with usual care reduces all-cause mortality in older , moderately hypercholesterolemic , hypertensive participants with at least 1 additional CHD risk factor . DESIGN AND SETTING Multicenter ( 513 primarily community-based North American clinical centers ) , r and omized , nonblinded trial conducted from 1994 through March 2002 in a subset of participants from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) . PARTICIPANTS Ambulatory persons ( n = 10 355 ) , aged 55 years or older , with low-density lipoprotein cholesterol ( LDL-C ) of 120 to 189 mg/dL ( 100 to 129 mg/dL if known CHD ) and triglycerides lower than 350 mg/dL , were r and omized to  pravastatin  ( n = 5170 ) or to  usual care  ( n = 5185 ) . Baseline mean total cholesterol was 224 mg/dL ; LDL-C , 146 mg/dL ; high-density lipoprotein cholesterol , 48 mg/dL ; and triglycerides , 152 mg/dL. Mean age was 66 years , 49 % were women , 38 % black and 23 % Hispanic , 14 % had a history of CHD , and 35 % had type 2 diabetes . INTERVENTION Pravastatin , 40 mg/d , vs usual care . MAIN OUTCOME MEASURES The primary outcome was all-cause mortality , with follow-up for up to 8 years . Secondary outcomes included nonfatal myocardial infa rct ion or fatal CHD ( CHD events ) combined , cause-specific mortality , and cancer . RESULTS Mean follow-up was 4.8 years . During the trial , 32 % of usual care participants with and 29 % without CHD started taking lipid-lowering drugs . At year 4 , total cholesterol levels were reduced by 17 % with pravastatin vs 8 % with usual care ; among the r and om sample who had LDL-C levels assessed , levels were reduced by 28 % with pravastatin vs 11 % with usual care .  All-cause mortality was similar for the 2 groups ( relative risk [ RR ] , 0.99 ; 95 % confidence interval [ CI ] , 0.89 - 1.11 ; P = .88 ) , with 6-year mortality rates of 14.9 % for pravastatin vs 15.3 % with usual care .  CHD event rates were not significantly different between the groups ( RR , 0.91 ; 95 % CI , 0.79 - 1.04 ; P = .16 ) , with 6-year CHD event rates of 9.3 % for pravastatin and 10.4 % for usual care . CONCLUSIONS Pravastatin did not reduce either all-cause mortality or CHD significantly when compared with usual care in older participants with well-controlled hypertension and moderately elevated LDL-C. The results may be due to the modest differential in total cholesterol ( 9.6 % ) and LDL-C ( 16.7 % ) between pravastatin and usual care compared with prior statin trials supporting cardiovascular disease prevention OBJECTIVE This study aims to establish the benefits of lowering cholesterol in diabetic patients with well-controlled hypertension and average/below-average cholesterol concentrations , but without established coronary disease . RESEARCH DESIGN AND METHODS In the lipid-lowering arm of the Anglo-Sc and inavian Cardiac Outcomes Trial ( ASCOT-LLA ) , 10,305 hypertensive patients with no history of coronary heart disease ( CHD ) but at least three cardiovascular risk factors were r and omly assigned to receive 10 mg atorvastatin or placebo . Effects on total cardiovascular outcomes in 2,532 patients who had type 2 diabetes at r and omization were compared . RESULTS During a median follow-up of 3.3 years , concentrations of total and LDL cholesterol among diabetic participants included in ASCOT-LLA were approximately 1 mmol/l lower in those allocated atorvastatin compared with placebo . There were 116 ( 9.2 % ) major cardiovascular events or procedures in the atorvastatin group and 151 ( 11.9 % ) events in the placebo group ( hazard ratio 0.77 , 95 % CI 0.61 - 0.98 ; P = 0.036 ) . For the individual components of this composite end point , the number of events occurring in the diabetes subgroup was small . Therefore , although fewer coronary events ( 0.84 , 0.55 - 1.29 ; P = 0.14 ) and strokes ( 0.67 , 0.41 - 1.09 ; P = 0.66 ) were observed among the patients allocated atorvastatin , these reductions were not statistically significant . CONCLUSIONS Atorvastatin significantly reduced the risk of major cardiovascular events and procedures among diabetic patients with well-controlled hypertension and without a history of CHD or markedly elevated cholesterol concentrations . The proportional reduction in risk was similar to that among participants who did not have diagnosed diabetes . Allocation to atorvastatin prevented approximately 9 diabetic participants from suffering a first major cardiovascular event or procedure for every 1,000 treated for 1 year BACKGROUND Although it is generally accepted that lowering elevated serum levels of low-density lipoprotein ( LDL ) cholesterol in patients with coronary heart disease is beneficial , there are few data to guide decisions about therapy for patients whose primary lipid abnormality is a low level of high-density lipoprotein ( HDL ) cholesterol . METHODS We conducted a double-blind trial comparing gemfibrozil ( 1200 mg per day ) with placebo in 2531 men with coronary heart disease , an HDL cholesterol level of 40 mg per deciliter ( 1.0 mmol per liter ) or less , and an LDL cholesterol level of 140 mg per deciliter ( 3.6 mmol per liter ) or less . The primary study outcome was nonfatal myocardial infa rct ion or death from coronary causes . RESULTS The median follow-up was 5.1 years . At one year , the mean HDL cholesterol level was 6 percent higher , the mean triglyceride level was 31 percent lower , and the mean total cholesterol level was 4 percent lower in the gemfibrozil group than in the placebo group . LDL cholesterol levels did not differ significantly between the groups . A primary event occurred in 275 of the 1267 patients assigned to placebo ( 21.7 percent ) and in 219 of the 1264 patients assigned to gemfibrozil ( 17.3 percent ) . The overall reduction in the risk of an event was 4.4 percentage points , and the reduction in relative risk was 22 percent ( 95 percent confidence interval , 7 to 35 percent ; P=0.006 ) . We observed a 24 percent reduction in the combined outcome of death from coronary heart disease , nonfatal myocardial infa rct ion , and stroke ( P < 0.001 ) . There were no significant differences in the rates of coronary revascularization , hospitalization for unstable angina , death from any cause , and cancer . CONCLUSIONS Gemfibrozil therapy result ed in a significant reduction in the risk of major cardiovascular events in patients with coronary disease whose primary lipid abnormality was a low HDL cholesterol level . The findings suggest that the rate of coronary events is reduced by raising HDL cholesterol levels and lowering levels of triglycerides without lowering LDL cholesterol levels Background Traditional methods for analyzing clinical and epidemiological cohort study data have been focused on the first occurrence of a health outcome . However , in many situations , recurrent event data are frequently observed . It is inefficient to use methods for the analysis of first events to analyse recurrent event data . Methods We applied several semi-parametric proportional hazards models to analyze the risk of recurrent myocardial infa rct ion ( MI ) events based on data from a very large r and omized placebo-controlled trial of cholesterol-lowering drug .  The backward selection procedure was used to select the significant risk factors in a model . The best fitting model was selected using the log-likelihood ratio test , Akaike Information and Bayesian Information Criteria . Results A total of 8557 persons were included in the LIPID study . Risk factors such as age , smoking status , total cholesterol and high density lipoprotein cholesterol levels , qualifying event for the acute coronary syndrome , revascularization , history of stroke or diabetes , angina grade and treatment with pravastatin were significant for development of both first and subsequent MI events . No significant difference was found for the effects of these risk factors between the first and subsequent MI events . The significant risk factors selected in this study were the same as those selected by the parametric conditional frailty model . Estimates of the relative risks and 95 % confidence intervals were also similar between these two methods . Conclusions Our study shows the usefulness and convenience of the semi-parametric proportional hazards models for the analysis of recurrent event data , especially in estimation of regression coefficients and cumulative risks BACKGROUND There are few data on the role of lipid lowering in the primary prevention of  coronary heart disease ( CHD ) in diabetic patients . This paper describes the design of a collaborative clinical trial between Diabetes UK , the NHS Research and Development Directorate and Pfizer UK , that addresses this question . METHODS The Collaborative AtoRvastatin Diabetes Study ( CARDS ) is a multicentre , r and omized , placebo-controlled , double-blind clinical trial of primary prevention of cardiovascular disease in patients with Type 2 diabetes . The primary objective is to investigate whether treatment with the hydroxymethylglutaryl coenzyme A reductase inhibitor , atorvastatin , reduces the incidence of major cardiovascular events . At entry patients have at least one other risk factor for CHD in addition to diabetes , namely current smoking , hypertension , retinopathy , or micro- or macroalbuminuria . At r and omization patients have been selected for a serum low-density lipoprotein ( LDL ) cholesterol concentration < or = 4.14 mmol/l ( 160 mg/dl ) and triglycerides < or = 6.78 mmol/l ( 600 mg/dl ) . R and omization was completed in June 2001 . Patients will be followed until 304 primary endpoints have accrued ( expected date early 2005 ) . The trial includes 2838 men and women aged 40 - 75 years . This report describes the design and administration of the study and review s the evidence to date of the effectiveness of  lipid-lowering therapy in Type 2 diabetes . CONCLUSIONS The case for lipid-lowering therapy for the primary prevention of CHD in diabetes has not been demonstrated . CARDS will provide essential information on the extent of any benefits and adverse effects of lipid-lowering therapy in diabetic patients without prior CHD Context Risk factors for recurrent events among women with known coronary disease and whether these women commonly receive secondary prevention treatments are mostly unknown . Contribution This large cohort study showed that 11 different factors , including several previous infa rct ions , renal dysfunction , diabetes , angina , heart failure , and uncontrolled hypertension , predicted up to a sixfold increased rate of coronary disease events in postmenopausal women with preexisting coronary disblockers , angiotensin-converting enzyme inhibitors , or cholesterol-lowering drugs . Implication s Clinicians can identify women who have high risks for recurrent coronary events and should promote greater use of secondary prevention treatments for them . The Editors Coronary heart disease ( CHD ) is the leading cause of death in women . The major independent risk factors that predict CHD onset in healthy women are similar to those identified by epidemiologic studies of healthy men ( 1 - 7 ) . A recent report described six independent risk factorsage , low-density lipoprotein ( LDL ) and high-density lipoprotein ( HDL ) cholesterol levels , high blood pressure , diabetes mellitus , and smokingthat were strongly associated with risk for a first CHD event in both men and women ( 8) . However , the strength of the association of certain risk factors with CHD events may vary by sex ( 9 ) as well as age . Diabetes may be a stronger risk factor in women than in men ( 7 ) ; among older women , HDL cholesterol level may be a relatively strong risk factor and LDL cholesterol level a relatively weak one ( 6 ) . In the period immediately after myocardial infa rct ion ( MI ) , studies of mostly male sample s have found that persistent ischemia , impaired left ventricular systolic function , and ventricular arrhythmias are the major determinants of subsequent MI and death ( 10 - 13 ) . In the Coronary Drug Project study of men with a history of heart attack , electrocardiographic abnormalities and heart failure  were stronger predictors than the atherosclerosis risk factors identified in primary prevention setting s ( 14 ) . However , the risk factors for coronary events among women with recognized but stable coronary disease are mostly unknown . Better underst and ing of these factors could improve secondary prevention in this large and high-risk group . The Heart and Estrogen/progestin Replacement Study ( HERS ) was a r and omized clinical trial of estrogen plus progestin for prevention of CHD events in women with coronary disease ( 15 ) . Overall , no significant differences were noted between the hormone and placebo groups in CHD events ; trends of more CHD events with therapy in year 1 were offset by fewer such outcomes during years 4 and 5 . The trial collected extensive data on CHD risk factors and medication use and performed exhaustive outcome ascertainment procedures , with complete mortality follow-up . Therefore , HERS offers a unique opportunity to assess the long-term effect of coronary risk factors and use of recommended treatments in women with established coronary disease . Methods Participants Participants in HERS were postmenopausal women who were younger than 80 years of age , had not had a hysterectomy , and had known coronary artery disease ( MI , coronary artery bypass surgery , percutaneous transluminal coronary angioplasty , or angiographic evidence of 50 % narrowing of one or more major coronary arteries ) . Women were excluded if they had had a coronary event within the 6 months before r and omization , had a serum triglyceride level greater than 3.39 mmol/L ( 300 mg/dL ) , had used hormones within 3 months , or had a history of conditions that would contraindicate estrogen therapy ( 16 ) . Participants in HERS were r and omly assigned within clinical centers to 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate in one tablet daily ( n = 1380 ) or a placebo of identical appearance ( n = 1383 ) . The institutional review boards at the coordinating center and each of the 20 HERS clinical centers approved the protocol , and all participants provided written informed consent . Predictors In the baseline interview , information was obtained by self-report on demographic characteristics , behavioral risk factors , and medical history . Among women who reported ever having smoked at least 100 cigarettes , years of smoking , average cigarettes per day , and current smoking were ascertained . Alcohol use in the past 30 days was assessed for frequency and usual numbers of drinks per occasion .  Exercise  was measured as participation in a regular exercise program such as cardiac rehabilitation or aerobics or walking at least occasionally for exercise more than 10 minutes at a time . Use of  aspirin , -blockers , lipid-lowering medications ( statins , niacin , fibrates , bile acidbinding resins , and probucol ) , angiotensin-converting enzyme ( ACE ) inhibitors , calcium antagonists , and folate or vitamin B was assessed by self-report . In the baseline physical examination , blood pressure , waist-to-hip ratio , and body mass index were measured . A physician assessed history and symptoms of heart failure ( jugular venous distention , third heart sound , significant murmurs , pulmonary rales , and peripheral edema ) . High blood pressure was defined as systolic blood pressure greater than or equal to 140 mm Hg or diastolic blood pressure greater than or equal to 90 mm Hg , according to the Sixth Report of the Joint National Committee on Prevention , Detection , Evaluation and Treatment of High Blood Pressure ( 17 ) . Angina was defined as self-report of chest discomfort in the previous 4 weeks during exercise , emotion , or sexual activity . Serum specimens were obtained , and a central ized laboratory measured fasting levels of LDL cholesterol , HDL cholesterol , lipoprotein(a ) , triglycerides , glucose , and creatinine ( 15 , 16 ) . Creatinine clearance was estimated by using the CockcroftGault equation ( 18 , 19 ) . Outcomes The primary HERS outcome was CHD events , defined as nonfatal MI or CHD death . Suspected outcome events were reported within 24 hours to the coordinating center and were systematic ally assessed every 4 months at the follow-up contacts . An independent morbidity and mortality subcommittee that was blinded to treatment assignment adjudicated all deaths and suspected outcome events . Nonfatal MI was diagnosed by using an algorithm based on ischemic symptoms , electrocardiographic abnormalities , and elevated cardiac enzyme levels ( 16 ) . Death from CHD included fatal documented MI , sudden death within 1 hour of symptom onset , unobserved death that occurred out of the hospital in the absence of other known causes , or death due to a coronary revascularization procedure or congestive heart failure . The date of each event was determined from the documentation obtained by the clinical centers . The total number of events reported here is slightly larger than that published in the primary HERS results ( 15 ) because of subsequent adjudications ( 20 ) . Statistical Analyses We used multivariable Cox proportional-hazards models to assess the associations between risk factors and CHD events . These models were stratified by clinical center to account for potential clustering . Waist-to-hip ratio and LDL and HDL cholesterol levels were modeled as continuous variables , but lipoprotein(a ) level was dichotomized at the median and creatinine clearance was dichotomized at 0.66 mL/s ( 40 mL/min ) to reflect the nonlinear responses we have reported elsewhere ( 19 , 21 ) . We used an indicator for any alcohol use , since almost all of the 39 % of HERS women who reported alcohol use were light or moderate drinkers . Exercise was modeled by an indicator for participation in an exercise program or walking for exercise for more than 10 minutes . The multivariable model includes previously identified risk factors that were significant ( P 0.20 ) in unadjusted models and were not judged redundant on substantive grounds . Body mass index was excluded because it was clearly nonsignificant after adjustment ( P > 0.2 ) and was also highly correlated with waist-to-hip ratio , which was the stronger predictor in unadjusted analysis . Similarly , triglyceride levels were excluded because of their strong negative correlation with HDL cholesterol levels , which in our judgment were more likely to be causal . We also controlled for use of aspirin , statins , other lipid-lowering medications , diuretics , -blockers , ACE inhibitors , calcium antagonists , and folate or vitamin B. The effect of assignment to hormone therapy was modeled separately for each year of follow-up , as in the post hoc analysis of HERS ( 15 ) . Interactions between risk factors and relevant treatments were also examined . Specifically , we compared hazard rates among patients with diagnosed diabetes who reported use of insulin or oral hypoglycemic agents  with rates in the combined group of diabetic persons not using these medications and women with fasting glucose levels greater than 6.94 mmol/L ( > 125 mg/dL ) but no history of diabetes diagnosis . Likewise , we compared estimates for LDL and HDL cholesterol levels stratified by use of any lipid-lowering medication or assignment to hormone therapy ; for lipoprotein(a ) level , stratified by assignment to hormone therapy ; for high blood pressure on examination , stratified by use of at least one antihypertensive medication ; for heart failure and creatinine clearance less than or equal to 0.66 mL/s ( 40 mL/min ) , stratified by use of ACE inhibitors ; and for more than one previous MI and angina , stratified by use of any indicated medications . The final model includes interactions that were significant at a P value less than or equal to 0.2 . We used residuals to assess overall model fit , validity of the proportional hazards assumption , and linearity of associations with continuous predictors . The study lacked power to examine interactions between clinical center and potential risk factors . We tested the assumption of noninformative censoring by considering the two extremes of the possible outcomes Background Case management has emerged as a promising alternative approach to supplement traditional one-on-one sessions between patients and doctors for improving the quality of care in chronic diseases such as coronary heart disease ( CHD ) . However , data are lacking in terms of its efficacy and cost-effectiveness when implemented in ethnic and low-income population s. Methods The Stanford and San Mateo Heart to Heart ( HTH ) project is a r and omized controlled clinical trial design ed to rigorously evaluate the efficacy and cost-effectiveness of a multi-risk cardiovascular case management program in low-income , primarily ethnic minority patients served by a local county health care system in California . R and omization occurred at the patient level . The primary outcome measure is the absolute CHD risk over 10 years . Secondary outcome measures include adherence to guidelines on CHD prevention practice . We documented the study design , methodology , and baseline sociodemographic , clinical and lifestyle characteristics of 419 participants . Results We achieved equal distributions of the sociodemographic , biophysical and lifestyle characteristics between the two r and omization groups . HTH participants had a mean age of 56 years , 63 % were Latinos/Hispanics , 65 % female , 61 % less educated , and 62 % were not employed . Twenty percent of participants reported having a prior  cardiovascular event . 10-year CHD risk averaged 18 % in men and 13 % in women despite a modest low-density lipoprotein cholesterol level and a high on-treatment percentage at baseline . Sixty-three percent of participants were diagnosed with diabetes and an additional 22 % had metabolic syndrome . In addition , many participants had depressed high-density lipoprotein ( HDL ) cholesterol levels and elevated values of total cholesterol-to-HDL ratio , triglycerides , triglyceride-to-HDL ratio , and blood pressure . Furthermore , nearly 70 % of participants were obese , 45 % had a family history of CHD or stroke , and 16 % were current smokers . Conclusion We have recruited an ethnically diverse , low-income cohort in which to implement a case management approach and test its efficacy and cost-effectiveness . HTH will advance the scientific underst and ing of better strategies for CHD prevention among these priority sub population s and aid in guiding future practice that will reduce health disparities BACKGROUND Previous trials have demonstrated that lowering low-density lipoprotein ( LDL ) cholesterol levels below currently recommended levels is beneficial in patients with acute coronary syndromes . We prospect ively assessed the efficacy and safety of lowering LDL cholesterol levels below 100 mg per deciliter ( 2.6 mmol per liter ) in patients with stable coronary heart disease ( CHD ) . METHODS A total of 10,001 patients with clinical ly evident CHD and LDL cholesterol levels of less than 130 mg per deciliter ( 3.4 mmol per liter ) were r and omly assigned to double-blind therapy and received either 10 mg or 80 mg of atorvastatin per day . Patients were followed for a median of 4.9 years . The primary end point was the occurrence of a first major cardiovascular event , defined as death from CHD , nonfatal non-procedure-related myocardial infa rct ion , resuscitation after cardiac arrest , or fatal or nonfatal stroke . RESULTS The mean LDL cholesterol levels were 77 mg per deciliter ( 2.0 mmol per liter ) during treatment with 80 mg of atorvastatin and 101 mg per deciliter ( 2.6 mmol per liter ) during treatment with 10 mg of atorvastatin . The incidence of persistent elevations in liver aminotransferase levels was 0.2 percent in the group given 10 mg of atorvastatin and 1.2 percent in the group given 80 mg of atorvastatin ( P<0.001 ) . A primary event occurred in 434 patients ( 8.7 percent ) receiving 80 mg of atorvastatin , as compared with 548 patients ( 10.9 percent ) receiving 10 mg of atorvastatin , representing an absolute reduction in the rate of major cardiovascular events of 2.2 percent and a 22 percent relative reduction in risk ( hazard ratio , 0.78 ; 95 percent confidence interval , 0.69 to 0.89 ; P<0.001 ) . There was no difference between the two treatment groups in overall mortality . CONCLUSIONS Intensive lipid-lowering therapy with 80 mg of atorvastatin per day in patients with stable CHD provides significant clinical benefit beyond that afforded by treatment with 10 mg of atorvastatin per day . This occurred with a greater incidence of elevated aminotransferase levels BACKGROUND The lowering of cholesterol concentrations in individuals at high risk of cardiovascular disease improves outcome . No study , however , has assessed benefits of cholesterol lowering in the primary prevention of coronary heart disease ( CHD ) in hypertensive patients who are not conventionally deemed dyslipidaemic . METHODS Of 19342 hypertensive patients ( aged 40 - 79 years with at least three other cardiovascular risk factors ) r and omised to one of two antihypertensive regimens in the Anglo-Sc and inavian Cardiac Outcomes Trial , 10305 with non-fasting total cholesterol concentrations 6.5 mmol/L or less were r and omly assigned additional atorvastatin 10 mg or placebo .  These patients formed the lipid-lowering arm of the study . We planned follow-up for an average of 5 years , the primary endpoint being non-fatal myocardial infa rct ion and fatal CHD . Data were analysed by intention to treat . FINDINGS Treatment was stopped after a median follow-up of 3.3 years . By that time , 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group ( hazard ratio 0.64 [ 95 % CI 0.50 - 0.83 ] , p=0.0005 ) . This benefit emerged in the first year of follow-up . There was no significant heterogeneity among prespecified subgroups . Fatal and non-fatal stroke ( 89 atorvastatin vs 121 placebo , 0.73 [ 0.56 - 0.96 ] , p=0.024 ) , total cardiovascular events ( 389 vs 486 , 0.79 [ 0.69 - 0.90 ] , p=0.0005 ) , and total coronary events ( 178 vs 247 , 0.71 [ 0.59 - 0.86 ] , p=0.0005 ) were also significantly lowered . There were 185 deaths in the atorvastatin group and 212 in the placebo group ( 0.87 [ 0.71 - 1.06 ] , p=0.16 ) . Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months , and by 1.1 mmol/L after 3 years of follow-up . INTERPRETATION The reductions in major cardiovascular events with atorvastatin are large , given the short follow-up time . These findings may have implication s for future lipid-lowering guidelines BACKGROUND Although diabetes is a major risk factor for coronary heart disease ( CHD ) , little information is available on the effects of lipid lowering in diabetic patients . We determined whether lipid-lowering treatment with pravastatin prevents recurrent cardiovascular events in diabetic patients with CHD and average cholesterol levels . METHODS AND RESULTS The Cholesterol And Recurrent Events ( CARE ) trial , a 5-year trial that compared the effect of pravastatin and placebo , included 586 patients ( 14.1 % ) with clinical diagnoses of diabetes . The participants with diabetes were older , more obese , and more hypertensive . The mean baseline lipid concentrations in the group with diabetes--136 mg/dL LDL cholesterol , 38 mg/dL HDL cholesterol , and 164 mg/dL triglycerides -- were similar to those in the nondiabetic group . LDL cholesterol reduction by pravastatin was similar ( 27 % and 28 % ) in the diabetic and nondiabetic groups , respectively . In the placebo group , the diabetic patients suffered more recurrent coronary events ( CHD death , nonfatal myocardial infa rct ion [ MI ] , CABG , and PTCA ) than did the nondiabetic patients ( 37 % versus 25 % ) . Pravastatin treatment reduced the absolute risk of coronary events for the diabetic and nondiabetic patients by 8.1 % and 5.2 % and the relative risk by 25 % ( P=0.05 ) and 23 % ( P<0.001 ) , respectively . Pravastatin reduced the relative risk for revascularization procedures by 32 % ( P=0.04 ) in the diabetic patients . In the 3553 patients who were not diagnosed as diabetic , 342 had impaired fasting glucose at entry defined by the American Diabetes Association as 110 to 125 mg/dL. These nondiabetic patients with impaired fasting glucose had a higher rate of recurrent coronary events than those with normal fasting glucose ( eg , 13 % versus 10 % for nonfatal MI ) . Recurrence rates tended to be lower in the pravastatin compared with placebo group ( eg , -50 % , P=0.05 for nonfatal MI ) . CONCLUSIONS Diabetic patients and nondiabetic patients with impaired fasting glucose are at high risk of recurrent coronary events that can be substantially reduced by pravastatin treatment Summary Background The lowering of cholesterol concentrations in individuals at high risk of cardiovascular disease improves outcome . No study , however , has assessed benefits of cholesterol lowering in the primary prevention of coronary heart disease ( CHD ) in hypertensive patients who are not conventionally deemed dyslipidaemic . Methods Of 19 342 hypertensive patients ( aged 40–79 years with at least three other cardiovascular risk factors ) r and omised to one of two antihypertensive regimens in the Anglo-Sc and inavian Cardiac Outcomes Trial , 10 305 with nonfasting total cholesterol concentrations 6.5 mmol/L or less were r and omly assigned additional atorvastatin 10 mg or placebo .  These patients formed the lipid-lowering arm of the study . We planned follow-up for an average of 5 years , the primary endpoint being non-fatal myocardial infa rct ion and fatal CHD . Data were analysed by intention to treat . Findings Treatment was stopped after a median follow-up of 3.3 years . By that time , 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group ( hazard ratio 0.64 [ 95 % CI 0.50–0.83 ] , p = 0.0005 ) . This benefit emerged in the first year of follow-up . There was no significant heterogeneity among prespecified subgroups . Fatal and non-fatal stroke ( 89 atorvastatin vs 121 placebo , 0.73 [ 0.56–0.96 ] , p = 0.024 ) , total cardiovascular events ( 389 vs 486 , 0.79 [ 0.69–0.90 ] , p = 0.0005 ) , and total coronary events ( 178 vs 247 , 0.71 [ 0.59–0.86 ] , p = 0.0005 ) were also significantly lowered . There were 185 deaths in the atorvastatin group and 212 in the placebo group ( 0.87 [ 0.71–1.06 ] , p = 0.16 ) . Atorvastatin  lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months , and by 1.1 mmol/L after 3 years of follow-up . Interpretation The reductions in major cardiovascular events with atorvastatin are large , given the short follow-up time . These findings may have implication s for future lipid-lowering guidelines Aim : It is not clear whether elevated serum non-high-density lipoprotein cholesterol  ( non-HDL-C ) levels are a risk factor for cardiovascular disease ( CVD ) in subjects with chronic kidney disease ( CKD ) in the general population . Methods : A total of 2,630 community-dwelling Japanese subjects ( 1,107 men and 1,523 women ) without history of CVD and aged ≥ 40 years were prospect ively followed up for an average of 19 years , and the association between serum non-HDL-C levels and the incidence of type-specific CVD was estimated using a Cox proportional hazards model . CKD was defined as estimated glomerular filtration rate < 60 mL/min/1.73 m2 or proteinuria ( ≥ 1 + on dipstick ) . Results : At baseline , 357 subjects had CKD . During the follow up , 186 coronary heart disease ( CHD ) and 277 stroke events occurred . The age- and sex-adjusted incidence of CHD was significantly higher in subjects with higher non-HDL-C levels , both in those with and without CKD . In the CKD group , the risk of CHD was significantly higher in those with non-HDL-C levels of 150–189 mg/dL [ adjusted hazard ratio ( HR ) , 2.23 ; 95 % confidence interval ( CI ) , 1.04–4.77 ] and those with levels ≥ 190 mg/dL ( adjusted HR , 3.20 ; 95 % CI , 1.46–7.03 ) than in those with levels < 150 mg/dL. In the non-CKD group , the risk of CHD was significantly higher only in those with non-HDL-C levels ≥ 190 mg/dL ( adjusted HR , 2.12 ; 95 % CI , 1.33 –3.38 ) . However , no such association was observed for the risk of stroke . Conclusions : Our findings suggest that higher serum non-HDL-C levels are associated with greater risk of CHD in subjects with and without CKD and that this association is greater in subjects with CKD  than in those without CKD Context National guidelines recommend aspirin or statin drugs individually to reduce first coronary heart disease ( CHD )  events , but there are no guidelines about taking both . Contribution The authors used a Markov model to estimate the cost-effectiveness of aspirin , statins , both drugs , or neither in men . In patients with a 10-year risk for CHD of 7.5 % , aspirin alone reduced costs and lengthened life compared with no treatment . Adding a statin cost $ 56200 per additional quality -adjusted life-year at a 7.5 % risk but only $ 42500 at a 10 % risk . Caution s The authors ' analysis was limited to men . Implication s Therapy with aspirin alone is effective and cost-effective in men with an average level of risk for CHD . The addition of a statin is more cost-effective as risk increases . The Editors Aspirin and statin drugs have been shown to be effective for preventing first coronary heart disease ( CHD ) events ( 1 - 3 ) . Systematic review s and meta-analyses suggest that the relative risk reductions with both forms of therapy are similar in magnitude and seem to be independent and relatively constant across the range of underlying risk for CHD ( 2 - 5 ) . The absolute benefit from these treatments seems to be proportional to the patient 's underlying risk for CHD . National treatment guidelines recommend aspirin and statin drugs individually for the primary prevention of cardiovascular events in men who are at increased risk ( 4 , 6 , 7 ) . However , no U.S. guidelines have addressed how these drugs should be used together , and we are unaware of any previous analyses that have reported the cost-effectiveness of these drugs when used in combination for CHD prevention . To help inform clinical and policy decisions about primary CHD prevention , we performed a costutility analysis that examined the use of aspirin therapy , statin therapy , or combination therapy with both drugs in men with various underlying levels of risk for CHD . Methods To examine the cost and utility associated with aspirin and with statin use , we used Microsoft Excel 2002 for Windows ( Microsoft Corp. , Redmond , Washington ) to develop a Markov state-transition model . The model was design ed to simulate cohorts of initially healthy middle-aged men with no history of cardiovascular events and with various levels of 10-year risk for CHD ( Figure 1 ) . Figure 1 . General structure of the Markov model . Base-Case Scenario In our base-case scenario , we compared the effectiveness of 10 years of aspirin therapy , statin therapy , combination therapy with both drugs , and no therapy in 45-year-old men with a 10-year risk for CHD of 7.5 % . After 10 years , both groups adopted the treatment used in the intervention group . Although the differences in therapy were maintained for only 10 years , we examined the effects of these therapies over a lifetime . Model Assumptions All persons were initially healthy and progressed through the model in annual cycles . In each cycle , an individual remained healthy , had an initial cardiovascular event ( angina , myocardial infa rct ion , or stroke ) , experienced adverse effects from therapy ( gastrointestinal bleeding from aspirin or myopathy from statins ) , or died . We assumed that those who had cardiovascular events or adverse events stayed in the subacute state for the remainder of that cycle and then entered a postevent state . Adherence to treatment was assumed to be 100 % in the absence of adverse effects , although the treatment efficacy data were based on the actual rates of adherence in the clinical trials . Persons who had adverse effects from therapy stopped taking the offending medication ; their procession through the model was similar to that of healthy patients after the initial cycle . All costs and outcomes were discounted at 3 % in accordance with current consensus recommendations ( 8) . Model Parameters Model parameters , including base-case values , ranges , and references , are shown in Table 1 ( 1 - 3 , 9 - 29 ) . Table 1 . Base-Case Estimates and Ranges Used in Sensitivity Analyses Noncardiovascular Mortality Age-dependent noncardiovascular mortality rates were estimated from the National Vital Statistics life tables ( 31 ) . Rates were adjusted as the cohort aged over the time horizon of the analysis . Cardiovascular Event Rates Baseline risks for initial cardiovascular events ( myocardial infa rct ion , stroke , angina , and death from CHD ) were drawn from Framingham risk equations by using hypothetical scenarios of nonsmoking , nonhypertensive , nondiabetic men at different levels of risk for CHD ( Appendix Table ) ( 32 ) . Assuming an exponential distribution , we translated these 10-year risks into annual event-related transition probabilities . These probabilities were allowed to change over time to reflect increasing risk for CHD over the time horizon of the analysis . Appendix Table . Sample Baseline Characteristics of 45-Year-Old Men by Risk Level Because we were interested in primary prevention , we did not simulate or examine the details of a patient 's course after a primary , nonfatal event . Instead , we assigned them an increased risk for death , increased costs , and decreased utilities by using data from the literature regarding the average experience of patients after an initial event . The increased relative risk for death after an initial event ( Table 1 ) was drawn from population -based studies in the United Kingdom ( 12 , 16 ) and applied to the general mortality rates from the U.S. life tables to generate the estimated postevent mortality rates . We modified these event rates by assuming that all patients received optimal secondary prevention . Adverse Effects The excess risks for gastrointestinal bleeding with aspirin use and for myopathy with statin use were drawn from systematic review s of r and omized trials and a recent secondary data analysis ( 2 , 26 , 27 ) . Risks for gastrointestinal bleeding and myopathy in untreated patients were assumed to be zero so that only treatment-induced adverse events were counted . Because better data were not available , we estimated the risks for death from aspirin-related gastrointestinal bleeding and statin-induced myopathy and varied them in sensitivity analysis . Patients who had nonfatal adverse effects were not given therapy with alternate agents for primary prevention of CHD . Modeling Stroke Because many r and omized trials of aspirin prophylaxis did not distinguish by stroke type , we had difficulty estimating the precise effect of aspirin on ischemic and hemorrhagic strokes ( 30 ) . To account for this limitation , we used 2 approaches to model the effect of aspirin on stroke . In the base-case analysis , we followed the approach that was used in a recent meta- analysis ( 9 ) by including hemorrhagic stroke and ischemic stroke together in 1 estimate of the effect of aspirin on total stroke ( relative risk for stroke with aspirin , 1.06 ) . In an alternate scenario , we modeled hemorrhagic stroke and ischemic stroke as separate health states . We assumed that aspirin was associated with an excess annual risk of 20 hemorrhagic strokes per 100000 users on the basis of published meta-analyses and that one third of these hemorrhagic strokes would be fatal ( 19 , 30 , 33 ) . We conservatively assumed that aspirin had no effect on ischemic stroke ( 30 ) . The costs and utilities of ischemic stroke and hemorrhagic stroke were also considered separately . Treatment Efficacy We used summary relative risk estimates from existing meta-analyses or relative risks from individual trials to estimate the efficacy of aspirin and statin therapy , either alone or in combination , for preventing CHD events ( 3 , 24 , 29 ) . Where data were limited , we made conservative assumptions . The efficacy of the combined use of aspirin and statins was assumed to be independent on the basis of data from secondary prevention trials ( 5 ) . We did not model the effect of aspirin or statins on initial use of revascularization procedures in the absence of a cardiovascular event . All patients who survived an initial cardiovascular event were assumed to have received secondary preventive therapy with aspirin and a statin or with an alternate agent if  they could not tolerate  aspirin  or  statins . The effect of treatments on all-cause mortality was estimated from meta-analyses of secondary prevention trials ( 18 - 20 ) . Costs We conducted our analysis from the perspective of a third-party payer . State costs ( Table 1 ) , which were derived from data from the published literature and several recent national data bases , are expressed in 2003 dollars . To estimate the costs during the year in which an event occurred , we estimated acute care costs by drawing on data regarding hospital charges from the Healthcare Utilization Project data base and by converting these values to costs . To convert hospital charges to costs , we used the 1999 cost-to-charge ratio value of 0.4501 , which was derived from the Medicare Provider Analysis and Review of short-stay hospitals ( 28 ) . We then used the Medical Consumer Price Index to generate an inflation factor of 1.195 , which was applied to the 1999 cost figure to convert 1999 dollars to 2003 dollars ( 17 ) . In addition to the acute care costs , we assumed that each patient who survived an acute event would also incur one half of the estimated ongoing annual costs of care for the first year . Costs for subsequent years were based on ongoing costs of care that were drawn from the medical literature ( 22 - 25 ) . Drug costs were obtained from the 2003 Red Book average wholesale prices ( 21 ) . For our base-case analysis , we set the annual  statin cost to $ 730 by averaging the Red Book prices of simvastatin ( $ 922 for 10 mg/d ) and lovastatin ( $ 503 for 10 mg/d ) . The base-case cost of aspirin was based on an annual cost of $ 16 for Bayer aspirin ( Bayer Healthcare LLC , Morristown , New Jersey ) . The annual cost of generic aspirin  was estimated at approximately $ 6 ( 21 ) . We varied the costs of each drug over wide ranges in sensitivity analysis . To check our cost estimates , we compared our derived values with other cost estimates Summary Background : Atorvastatin is very effective in reducing plasma low-density lipoprotein cholesterol ( LDL-C ) levels . However , there is no long-term survival study that evaluated this statin . Patients − Methods : To assess the effect of atorvastatin on morbidity and mortality ( total and coronary ) of patients with established coronary heart disease ( CHD ) , 1600 consecutive patients were r and omised either to  atorvastatin  or to  ' usual ' medical care . The dose of atorvastatin was titrated from 10 to 80mg/day , in order to reach the National Cholesterol Education Program ( NCEP ) goal of LDL-C < 100mg/dl ( 2.6mmol/l ) . All patients were followed up for a mean period of 3 years . Main Outcome Measures : Primary endpoints of the study were defined as death , non-fatal myocardial infa rct ion , unstable angina , congestive heart failure , revascularisation ( coronary morbidity ) and stroke . Secondary endpoints were the safety and efficacy of the hypolipidaemic drugs as well as the cost-effectiveness of atorvastatin . Results : The mean dosage of atorvastatin was 24 mg/day . This statin reduced total cholesterol by 36 % , LDL-C by 46 % , triglycerides by 31 % , and non-high-density lipoprotein cholesterol ( non-HDL-C ) by 44 % , while it increased HDL-C by 7 % ; all these changes were significant . The NCEP LDL-C and non-HDL-C treatment goals were reached by 95 % ( n = 759 ) and 97 % ( n = 776 ) , respectively , of patients on atorvastatin . Only 14 % of the ' usual ' care patients received any hypolipidaemic drugs throughout the study and 3 % of them reached the NCEP LDL-C treatment goal . The cost per quality -adjusted life-year gained with atorvastatin was estimated at $ US 8350 . During this study 196 ( 24.5 % ) CHD patients on ' usual ' care had a CHD recurrent event or died vs. 96 ( 12 % ) CHD patients on atorvastatin ; risk ratio ( RR ) 0.49 , confidence interval ( CI ) 0.27 - 0.73 , p < 0.0001 . In detail , atorvastatin reduced , in comparison to ' usual ' care , total mortality ( RR 0.57 , CI 0.39 - 0.78 , p = 0.0021 ) , coronary mortality ( RR 0.53 , CI 0.29 - 0.74 , p = 0.0017 ) , coronary morbidity ( RR 0.46 , CI 0.25 - 0.71 , p < 0.0001 ) , and stroke ( RR 0.53 , CI 0.30 - 0.82 , p = 0.034 ) . All subgroups of patients ( women , those with diabetes mellitus , arterial hypertension , age 60 to 75 years , congestive heart failure , recent unstable angina or prior revascularisation ) benefited from treatment with atorvastatin . Withdrawal of patients because of side-effects from the atorvastatin group was low ( 0.75 % ) and similar to that of the ' usual ' care group ( 0.4 % ) . Conclusions : Long-term treatment of CHD patients with atorvastatin  to achieve NCEP lipid targets significantly reduces total and coronary mortality , coronary morbidity and stroke , in comparison to patients receiving ' usual ' medical care . Treatment with atorvastatin is well tolerated and cost-effective
There is evidence that statin therapy in patients with a history of ischaemic stroke or TIA significantly reduces subsequent major coronary events but only marginally reduces the risk of stroke recurrence .
There is no clear evidence of beneficial effect from statins in those with previous haemorrhagic stroke and it is unclear whether statins should be started immediately post stroke or later .
BACKGROUND Studies have shown that interventions which reduce total and low-density lipoprotein cholesterol levels also reduce coronary heart disease ( CHD ) and stroke events in those with a history of CHD .
However , it is uncertain whether treatment to alter cholesterol levels can prevent recurrence of either stroke or subsequent cardiovascular events and whether differences in outcomes exist between classes of lipid-lowering therapy .
This is an up date of a Cochrane review first published in 2002 .
OBJECTIVES To investigate the effect of altering serum lipids pharmacologically for preventing subsequent cardiovascular disease and stroke recurrence in patients with a history of stroke .