Safety of continuous anticoagulation with dabigatran during implantation of cardiac rhythm devices. Dual antiplatelet therapy versus oral anticoagulation plus dual antiplatelet therapy in patients with atrial fibrillation and low-to-moderate thromboembolic risk undergoing coronary stenting: design of the MUSICA-2 randomized trial. Apixaban versus Antiplatelet drugs or no antithrombotic drugs after anticoagulation-associated intraCerebral HaEmorrhage in patients with Atrial Fibrillation (APACHE-AF): study protocol for a randomised controlled trial Anticoagulation therapy for the prevention of hemodialysis tunneled cuffed catheter (TCC) thrombosis Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance. Evaluation of the safety and efficacy of an edoxaban‐based antithrombotic regimen in patients with atrial fibrillation following successful percutaneous coronary intervention (PCI) with stent placement: Rationale and design of the ENTRUST‐AF PCI trial Outcome of patients on oral anticoagulation undergoing coronary artery stenting: data from discharge to 12 months in the Warfarin and Coronary Stenting (WAR-STENT) Registry. Antithrombotic therapy in elderly patients with atrial fibrillation: effects and bleeding complications: a stratified analysis of the NASPEAF randomized trial. [Study of combined anticoagulant (fluindione)-aspirin therapy in patients with atrial fibrillation at high risk for thromboembolic complications. A randomized trial (FFAACS)]. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. Legacy Effect of Delayed Blood Pressure-Lowering Pharmacotherapy in Middle-Aged Individuals Stratified by Absolute Cardiovascular Disease Risk: Protocol for a Systematic Review Anticoagulant therapy in cerebral infarction Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. Platelet activation is a preoperative risk factor for the development of thromboembolic complications in patients with continuous‐flow left ventricular assist device Antithrombotic management and 1-year outcome of patients on oral anticoagulation undergoing coronary stent implantation (from the Registro Regionale Angioplastiche Emilia-Romagna Registry). The Long-Term Clinical Course of Acute Deep Venous Thrombosis Trial Protocol: A randomised controlled trial of extended anticoagulation treatment versus routine anticoagulation treatment for the prevention of recurrent VTE and post thrombotic syndrome in patients being treated for a first episode of unprovoked VTE (The ExACT Study) [A longitudinal study on left atrial thrombosis in patients with non-rheumatic atrial fibrillation treated with anticoagulants]. Rationale and design of MANJUSRI trial: a randomized, open-label, active-controlled multicenter study to evaluate the safety of combined therapy with ticagrelor and warfarin in AF subjects after PCI-eS. Subgroup and per-protocol analysis of the randomized European Trial on Isolated Systolic Hypertension in the Elderly. close: Closure of patent foramen ovale, oral anticoagulants or antiplatelet therapy to prevent stroke recurrence: Study design Rationale and design of the dual antiplatelet therapy study, a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy in subjects undergoing percutaneous coronary intervention with either drug-eluting stent  Self-management of oral anticoagulation reduces major outcomes in the elderly. A randomized controlled trial. Effectiveness of blood pressure-lowering drug treatment by levels of absolute risk: post hoc analysis of the Australian National Blood Pressure Study Long-Term Outcome after Anticoagulation-Associated Intracerebral Haemorrhage with or without Restarting Antithrombotic Therapy Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin Anticoagulant (Fluindione)-Aspirin Combination in Patients with High-Risk Atrial Fibrillation Standardized Bleeding Definitions for Cardiovascular Clinical Trials: A Consensus Report From the Bleeding Academic Research Consortium Indobufen versus warfarin in the secondary prevention of major vascular events in nonrheumatic atrial fibrillation. SIFA (Studio Italiano Fibrillazione Atriale) Investigators. Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Extended Oral Anticoagulant Therapy after a First Episode of Pulmonary Embolism Efficacy and safety of percutaneous left atrial appendage closure to prevent thromboembolic events in atrial fibrillation patients with high stroke and bleeding risk Dabigatran etexilate shows at least similar effect compared with enoxaparin in prevention of embolic thromboembolism following total hip arthroplasty: (RENOVATE 2 trial). Controlling hypertension and hypotension immediately post stroke (CHHIPS)--a randomised controlled trial. Risk of major haemorrhage in patients after infrainguinal venous bypass surgery: therapeutic consequences? The Dutch BOA (Bypass Oral Anticoagulants or Aspirin) Study. Renal function and intensive lowering of blood pressure in hypertensive participants of the hypertension optimal treatment (HOT) study. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). Comparison of 3 and 6 Months of Oral Anticoagulant Therapy After a First Episode of Proximal Deep Vein Thrombosis or Pulmonary Embolism and Comparison of 6 and 12 Weeks of Therapy After Isolated Calf Deep Vein Thrombosis Aspirin and clopidogrel with or without phenprocoumon after drug eluting coronary stent placement in patients on chronic oral anticoagulation. Home Therapy With LMWH in Deep Vein Thrombosis: Randomized Study Comparing Single and Double Daily Administrations Assessment of the novel selective aldosterone blocker eplerenone using ambulatory and clinical blood pressure in patients with systemic hypertension. Impact of elevated blood pressure on mortality from all causes, cardiovascular diseases, heart disease and stroke among Japanese: 14 year follow-up of randomly selected population from Japanese — Nippon data 80 PROTHROMBINEX(®)-VF (PTX-VF) usage for reversal of coagulopathy: prospective evaluation of thrombogenic risk. High risk of thromboemboli early after bioprosthetic cardiac valve replacement. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT) The Anticoagulation of Calf Thrombosis (ACT) project: study protocol for a randomized controlled trial Residual Venous Thrombosis as a Predictive Factor of Recurrent Venous Thromboembolism Prevention of Bleeding in Patients With Atrial Fibrillation Undergoing PCI (PIONEER): Three May End Up Being a Crowd Thromboembolic stroke in patients with a HeartMate-II left ventricular assist device – the role of anticoagulation Pharmacomechanical Catheter‐Directed Thrombolysis for Deep‐Vein Thrombosis Double-blind randomised trial of very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer Prevention of hypertension in patients with pre-hypertension: protocol for the PREVER-prevention trial EDUC’AVK: Reduction of Oral Anticoagulant-related Adverse Events After Patient Education: A Prospective Multicenter Open Randomized Study New antiplatelet therapies in development. A double-blind randomized comparison of combined aspirin and ticlopidine therapy versus aspirin or ticlopidine alone on experimental arterial thrombogenesis in humans. Selecting an anticoagulant for recurrent venous thromboembolism in cancer. Morbidity and mortality in 229 elderly patients with nonrheumatic atrial fibrillation. A five-year follow-up. Long‐term health outcome and mortality evaluation after invasive coronary treatment using drug eluting stents with or without the IVUS guidance. Randomized control trial. HOME DES IVUS Global Risk Assessment to Guide Blood Pressure Management in Cardiovascular Disease Prevention
The perioperative bleeding risk associated with therapeutic anticoagulation at cardiac implantable electronic device implantation has previously been demonstrated to vary by the specific anticoagulant used . Although uninterrupted anticoagulation with warfarin appears to be safe , heparin products have been shown to increase the risk of perioperative bleeding . However , the risk associated with cardiac implantable electronic device implantation with anticoagulation using dabigatran , a novel oral direct thrombin inhibitor , is not known . We performed a prospect i ve observational study of patients receiving dabigatran for anticoagulation who underwent cardiac implantable electronic device implantation from June 2011 through May 2012 . The study end points included thromboembolic and bleeding complications within 30 days of surgery . Major bleeding complications were defined as bleeding requiring surgical intervention , prolongation of hospitalization , and discontinuation of the anticoagulant or transfusion of blood products within 30 days of surgery . Minor bleeding complications included the development of a hematoma not requiring additional intervention . The thrombotic end points included stroke , transient ischemic attack , myocardial infa rct ion , pulmonary embolism , and deep vein thrombosis .  A total of 25 patients were identified for inclusion . During the index hospitalization , no thromboembolic or bleeding complications developed . No major bleeding complications occurred within 30 days of surgery . One minor bleeding event ( 4 % ) occurred within 30 days of surgery in 1 patient who was also receiving dual antiplatelet therapy . In conclusion , although no thromboembolic or major bleeding events were observed , additional studies are required to define the optimal antithrombotic management in the perioperative period BACKGROUND Oral anticoagulation ( OAC ) is the recommended therapy for patients with atrial fibrillation ( AF ) because it reduces the risk of stroke and other thromboembolic events . Dual antiplatelet therapy ( DAPT ) is required after percutaneous coronary intervention and stenting ( PCI-S ) . In patients with AF requiring PCI-S  , the association of DAPT and OAC carries an increased risk of bleeding , whereas OAC therapy or DAPT alone may not protect against the risk of developing new ischemic or thromboembolic events . OBJECTIVE The MUSICA-2 study will test the hypothesis that DAPT compared with triple therapy ( TT ) in patients with nonvalvular AF at low-to-moderate risk of stroke ( CHADS2 score ≤2 ) after PCI-S reduces the risk of bleeding and is not inferior to TT for preventing thromboembolic complications . DESIGN The MUSICA-2 is a multicenter , open-label r and omized trial that will compare TT with DAPT in patients with AF and CHADS2 score ≤2 undergoing PCI-S.  The primary end point is the incidence of stroke or any systemic embolism or major adverse cardiac events : death , myocardial infa rct ion , stent thrombosis , or target vessel revascularization at 1 year of PCI-S. The secondary end point is the combination of any cardiovascular event with major or minor bleeding at 1 year of PCI-S. The calculated sample size is 304 patients . CONCLUSIONS The MUSICA-2 will attempt to determine the most effective and safe treatment in patients with nonvalvular AF and CHADS2 score ≤2 after PCI-S. Restricting TT for AF patients at high risk for stroke may reduce the incidence of bleeding without increasing the risk of thromboembolic complications Background There is a marked lack of evidence on the optimal prevention of ischaemic stroke and other thromboembolic events in patients with non-valvular atrial fibrillation and a recent intracerebral haemorrhage during treatment with oral anticoagulation .  These patients are currently treated with oral anticoagulants , antiplatelet drugs , or no antithrombotic treatment , depending on personal and institutional preferences . Compared with warfarin , the direct oral anticoagulant apixaban reduces the risk of stroke or systemic embolism , intracranial haemorrhage , and case fatality in patients with atrial fibrillation . Compared with aspirin , apixaban reduces the risk of stroke or systemic embolism in patients with atrial fibrillation , and has a similar risk of intracerebral haemorrhage . Novel oral anticoagulants have not been evaluated in patients with atrial fibrillation and a recent intracerebral haemorrhage . To inform a phase III trial , the phase II Apixaban versus Antiplatelet drugs or no antithrombotic drugs after anticoagulation-associated intraCerebral HaEmorrhage in patients with Atrial Fibrillation ( APACHE-AF ) trial aims to obtain estimates of the rates of vascular death or non-fatal stroke in patients with atrial fibrillation and a recent anticoagulation-associated intracerebral haemorrhage treated with apixaban and in those in whom oral anticoagulation is avoided . Methods / Design APACHE-AF is a phase II , multicentre , open-label , parallel-group , r and omised clinical trial with masked outcome assessment . One hundred adults with a history of atrial fibrillation and a recent intracerebral haemorrhage during treatment with anticoagulation in whom clinical equipoise exists on the optimal stroke prevention strategy will be enrolled in 14 hospitals in The Netherl and s . These patients will be r and omly assigned in a 1:1 ratio to either apixaban or to avoiding oral anticoagulation . Patients in the control group may be treated with antiplatelet drugs at the discretion of the treating physician . The primary outcome is the composite of vascular death or non-fatal stroke during follow-up . We aim to include 100 patients in 2.5 years . All patients will be followed-up for the duration of the study , but at least for 1 year . Recruitment commenced in September 2014 and is ongoing . This trial is funded by the Dutch Heart Foundation ( 2012 T077 ) and ZonMW (015008048).Trial registration NTR4526 ( 16 April 2014 ) Background Chronic oral anticoagulation is currently used to avoid thrombosis and the malfunction of tunneled cuffed catheters ( TCCs ) for hemodialysis ( HD ) . The aim of the study was to assess the efficacy of early warfarin administration , after TCC placement , in comparison to its administration after the first thrombosis or malfunction event of the TCC . Patients and methods One hundred and forty-four chronic dialysis patients , who underwent TCC placement between June 2001 and June 2005 , were r and omized into two groups : 81 patients , group A , started oral anticoagulation 12 hr after the TCC placement ( target international normalized ratio ( INR ) 1.8–2.5 ) , in association with ticlopidine 250 mg/die ; 63 patients , group B , started warfarin after the first thrombosis/malfunction episode ( target INR 1.8–2.5 ) in association with ticlopidine 250 mg/die . The efficacy of oral anticoagulation therapy in preventing TCC thrombotic complications was evaluated in a 12-month follow-up period , after TCC placement , in terms of : a ) the number of patients with thrombotic-malfunction events ; b ) the number of thrombotic-malfunction events with urokinase infusion ( events/patient/year ) ; c ) intradialytic blood flow rate ( BFR , ml/min ) ; d ) negative blood pressure ( BP ) from the arterial line of the TCC ( AP , mmHg ) ; e ) positive BP , in the extracorporeal circuit from the venous line ( VP , mmHg ) ; and f ) bleeding complications . Results Ten patients ( 12 % ) in group A showed TCC thrombosis/malfunction vs. 33 patients ( 52 % ) in group B ( p<0.01 ) . In group A , 0.16 events of thrombosis/malfunction per patient/year vs. 1.65 in group B ( p<0.001 ) were observed . BFR was respectively 305 ± 34 vs. 246 ± 42 ml/min ( p<0.001 ) . AP was –124 ± 13 in group A vs. –174 ± 21 mmHg in group B ( p<0.05 ) . VP was 112 ± 28 in group A vs. 168 ± 41 mmHg in group B ( p<0.05 ) . No patient showed any bleeding events .  Conclusions Early warfarin therapy allows a significant reduction in TCC thrombotic complications and an improvement in both arterial and venous fluxes in comparison with the same therapy administered after the first TCC thrombotic/malfunction event . This therapy did not induce any bleeding complications in the patients included in the study BACKGROUND The placement of stents in coronary arteries has been shown to reduce restenosis in comparison to balloon angioplasty . However , clinical use of intracoronary stents is impeded by the risk of subacute stent thrombosis and complications associated with the anticoagulant regimen . To reduce these complications , the hypothesis that systemic anticoagulation is not necessary when adequate stent expansion is achieved was prospect ively evaluated on a consecutive series of patients who received intracoronary stents .  METHODS AND RESULTS From March 1993 to January 1994 , 359 patients underwent Palmaz-Schatz coronary stent insertion .  After an initial successful angiographic result with < 20 % stenosis by visual estimation had been achieved , intravascular ultrasound imaging was performed . Further balloon dilatation of the stent was guided by observation of the intravascular ultrasound images . All patients with adequate stent expansion confirmed by ultrasound were treated only with antiplatelet therapy ( either ticlopidine for 1 month with short-term aspirin for 5 days or only aspirin ) after the procedure . Clinical success ( procedure success without early postprocedural events ) at 2 months was achieved in 338 patients ( 94 % ) . With an inflation pressure of 14.9 + /- 3.0 atm and a balloon-to-vessel ratio of 1.17 + /- 0.19 , optimal stent expansion was achieved in 321 of the 334 patients ( 96 % ) who underwent intravascular ultrasound evaluation , with these patients receiving only antiplatelet therapy after the procedure . Despite the absence of anticoagulation , there were only two acute stent thromboses ( 0.6 % ) and one subacute stent thrombosis ( 0.3 % ) at 2-month clinical follow-up . Follow-up angiography at 3 to 6 months documented two additional occlusions ( 0.6 % ) at the stent site . At 6-month clinical follow-up , angiographically documented stent occlusion had occurred in 5 patients ( 1.6 % ) . At 6-month clinical follow-up , there was a 5.7 % incidence of myocardial infa rct ion , a 6.4 % rate of coronary bypass surgery , and a 1.9 % incidence of death . Emergency intervention ( emergency angioplasty or bailout stent ) for a stent thrombosis event was performed in 3 patients ( 0.8 % ) . The overall event rate was relatively high because of intraprocedural complications that occurred in 16 patients ( 4.5 % ) . Intraprocedural complications , however , decreased to 1 % when angiographically appropriately sized balloons were used for final stent dilations . There was one ischemic vascular complication that occurred at the time of the procedure and one ischemic vascular complication that occurred at the time of angiographic follow-up . By 6 months , repeat angioplasty for symptomatic restenosis was performed in 47 patients ( 13.1 % ) . CONCLUSIONS The Palmaz-Schatz stent can be safely inserted in coronary arteries without subsequent anticoagulation provided that stent expansion is adequate and there are no other flow-limiting lesions present . The use of high-pressure final balloon dilatations and confirmation of adequate stent expansion by intravascular ultrasound provide assurance that anticoagulation therapy can be safely omitted . This technique significantly reduces hospital time and vascular complications and has a low stent thrombosis rate Background The optimal antithrombotic treatment after percutaneous coronary intervention ( PCI ) with stenting in patients with atrial fibrillation ( AF ) is unknown . In the ENGAGE AF‐TIMI 48 trial , edoxaban was noninferior to a vitamin K antagonist ( VKA ) with respect to the prevention of stroke or systemic embolism and was associated with significantly lower rates of bleeding and cardiovascular death in patients with nonvalvular AF . The effects of edoxaban in combination with single‐ or dual‐antiplatelet therapy in the setting of PCI are unexplored . Design The ENTRUST‐AF PCI trial is a multinational , multicenter , r and omized , open‐label phase 3b trial with blinded end point evaluation involving 1,500 patients on oral anticoagulation for AF . Patients are r and omized between 4 hours and 5 days after successful PCI to either an edoxaban‐based strategy ( experimental arm ; 60 mg [ or 30 mg according to dose reduction criteria ] once daily plus a P2Y12 antagonist [ default clopidogrel , 75 mg once daily ] for 12 months ) or a VKA‐based strategy ( control arm ; VKA plus a P2Y12 antagonist [ as above ] plus acetylsalicylic acid [ 100 mg once daily ] for 30 days to 12 months ) . The primary safety end point is the incidence of International Society on Thrombosis and Haemostasis – defined major or clinical ly relevant nonmajor bleeding . The main efficacy end point is the composite of cardiovascular death , stroke , systemic embolic events , spontaneous myocardial infa rct ion , and definite stent thrombosis . Summary The ENTRUST‐AF PCI trial tests the hypothesis that an edoxaban‐based antithrombotic strategy reduces the risk of bleeding complications after PCI compared with VKA plus conventional dual‐antiplatelet therapy in patients with AF in need of oral anticoagulation . The relative risk of ischemic events between groups will be compared OBJECTIVES To obtain further , and more focused , information on the efficacy and safety of the antithrombotic regimens , including triple therapy ( TT ) of warfarin , aspirin , and clopidogrel ; dual therapy ( DT ) of warfarin and single antiplatelet agent ( aspirin or clopidogrel ) ; and dual-antiplatelet therapy ( DAPT ) of aspirin and clopidogrel , prescribed to patients on oral anticoagulation ( OAC ) undergoing percutaneous coronary intervention with stent ( PCI-S ) . BACKGROUND The true efficacy and safety of TT , DT , and DAPT in OAC patients undergoing PCI-S is largely undefined . METHODS We analyzed the data base of the prospect i ve , multicenter WARfarin and coronary STENTing ( WAR-STENT ) registry ( Clinical Trials.gov identifier NCT00722319 ) , only including the post-discharge period . RESULTS Of the 401 patients discharged alive from index hospitalization , 339 ( 85 % ) , 20 ( 5 % ) , and 42 ( 10 % ) were prescribed TT , DT , and DAPT , respectively . Throughout a mean follow-up of 368.3 ± 22.8 days , major adverse cardiovascular events ( MACE ) ( including cardiovascular death , myocardial infa rct ion , repeat revascularization , stent thrombosis , and thromboembolism ) , total bleeding , major bleeding , and combination of MACE plus total bleeding were comparable across the three treatment groups . The absolute rate of major bleeding with TT was 4 % . The antithrombotic treatment actually ongoing at major bleeding was TT in 44 % , DT in 50 % , and DAPT in 6 % of cases . CONCLUSION In the real-world population of OAC patients undergoing PCI-S in the WAR-STENT registry , the three antithrombotic regimens of TT , DT , and DAPT showed comparable efficacy and safety . Due to several limitations , our data can not be considered conclusive in confuting the current recommendations to prescribe TT . Further properly design ed and sized studies are warranted AIMS Atrial fibrillation patients with prior embolism have a high risk of vascular events in spite of anticoagulant therapy and elderly patients carry an additional risk . We analysed and compared vascular events-rate between older and younger than 75 years atrial fibrillation patients r and omized to anticoagulant-alone or combined antiplatelet plus moderate-level anticoagulant therapy . METHODS AND RESULTS A total of 967 patients stratified by age and the history of prior embolism were r and omized to therapeutic doses of anticoagulant-alone or combined antithrombotic therapy . Primary events were fatal and non-fatal ischaemic or haemorrhagic stroke/transient ischaemic attack , systemic embolism and myocardial infa rct ion , sudden death and death from bleeding . The elderly , compared with the younger patients , had higher event-rate [ hazard ratio 2.31 ( 95 % confidence interval 1.37 - 3.90 ) , P < 0.003 ] . The elderly suffered higher severe bleeding event-rate during anticoagulant therapy . The combined , compared with the anticoagulant therapy , reduced the vascular events-rate in the elderly ( P = 0.012 ) and caused less intracranial haemorrhages and less bleeding mortality , although more non-fatal gastric bleeding . CONCLUSION The elderly with AF had a higher event-rate than the younger patients . A higher severe bleeding event-rate was also registered in elderly patients receiving anticoagulant therapy .  Combined , compared with anticoagulant therapy , significantly reduced vascular events and bleeding mortality in elderly patients BACKGROUND A combination of low-dose aspirin ( A ) and anticoagulation ( AC ) may provide better protection against thromboembolic events compared with AC alone in high-risk patients with atrial fibrillation ( AF ) . METHODS We performed a multicentric placebo-controlled double blind-trial to test the preventive efficacy against thromboembolic events of the addition of aspirin ( A ) ( 100 mg ) or placebo ( P ) to anticoagulant treatment in patients with high-risk atrial fibrillation . A total of 157 patients were included , with atrial fibrillation and previous thromboembolic event or older than 65 years with either a history of hypertension , a recent episode of heart failure or a left ventricular dysfunction . All patients received fluindione ( F ) and P or F and A , with an INR target between 2 and 2.6 . The primary endpoint was a combined endpoint of stroke ( ischaemic or haemorrhagic ) , myocardial infa rct ion , systemic arterial emboli or vascular death . RESULTS The study had to be stopped prematurely owing to a too low recruitment rate . During follow-up ( 0.84 years ) 3 non-fatal thromboembolic events were recorded ( 1P , 2A ) and 6 patients died ( 3P , 3A ) , none of them from a thromboembolic complication . However , 3 deaths were secondary to severe haemorrhagic complications ( 1P , 2A ) . Non-fatal haemorrhagic complications occurred more often in group A ( n = 10 , 13.1 pour cent ) compared with group P ( n = 1 , 1.2 pour cent ) , p = 0.003 . CONCLUSION The FFAACS study was not able to show any therapeutic benefit from the addition of aspirin to anticoagulant in patients with high-risk AF . Such a combination increased the incidence rate of bleeding complications , which therefore greatly reduces its potential overall benefit BACKGROUND Dual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications , yet the benefits and risks of treatment beyond 1 year are uncertain . METHODS Patients were enrolled after they had undergone a coronary stent procedure in which a drug-eluting stent was placed . After 12 months of treatment with a thienopyridine drug ( clopidogrel or prasugrel ) and aspirin , patients were r and omly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months ; all patients continued receiving aspirin . The co primary efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events ( a composite of death , myocardial infa rct ion , or stroke ) during the period from 12 to 30 months . The primary safety end point was moderate or severe bleeding . RESULTS A total of 9961 patients were r and omly assigned to continue thienopyridine treatment or to receive placebo . Continued treatment with thienopyridine , as compared with placebo , reduced the rates of stent thrombosis ( 0.4 % vs. 1.4 % ; hazard ratio , 0.29 [ 95 % confidence interval { CI } , 0.17 to 0.48 ] ; P<0.001 ) and major adverse cardiovascular and cerebrovascular events ( 4.3 % vs. 5.9 % ; hazard ratio , 0.71 [ 95 % CI , 0.59 to 0.85 ] ; P<0.001 ) . The rate of myocardial infa rct ion was lower with thienopyridine treatment than with placebo ( 2.1 % vs. 4.1 % ; hazard ratio , 0.47 ; P<0.001 ) . The rate of death from any cause was 2.0 % in the group that continued thienopyridine therapy and 1.5 % in the placebo group ( hazard ratio , 1.36 [ 95 % CI , 1.00 to 1.85 ] ; P=0.05 ) . The rate of moderate or severe bleeding was increased with continued thienopyridine treatment ( 2.5 % vs. 1.6 % , P=0.001 ) . An elevated risk of stent thrombosis and myocardial infa rct ion was observed in both groups during the 3 months after discontinuation of thienopyridine treatment . CONCLUSIONS Dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent , as compared with aspirin therapy alone , significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding . ( Funded by a consortium of eight device and drug manufacturers and others ; DAPT Clinical Trials.gov number , NCT00977938 . ) Background Many national and international guidelines recommend that the initiation of blood pressure (BP)-lowering drug treatment for the primary prevention of cardiovascular disease ( CVD ) should no longer be based on BP level alone , but on absolute cardiovascular risk . While BP-lowering drug treatment is beneficial in high-risk individuals at any level of elevated BP , clinicians are concerned about legacy effects on patients with low-to-moderate risk and mildly elevated BP who remain “ untreated ” . Objective We aim to investigate the legacy effect of delayed BP-lowering pharmacotherapy in middle-aged individuals ( 45 - 65 years ) with mildly elevated BP ( systolic BP 140 - 159 mmHg and /or diastolic BP 90 - 99 mmHg ) stratified by absolute risk for primary prevention of CVD , but particularly in the low-risk ( < 10 % five-year absolute risk ) group . Methods R and omized trials of BP-lowering therapy versus placebo or pretreated subjects in active comparator studies with posttrial follow-up will be identified using a 2-step process . First , r and omized trials of BP-lowering therapy will be identified by ( 1 ) retrieving the references of trials included in published systematic review s of BP-lowering therapy , ( 2 ) retrieving studies published by the Blood Pressure Lowering Treatment Trialists ’ Collaboration ( BPLTTC ) , and ( 3 ) checking studies referenced in the 1993 World Health Organization/International Society of Hypertension meeting memor and um on BP management . Posttrial follow-up studies will then be identified by forward citation search ing the r and omized trials identified in step 1 through Web of Science . The search will include r and omized controlled trials with at least 1-year in-trial period and a posttrial follow-up phase . Age is the major determinant of absolute cardiovascular risk , so the participants in our review will be restricted to middle-aged adults who are more likely to have a lower cardiovascular risk profile . The primary outcome will be all-cause mortality . Secondary outcomes will include cardiovascular mortality , fatal stroke , fatal myocardial infa rct ion , and death due to heart failure . Results The search es for existing systematic review s and BPLTTC studies were piloted and modified . The study is expected to be completed before June 2018 . Conclusions The findings of this study will contribute to the body of knowledge concerning the beneficial , neutral , or harmful effects of delayed BP-lowering drug treatment on the primary prevention of CVD in patients with mildly elevated BP and low-to-moderate CVD risk . Trial Registration PROSPERO International Prospect i ve Register of Systematic Review s : CRD42017058414 ; https://www.crd.york.ac.uk/ PROSPERO /display_record.asp?ID = CRD42017058414 ( Archived by WebCite ® at http://www.webcitation.org/6t6sa8O2Q IN A PREVIOUS issue of this journa1,l the details of our national cooperative ControIled study of long-term anticoagulant therapy in cerebral ischemia and cerebral infa rct ion were presented along with an interim report covering some eighteen months . At that time , longterm anticoagulation did not appear to reduce the mortality and there was an added risk due to hemorrhagic complications . The study , embracing 7 clinical centers and extending over a period of forty-two months , was brought to an end in August 1961 , and this is a report of our findings and final conclusions . The important aspects of the study , including selection and classification of cases and method of anticoagulation , were fully covered previously and will not be repeated here . A total of 443 patients were enrolled in the study , each patient being assigned to the anticoagulant or nonanticoagulant therapeutic groups on a statistically r and om basis by means of sealed envelopes . All the patients in the study were divided into 5 diagnostic categories : ( 1 ) transient ischemic attacks , ( 2 ) thrombosis-in-evolution , ( 3 ) thrombosis-completed stroke , ( 4 ) thorem ( thrombosis or embolism ) , and ( 5 ) cerebral embolism . Analysis of the control and treated groups showed that they were remarkably comparable in most respects ( table 1 ) . The number of cases involving the internal carotidmiddle cerebral and vertebral-basilar systems varied from category to category ; in the whole series there were 328 in the carotid and 102 in the vertebral-basilar . In regard to blood pressure , 59.6 per cent of the entire group had an elevated blood pressure . To determine the effect of anticoagulant therapy , the cases were analyzed as to the incidence of ( 1 ) deaths , ( 2 ) progression of cerebral infa rct ion due to either extension of the infa rct ed area or a new infa rct ion , ( 3 ) the advent of extracerebral thrombotic episodes ( ECTE ) , including myocardial infa rct ion , pulmonary embolism , thrombophlebitis , and so forth , and ( 4 ) hemorrhagic complications . Patients whose anticoagulants were stopped within two weeks of death when the patient 's condition was deteriorating were reckoned as deaths while on anticoagulants BACKGROUND Atherosclerotic peripheral arterial disease is associated with an increased risk of myocardial infa rct ion , stroke , and death from cardiovascular causes . Antiplatelet drugs reduce this risk , but the role of oral anticoagulant agents in the prevention of cardiovascular complications in patients with peripheral arterial disease is unclear . METHODS We assigned patients with peripheral arterial disease to combination therapy with an antiplatelet agent and an oral anticoagulant agent ( target international normalized ratio [ INR ] , 2.0 to 3.0 ) or to antiplatelet therapy alone . The first co primary outcome was myocardial infa rct ion , stroke , or death from cardiovascular causes ; the second co primary outcome was myocardial infa rct ion , stroke , severe ischemia of the peripheral or coronary arteries leading to urgent intervention , or death from cardiovascular causes . RESULTS A total of 2161 patients were r and omly assigned to therapy . The mean follow-up time was 35 months . Myocardial infa rct ion , stroke , or death from cardiovascular causes occurred in 132 of 1080 patients receiving combination therapy ( 12.2 % ) and in 144 of 1081 patients receiving antiplatelet therapy alone ( 13.3 % ) ( relative risk , 0.92 ; 95 % confidence interval [ CI ] , 0.73 to 1.16 ; P=0.48 ) . Myocardial infa rct ion , stroke , severe ischemia , or death from cardiovascular causes occurred in 172 patients receiving combination therapy ( 15.9 % ) as compared with 188 patients receiving antiplatelet therapy alone ( 17.4 % ) ( relative risk , 0.91 ; 95 % CI , 0.74 to 1.12 ; P=0.37 ) . Life-threatening bleeding occurred in 43 patients receiving combination therapy ( 4.0 % ) as compared with 13 patients receiving antiplatelet therapy alone ( 1.2 % ) ( relative risk , 3.41 ; 95 % CI , 1.84 to 6.35 ; P<0.001 ) . CONCLUSIONS In patients with peripheral arterial disease , the combination of an oral anticoagulant and antiplatelet therapy was not more effective than antiplatelet therapy alone in preventing major cardiovascular complications and was associated with an increase in life-threatening bleeding . ( Clinical Trials.gov number , NCT00125671 [ Clinical Trials.gov ] . ) AIMS To correlate the dynamics of platelet activation with the development of thromboembolic events in patients with continuous-flow left ventricular assist device ( cf-LVAD ) . METHODS AND RESULTS The  platelet activity state ( PAS ) assay  was utilized to evaluate platelet activation in 68 cf-LVAD patients implanted with the HeartMate II ( n = 15 , 22 % ) , HeartMate 3 ( n = 15 , 22 % ) , or HeartWare HVAD ( n = 38 , 56 % ) .  PAS  was measured preoperatively , early post-implant , and at long-term follow-up ( 1 , 3 , 6 , 12 , 18 , and 24 months post-implant ) .  PAS  was also measured at the occurrence of adverse events in patients who developed thrombotic complications . Data on patient demographics , medical history , antithrombotic therapy , and coagulation parameters were also analysed . Over a median follow-up of 602 ( 234 - 942 ) days , PAS values did not increase over time in the overall population ( P = 0.15 ) . However , PAS measured at event was 15-fold higher in the six patients ( 9 % ) who suffered pump thrombosis ( n = 2 ) or ischaemic stroke ( n = 4 ) vs. the rest of the population [ 6.67 % ( 5.59%-11.98 % ) vs. 0.45 % ( 0.33%-0.75 % ) ; P = 0.012 ] , despite comparable coagulation profile . Pre-implant PAS values were 4.5-fold higher in these patients [ 1.90 % ( 1.24%-3.17 % ) vs. 0.42 % ( 0.32%-0.72 % ) ; P = 0.006 ] . Neither preoperative variables nor the type of the pump or the antiplatelet strategy were associated with a higher risk of complications . CONCLUSIONS Thrombotic events are associated with altered PAS values . Moreover , baseline elevated PAS values in patients who developed thrombotic events suggest patient-specific tendency to post-implant thromboembolic complications . Prospect ively , systematic monitoring of PAS might guide the development of refined patient-tailored antithrombotic strategies and the technological improvement of LVAD design Current recommendations for the antithrombotic management of patients receiving oral anticoagulation ( OAC ) who undergo percutaneous coronary intervention with stent implantation ( PCI-S ) are based on limited and relatively weak data . To broaden and strengthen available evidence , the management and 1-year outcomes of OAC patients who underwent PCI-S and were included in a prospect i ve , multicenter registry from 2003 to 2007 were evaluated . Among the 632 patients receiving OAC , mostly because of atrial fibrillation ( 58 % ) , who underwent PCI-S , mostly because of acute coronary syndromes ( 63 % ) , dual-antiplatelet therapy with aspirin and clopidogrel was the most frequently prescribed at discharge ( 48 % ) , followed by triple therapy with OAC , aspirin , and clopidogrel ( 32 % ) and OAC plus aspirin ( 18 % ) . The choice of antithrombotic therapy largely matched the thromboembolic risk profiles of patients , with the prescription of regimens including OAC predicted by the presence of non-low-risk features . The cumulative 1-year occurrence of major adverse cardiovascular events was as high as 27 % and was not significantly different among the 3 treatment groups . Stroke and stent thrombosis were limited to 2 % and 3 % , respectively , and although no significant differences were found among the 3 groups , stroke was 4 times less frequent when OAC , with either 1 or 2 antiplatelet agents , was administered . Major bleeding was also limited to 3 % , with no significant differences among the 3 groups . In conclusion , these findings suggest overall real-world management of OAC patients who undergo PCI-S  that is in accordance with their clinical risk profiles and give further support to the reported efficacy and safety of triple therapy for the optimal treatment of these patients Deep venous thrombosis of the lower extremity is a serious disorder ; the estimated incidence is 1 per 1000 persons per year [ 1 - 3 ] . The disease can occur after surgical procedures and trauma and in the presence of cancer or inherited coagulation disorders ; it can also develop without any of these factors [ 3 ] . The clinical course of deep venous thrombosis might be complicated by pulmonary embolism , recurrent episodes of deep venous thrombosis , and the development of serious post-thrombotic sequelae , such as venous ulceration , debilitating pain , and intractable edema [ 3 ] . Patients with deep venous thrombosis are usually treated with an initial course of heparin ( 5 to 10 days ) followed by 3 to 6 months of oral anticoagulant therapy . This treatment regimen reduces the risk for short-term thromboembolic complications to approximately 5 % [ 4 , 5 ] . The long-term risk for recurrent venous thromboembolism and the incidence and severity of post-thrombotic sequelae in patients with symptomatic deep venous thrombosis have not been well documented . In a recent large r and omized , clinical trial comparing 6 weeks of oral anticoagulant therapy with 6 months of therapy [ 6 ] , patients with symptomatic deep venous thrombosis were followed for 2 years for recurrences and death . This trial showed a substantial reduction in the risk for recurrent venous thromboembolism among patients in the 6-month oral anticoagulant group , but the investigators did not report on the occurrence of the post-thrombotic syndrome . Another recent study [ 7 ] reported the 8-year incidence of recurrences and post-thrombotic manifestations in patients with confirmed symptomatic deep venous thrombosis . However , only a few patients were included in this study , and data were collected retrospectively . We assessed the clinical course of a first episode of symptomatic deep venous thrombosis in a large consecutive series of patients who had long-term follow-up . We assessed mortality and the long-term incidences of recurrent venous thromboembolism and the post-thrombotic syndrome . We also evaluated the potential risk factors for these three outcomes . Methods Identification of Inception Cohort The Department of Internal Medicine of the University of Padua , Padua , Italy , is a diagnostic facility for out patients with clinical ly suspected venous thromboembolism in a community of approximately 350 000 persons . All consecutive out patients with a first episode of clinical ly suspected deep venous thrombosis who were referred by their general practitioners between January 1986 and December 1991 had noninvasive testing [ 8 ] . Patients were potentially eligible for the study if confirmatory venography showed deep venous thrombosis . Patients were excluded from the study if they had been referred because of recurrent venous thrombosis , were geographically inaccessible for follow-up , or refused to give informed consent . The Institutional Review Board of the hospital of the University of Padua approved the study . Baseline Assessment At the time of referral , demographic characteristics were recorded and a medical history was taken ; information was elicited on the period between the onset of symptoms and presentation to the thrombosis service ( patientphysician delay ) , the presence of risk factors for thrombosis ( that is , cancer , surgery , trauma or fracture , immobilization for more than 7 days , pregnancy or childbirth , or estrogen use ) , and symptoms of pulmonary embolism . Information was also obtained on the history of venous thromboembolism in first-degree relatives .  Antithrombin , protein C and S , and lupus-like anticoagulant levels were subsequently measured . Assays were done , and previously described criteria for abnormality and deficiency were used [ 9 ] . The venograms obtained at baseline were divided into those representing proximal venous thrombosis ( with or without concurrent venous thrombosis of the calf ) and those indicating isolated venous thrombosis of the calf . Proximal venous thrombosis was defined as thrombosis located above the trifurcation of the calf veins that involved at least the popliteal vein , superficial femoral vein , common femoral vein , or iliac vein . The location and occlusiveness of proximal thrombi were also determined . A patient was considered to have nonocclusive deep venous thrombosis if contrast material was seen between the thrombus and the vessel wall along the entire thrombus . Treatment Patients were admitted to the hospital and treated with an initial course of high-dose intravenous st and ard heparin ( a bolus of 5000 U followed by continuous infusion of 30 000 U/d , subsequently adjusted to maintain an activated partial thromboplastin time between 1.5 and 2.5 times the normal value ) or subcutaneous low-molecular-weight heparin ( 90 U of anti-factor Xa/kg of body weight twice daily ) . Therapy with oral anticoagulant agents ( warfarin ) was started on day 5 to 7 of treatment and was continued for 3 months . The oral anticoagulant dose was adjusted daily to maintain an international normalized ratio between 2.0 and 3.0 . Treatment with low-molecular-weight heparin was discontinued on day 10 or later if the international normalized ratio was less than 2.0 . This treatment strategy deviated in the following groups of patients : those with cancer , protein deficiencies , or lupus anticoagulant , in whom oral anticoagulation therapy was prolonged ; those with small isolated venous thrombosis of the calf , who received oral anticoagulation alone ; those with contraindications to anticoagulant treatment , who received no treatment or an inferior caval-vein filter ; those who refused to be hospitalized , who received low-dose heparin and oral anticoagulant agents ; and those with threatened viability of the leg , who received thrombolytic therapy .  The actual type and duration of treatments were recorded . All patients were instructed to wear elastic graduated compression stockings ( providing 40 mm Hg of pressure at the ankle ) for at least 2 years . Follow-up All patients were seen 3 and 6 months after the initial referral and thereafter returned to the study center every 6 months for follow-up assessment s. Patients were asked to return to the thrombosis center immediately if symptoms suggestive of recurrent venous thromboembolism developed . Follow-up was continued for as long as 8 years or until July 1995 . To avoid diagnostic suspicion bias , the medical history on general health , symptoms of recurrent venous thromboembolism , and the post-thrombotic syndrome was obtained by using a st and ardized form . Patients who could not attend the follow-up sessions were visited at home . For all patients who died during follow-up , the date and cause of death were documented . Diagnosis of Recurrent Venous Thromboembolism and Hemorrhage Contrast venography of the symptomatic leg or legs was done as described previously [ 10 ] . The criteria for deep venous thrombosis were a constant intraluminal filling defect confirmed in at least two different projections or nonvisualization of a vein or a segment thereof , despite adequate technique and repeated injections with contrast material . The presence or absence of venous thrombosis was assessed by a panel of independent observers who were unaware of the patient 's other clinical features or previous test results . If a patient presented with clinical ly suspected recurrent venous thrombosis of the leg , venography was done . The criterion for recurrent venous thrombosis of the leg was a new intraluminal filling defect on the venogram . If the venogram was not diagnostic , recurrent venous thrombosis was diagnosed on the basis of an abnormal 125I-fibrinogen leg scan or results of noninvasive tests that had changed from normal to abnormal [ 11 , 12 ] . Patients with suspected pulmonary embolism had venography if they had concurrent leg symptoms or perfusion lung scanning in the absence of leg symptoms . Pulmonary embolism was excluded if the perfusion scan was normal . Because ventilation lung scanning was not available during the first years of the study and because pulmonary angiography could not routinely be done , we could not definitively diagnose pulmonary embolism in some patients . If a definitive diagnosis could not be made , patients were classified as not having recurrent venous thromboembolism . Perfusion lung scanning and pulmonary angiography were done and their results were interpreted according to st and ard procedures [ 13 ] . Hemorrhagic episodes were classified as major or minor , as reported previously [ 14 ] . The documentation of all patients suspected of having a recurrent venous thromboembolic or bleeding event was review ed by a three-member adjudication committee that was unaware of further clinical details of the patient . Criteria for the Post-Thrombotic Syndrome Presence of the post-thrombotic syndrome was assessed by investigators who were unaware of previous post-thrombotic manifestations and further clinical details of the patient . The presence of leg symptoms ( pain , cramps , heaviness , pruritus , and paresthesia ) and signs ( pretibial edema , in duration of the skin , hyperpigmentation , new venous ectasia , redness , and pain during calf compression ) was scored . For each item , the investigators assigned a score of 0 ( not present or minimal ) to 3 ( severe ) . The presence of a venous ulcer of the lower limb was recorded . In patients with bilateral thrombosis , the higher score was used . A total score of 15 or more on two consecutive visits or the presence of a venous ulcer indicated severe post-thrombotic syndrome , and a total score of 5 to 14 on two consecutive visits indicated mild post-thrombotic syndrome . This score has been shown to have good reproducibility , and it correlates well with the patient 's perception of the interference of leg symptoms with daily life [ 15 ] . Statistical Analysis We calculated Kaplan-Meier estimates and 95 % CIs for a visual assessment of survival and calculated the risk for recurrent venous thromboembolism and mild and severe Background Venous thromboembolism comprising pulmonary embolism and deep vein thrombosis is a common condition with an incidence of approximately 1 per 1,000 per annum causing both mortality and serious morbidity . The principal aim of treatment of a venous thromboembolism with heparin and warfarin is to prevent extension or recurrence of clot . However , the recurrence rate following a deep vein thrombosis remains approximately 10 % per annum following treatment cessation irrespective of the duration of anticoagulation therapy . Patients with raised D-dimer levels after discontinuing oral anticoagulation treatment have also been shown to be at high risk of recurrence . Post thrombotic syndrome is a complication of a deep vein thrombosis which can lead to chronic venous insufficiency and ulceration . It has a cumulative incidence after 2 years of around 25 % and it has been suggested that extended oral anticoagulation should be investigated as a possible preventative measure . Methods / design Patients with a first idiopathic venous thromboembolism will be recruited through anticoagulation clinics and r and omly allocated to either continuing or discontinuing warfarin treatment for a further 2 years and followed up on a six monthly basis . At each visit D-dimer levels will be measured using a Roche Cobas h 232 POC device . In addition a venous sample will be taken for laboratory D-dimer analysis at the end of the study . Patients will be examined for signs and symptoms of PTS using the Villalta scale and complete VEINES and EQ5D quality of life question naires . Discussion The primary aim of the study is to investigate whether extending oral anticoagulation treatment ( prior to discontinuing treatment ) beyond 3–6 months for patients with a first unprovoked proximal deep vein thrombosis or pulmonary embolism prevents recurrence . The study will also determine the role of extending anticoagulation for patients with elevated D-dimer levels  prior to discontinuing treatment and identify the potential of D-dimer point of care testing for identification of high risk patients within a primary care setting .Trial registration IS RCT BACKGROUND Although atrial thrombosis is common in patients with non-rheumatic atrial fibrillation ( NRAF ) ( 6 - 27 % ) , there are no studies about the effect that anticoagulant or antiplatelet drugs have on it . AIM OF THE STUDY We have investigated the role of anticoagulant therapy , followed by family physicians , on left atrial thrombosis detected via transesophageal echocardiography ( TEE ) in patients with NRAF . METHODS Sixty patients enrolled in the TASAF ( Trieste Area Study on non-rheumatic Atrial Fibrillation ) ( 60 % males , mean age 72 + /- 7 years , 17 % with lone atrial fibrillation , duration of arrhythmia 111 + /- 79 months ) , in whom we found a left atrial and /or left atrial appendage thrombus via TEE , were anticoagulated .  The thrombus was in the left atrial appendage in 57 patients and in the left atrium in the others . In 28 of them it was mobile and in 50 , the left atrial appendage flow was low or absent . Lastly , in 46 patients we found  spontaneous echocontrast  and a bilobate appendage was present in 8 of them . At follow-up , we repeated the TEE to evaluate the effect of the therapy on the atrial thrombosis . RESULTS Only 53 patients received anticoagulant therapy  ( 45 correctly ) , while 7 were treated with antiplatelet drugs by their family physicians . After a mean follow-up of 16 months , all patients underwent a repeat TEE and the thrombus was no longer evident in 35 cases ( 58 % ) . The thrombosis disappeared in 26 ( 58 % ) of the 45 patients who correctly took anticoagulant therapy and in 5 of the 8 who were not adequately anticoagulated . Moreover , we did n't observe the thrombus in 4 of the 7 patients who were treated with antiplatelet drugs . There was no significant statistical difference between the benefits of anticoagulants and antiplatelet therapy in dissolving left atrial thrombosis . During follow-up , we recorded only one embolic event in the retina . None of the patients on antiplatelet drugs complained of any side effects , whereas in 5 of the 53 on anticoagulant therapy , we recorded one fatal intracranial hemorrhage , one gastric hemorrhage and three minor complications . CONCLUSIONS Left atrial thrombosis in NRAF disappears in anticoagulated patients in an high percentage of cases ( the therapy probably acts on more recent thrombi ) . Moreover , this therapy decreases the incidence of embolic events , although it increases the risk of hemorrages . Since the management of this preventive treatment in general medicine is very difficult , we hope that our health organization will establish Anticoagulation Clinics for the central ized management of this therapy BACKGROUND Long-term oral anticoagulant treatment is obligatory in patients with atrial fibrillation ( AF , score of CHA₂DS₂VASc≥2 ) . When these patients undergo  percutaneous coronary intervention with a drug-eluting stent ( PCI-eS ) , there is also an indication for aspirin and clopidogrel treatment , according to the ESC Guidelines . However , triple therapy has been known to increase the risk of bleeding complications . Unfortunately , there is little prospect i ve data available to resolve this issue . Therefore , it is imperative that an optimal therapy for AF patients with indications of both anticoagulation and antiplatelet intervention to prevent thrombotic complications without increasing the risk of bleeding is found . OBJECTIVES This prospect i ve , r and omized , multicenter study is going to assess the hypothesis that in persistent or permanent AF patients ( score of CHA₂DS₂VASc≥2 ) after PCI-eS , the combination therapy of oral anticoagulation ( warfarin ) and ticagrelor ( 90 mg/bid ) could reduce the risk of bleeding events . DESIGN A multicenter , active-controlled , open-label , r and omized trial is to be performed to evaluate dual antithrombotic therapy ( ticagrelor+warfarin ) in persistent or permanent AF patients ( score of CHA₂DS₂VASc≥2 ) after PCI-eS versus the combination of triple antithrombosis ( clopidogrel+aspirin+warfarin ) . The primary endpoint is the overall bleeding up to 6 months , according to TIMI criteria and classifications . The secondary endpoints are the major bleeding events up to 6 months , according to TIMI criteria . The sample size is estimated at 296 . CONCLUSION This study is intended to provide information about the safety characteristics  of warfarin and ticagrelor in persistent or permanent AF patients after PCI-eS. No prospect i ve r and omized study has been conducted on the issue of antithrombotic therapy using warfarin and ticagrelor in these patients . Therefore , the MANJUSRI trial will help to explore and determine a new potential therapeutic regimen for AF patients after PCI-eS. TRIAL REGISTRATION Clinical Trials.gov # NCT02206815 , registered July 30 , 2014 BACKGROUND In 1989 , the European Working Party on High Blood Pressure in the Elderly started the double-blind , placebo-controlled , Systolic Hypertension in Europe Trial to test the hypothesis that antihypertensive drug treatment would reduce the incidence of fatal and nonfatal stroke in older patients with isolated systolic hypertension . This report addresses whether the benefit of antihypertensive treatment varied according to sex , previous cardiovascular complications , age , initial blood pressure ( BP ) , and smoking or drinking habits in an intention-to-treat analysis and explores whether the morbidity and mortality results were consistent in a per- protocol analysis . METHODS After stratification for center , sex , and cardiovascular complications , 4695 patients 60 years of age or older with a systolic BP of 160 to 219 mm Hg and diastolic BP less than 95 mm Hg were r and omized . Active treatment consisted of nitrendipine ( 10 - 40 mg/d ) , with the possible addition of enalapril maleate ( 5 - 20 mg/d ) and /or hydrochlorothiazide ( 12.5 - 25 mg/d ) , titrated or combined to reduce the sitting systolic BP by at least 20 mm Hg , to below 150 mm Hg . In the control group , matching placebo tablets were employed similarly . RESULTS In the intention-to-treat analysis , male sex , previous cardiovascular complications , older age , higher systolic BP , and smoking at r and omization were positively and independently correlated with cardiovascular risk . Furthermore , for total ( P = .009 ) and cardiovascular ( P = .09 ) mortality , the benefit of antihypertensive drug treatment weakened with advancing age ; for total mortality ( P = .05 ) , the benefit increased with higher systolic BP at entry , while for fatal and nonfatal stroke ( P = .01 ) , it was most evident in nonsmokers ( 92.5 % of all patients ) . In the per protocol analysis , active treatment reduced total mortality by 24 % ( P = .05 ) , reduced all fatal and nonfatal cardiovascular end points by 32 % ( P<.001 ) , reduced all strokes by 44 % ( P = .004 ) , reduced nonfatal strokes by 48 % ( P = .005 ) , and reduced all cardiac end points , including sudden death , by 26 % ( P = .05 ) . CONCLUSIONS In elderly patients with isolated systolic hypertension , stepwise antihypertensive drug treatment , starting with the dihydropyridine calcium channel blocker nitrendipine , improves prognosis . The per- protocol analysis suggested that treating 1000 patients for 5 years would prevent 24 deaths , 54 major cardiovascular end points , 29 strokes , or 25 cardiac end points . The effects of antihypertensive drug treatment on total and cardiovascular mortality may be attenuated in very old patients Rationale Currently available data do not provide definitive evidence on the comparative benefits of closure of patent foramen ovale , oral anticoagulants and antiplatelet therapy in patients with patent foramen ovale-associated cryptogenic stroke Aim To assess whether transcatheter patent foramen ovale closure plus antiplatelet therapy is superior to antiplatelet therapy alone and whether oral anticoagulant therapy is superior to antiplatelet therapy , for secondary stroke prevention in patients aged 16 to 60 years with a large patent foramen ovale or a patent foramen ovale associated with an atrial septal aneurysm , and an otherwise unexplained ischaemic stroke or retinal ischaemia . Sample size Six hundred and sixty-four patients were included in the study . Methods and design CLOSE is an academic-driven , multicentre , r and omized , open-label , three-group , superiority trial with blinded adjudication of outcome events . The trial has been registered with Clinical Trials Register ( Clinical trials.gov , NCT00562289 ) . Patient recruitment started in December 2007 . Patient follow-up will continue until December 2016 . Expected mean follow-up = 5.6 years . Study outcomes The primary efficacy outcome is the occurrence of fatal or nonfatal stroke . Safety outcomes include fatal , life-threatening or major procedure- or device-related complications and fatal , life-threatening or major haemorrhagic complications . Discussion CLOSE is the first specifically design ed trial to assess the superiority of patent foramen ovale closure over antiplatelet therapy alone and the superiority of oral anticoagulants over antiplatelet therapy to prevent stroke recurrence in patients with patent foramen ovale-associated cryptogenic stroke BACKGROUND Dual antiplatelet therapy with aspirin and thienopyridines ( clopidogrel or prasugrel ) is required after placement of coronary stents to prevent thrombotic complications . Although current clinical practice guidelines recommend 12-month treatment after drug-eluting stent placement , even longer duration s may prevent thrombotic events . STUDY DESIGN The Dual Antiplatelet Therapy ( DAPT ) Study is comparing the benefits and risks of 12 versus 30 months of dual antiplatelet therapy in preventing stent thrombosis or major adverse cardiovascular and cerebrovascular events in subjects undergoing percutaneous coronary intervention ( PCI ) for the treatment of coronary artery obstructive lesions . The DAPT Study is a multicenter , international , r and omized , double-blind , placebo-controlled trial that will enroll 15,245 subjects treated with drug-eluting stent ( DES ) and 5,400 subjects treated with bare-metal stents ( BMS ) .  All subjects will receive 12 months of open-label thienopyridine treatment in addition to aspirin . After 12 months , subjects who are free from death , myocardial infa rct ion , or stroke ( MACCE ) , repeat revascularization , and GUSTO ( Global Use of Strategies to Open Occluded Coronary Arteries ) moderate or severe bleeding events will be r and omized to receive either 18 additional months of thienopyridine ( clopidogrel or prasugrel ) ( 30 month DAPT arm ) or placebo ( 12 month DAPT arm ) plus aspirin . Co primary end points are MACCE and stent thrombosis . The primary safety end point is GUSTO moderate or severe bleeding . CONCLUSIONS This r and omized trial is design ed to define the relative safety and effectiveness of 12 versus 30 months of dual antiplatelet therapy across the broad spectrum of patients receiving coronary stents Although many patients with long-term oral anticoagulation ( OAC )  can manage their medication safely and reliably themselves , no study on elderly patients has as yet assessed the safety and efficacy of OAC self-management  with major thromboembolic and haemorrhagic complications as primary outcomes . In this multi-centre trial , patients aged 60 years or more were r and omised into a  self-management ( SMG ) ( N = 99 ) or routine care group  ( RCG ) ( N = 96 ) . The primary outcome was the combined endpoint of all thromboembolic events requiring hospitalisation and all major bleeding complications . Mean follow-up was 2.9 + /- 1.2 and 3.0 + /- 1.1 years in the SMG and RCG , respectively . In intention-to-treat analysis , 12 patients in the SMG versus 22 patients in the RCG reached a primary endpoint ( hazard ratio [ HR ] : 0.50 ; 95 % confidence interval [ CI ] : 0.25 to 1.00 ; p = 0.049 ) . The post-hoc analysis on OAC treatment sensitivity supported the benefit of self-management ( HR 0.27 ; 95 % CI : 0.13 to 0.71 ; p = 0.006 ) . Fifteen patients in the SMG died during the study , but none of the deaths was directly associated with anticoagulation therapy . In the RCG , 11 patients died ; of those , three deaths were directly associated with anticoagulation therapy and there was one death of unknown cause . During follow-up , the quality of OAC control was significantly better in the SMG than in the RCG . In elderly patients , long-term self-management of oral anticoagulation is superior for the prevention of major thromboembolic and bleeding complications and for the quality of oral anticoagulation control compared to routine care for a mean follow-up period of three years Objectives In many current guidelines , blood pressure (BP)-lowering drug treatment for primary prevention of cardiovascular disease ( CVD ) is based on absolute risk . However , in clinical practice , therapeutic decisions are often based on BP levels alone . We sought to investigate which approach was superior by conducting a post hoc analysis of the Australian National Blood Pressure ( ANBP ) cohort , a seminal study establishing the efficacy of BP lowering in ‘ mild hypertensive ’ persons . Design A post hoc subgroup analysis of the ANBP trial results by baseline absolute risk tertile . Setting and participants 3244 participants aged 35–69 years in a community-based r and omised placebo controlled trial of blood pressure-lowering medication . Interventions Chlorothiazide500 mg versus placebo . Primary outcome measures All-cause mortality and non-fatal events ( non-fatal CVD , congestive cardiac failure , renal failure , hypertensive retinopathy or encephalopathy ) . Results Treatment effects were assessed by HR , absolute risk reduction and number needed to treat . Participants had an average 5-year CVD risk in the intermediate range ( 10.5±6.5 ) with moderately elevated BP ( mean 159/103 mmHg ) and were middle aged ( 52±8 years ) . In a subgroup analysis , the relative effects ( HR ) and absolute effects ( absolute risk reduction and number needed to treat ) did not statistically differ across the three risk groups except for the absolute benefit in all-cause mortality ( p for heterogeneity=0.04 ) . With respect to absolute benefit , drug treatment significantly reduced the number of events in the high-risk group regarding any event with a number needed to treat of 18 ( 10 to 64 ) , death from any cause with 45 ( 25 to 196 ) and major CVD events with 23 ( 12 to 193 ) . Conclusion Our analysis confirms that the benefit of treatment was substantial only in the high-risk tertile , reaffirming the rationale of treating elevated blood pressure in the setting of all risk factors rather than in isolation Background : For patients who survive intracerebral haemorrhage ( ICH ) during treatment with oral anticoagulation ( OAC )  , the balance between the benefits and risks of restarting OAC is unclear . The decision to restart OAC or to start antiplatelet therapy in these patients therefore poses a dilemma for all physicians involved . We assessed the long-term outcome of patients who did or did not restart antithrombotic therapy after OAC-associated ICH . Methods : We conducted a retrospective follow-up study of all patients discharged from our institution after OAC-associated ICH over a 10-year period . Data on the use of OAC or platelet inhibitors and the occurrence of vascular events during follow-up were assessed through question naires and patient files . The primary outcome was recurrent fatal or non-fatal stroke . Secondary outcomes were the occurrence of other haemorrhagic , thrombotic or thromboembolic events . With patients without antithrombotic treatment as reference , we calculated incidence ratios with corresponding 95 % confidence intervals ( CI ) for treatment with OAC and for treatment with antiplatelet therapy . Results : We included 38 patients , of whom 21 ( 55 % ) died during a mean follow-up of 3.5 years . The medication regime changed frequently during follow-up , illustrated by the fact that two thirds of the patients who had resumed OAC within 2 months of ICH terminated this at later points in time . Two recurrent strokes occurred during 35.4 patient-years without antithrombotic medication , 7 during 63.8 patient-years on antiplatelet medication ( incidence ratio 1.9 ; 95 % CI , 0.4 - 9.4 ) , and 3 during 19.5 patient-years on OAC ( incidence ratio 2.7 ; 95 % CI , 0.5 - 16.3 ) . There was only 1 recurrent ICH , which occurred during treatment with OAC . Conclusion : In this observational study , no significant difference in the primary outcome measure was found between the treatment groups , but there was a tendency towards a higher long-term risk of any stroke in patients who resumed OAC or started antiplatelet therapy . However , based on these results it is difficult to draw any concrete conclusions or make any strong recommendations . A r and omized trial to assess the optimal long-term strategy after OAC-related ICH is warranted . Based on the point estimates of our study , such a trial should involve at least 300 patient-years of follow-up Abstract Objective : To investigate the effectiveness of aspirin and coumarin in preventing thromboembolism in patients with non-rheumatic atrial fibrillation in general practice . Design : R and omised controlled trial . Participants : 729 patients aged ≥60 years with atrial fibrillation , recruited in general practice , who had no established indication for coumarin . Mean age was 75 years and mean follow up 2.7 years . Setting : Primary care in the Netherl and s. Interventions : Patients eligible for st and ard intensity coumarin ( international normalised ratio 2.5 - 3.5 ) were r and omly assigned to st and ard anticoagulation , very low intensity coumarin ( international normalised ratio 1.1 - 1.6 ) , or aspirin ( 150 mg/day ) ( stratum 1 ) . Patients ineligible for st and ard anticoagulation were r and omly assigned to low anticoagulation or aspirin ( stratum 2 ) . Main outcome measures : Stroke , systemic embolism , major haemorrhage , and vascular death . Results : 108 primary events occurred ( annual event rate 5.5 % ) , including 13 major haemorrhages ( 0.7 % a year ) . The hazard ratio was 0.91 ( 0.61 to 1.36 ) for low anticoagulation versus aspirin and 0.78 ( 0.34 to 1.81 ) for st and ard anticoagulation versus aspirin . Non-vascular death was less common in the low anticoagulation group than in the aspirin group ( 0.41 , 0.20 to 0.82 ) . There was no significant difference between the treatment groups in bleeding incidence . High systolic and low diastolic blood pressure and age were independent prognostic factors . Conclusion : In a general practice population ( without established indications for coumarin ) neither low nor st and ard intensity anticoagulation is better than aspirin in preventing primary outcome events . Aspirin may therefore be the first choice in patients with atrial fibrillation in general practice . Key messages Studies have shown that patients with non-rheumatic atrial fibrillation may benefit from anticoagulation This study in a general practice population found no benefit of st and ard or low dose anticoagulation on risk of stroke , systemic embolism , major haemorrhage , or vascular death when compared with aspirin Hypertension and age were prognostic factors for event occurrence Aspirin is the treatment of choice for preventing thromboembolism in primary care patients at low Background : A combination of low-dose aspirin with anticoagulants may provide better protection against thromboembolic events compared to anticoagulants alone in high-risk patients with atrial fibrillation . Objective : Evaluation of the preventive efficacy against nonfatal thromboembolic events and vascular deaths of the combination of the oral anticoagulant fluindione and aspirin ( 100 mg ) in patients with high-risk atrial fibrillation . Methods : A multicenter , placebo-controlled , double-blind , r and omized trial was conducted at 49 investigating centers in France . Atrial fibrillation patients with a previous thromboembolic event or older than 65 years and with either a history of hypertension , a recent episode of heart failure or decreased left ventricular function were included in the study . Patients were treated with fluindione plus placebo ( i.e. anticoagulant alone ) or fluindione plus aspirin ( i.e. combination therapy ) , with an international normalized ratio target of between 2 and 2.6 . The combined primary endpoint was stroke ( ischemic or hemorrhagic ) , myocardial infa rct ion , systemic arterial emboli or vascular death . The secondary endpoint was the incidence of hemorrhagic complications . Results : The 157 participants ( average age 74 years ; 52 % women ; 42 % with paroxysmal atrial fibrillation ) were followed for an average of 0.84 years . Three nonfatal thromboembolic events were observed ( 1 in the anticoagulation group , 2 in the combination group ) and 6 patients died ( 3 in the anticoagulation group , 3 in the combination group ) , none of them from a thromboembolic complication . However , 3 deaths were secondary to severe hemorrhagic complications ( 1 in the anticoagulation group , 2 in the combination group ) . Nonfatal hemorrhagic complications occurred more often in the combination group ( n = 10 , 13.1 % ) compared to the anticoagulation group ( n = 1 , 1.2 % ) ( p = 0.003 ) . Conclusion : The combination of aspirin with anticoagulant is associated with increased bleeding in elderly atrial fibrillation patients . The effect on thromboembolism and the overall balance of benefit to risk could not be accurately assessed in this study due to the limited number of ischemic events Advances in antithrombotic therapy , along with an early invasive strategy , have reduced the incidence of recurrent ischemic events and death in patients with acute coronary syndromes ( ACS ; unstable angina , non – ST-segment – elevation myocardial infa rct ion [ MI ] , and ST-segment – elevation MI).1,–,4 However , the combination of multiple pharmacotherapies , including aspirin , platelet P2Y12 inhibitors , heparin plus glycoprotein IIb/IIIa inhibitors , direct thrombin inhibitors , and the increasing use of invasive procedures , has also been associated with an increased risk of bleeding . Editorial see p 2664 Bleeding complications have been associated with an increased risk of subsequent adverse outcomes , including MI , stroke , stent thrombosis , and death , in patients with ACS and in those undergoing percutaneous coronary intervention (PCI),5,–,10 as well as in the long-term antithrombotic setting .11,12 Thus , balancing the anti-ischemic benefits against the bleeding risk of antithrombotic agents and interventions is of paramount importance in assessing new therapies and in managing patients . Prior r and omized trials comparing antithrombotic agents suggest that a reduction in bleeding events is associated with improved survival.13,14 Because prevention of major bleeding may represent an important step in improving outcomes by balancing safety and efficacy in the contemporary treatment of ACS , bleeding events have been systematic ally identified as a crucial end point for the assessment of the safety of drugs during the course of r and omized clinical trials , and are an important aspect of the evaluation of new devices and interventional therapies.15 Unlike ischemic clinical events ( eg , cardiac death , MI , stent thrombosis ) , for which there is now general consensus on end-point definitions,16,17 there is substantial heterogeneity among the many bleeding definitions currently in use . Lack of st and ardization makes it difficult to optimally organize key clinical trial processes such as adjudication , and even more difficult to interpret relative BACKGROUND AND PURPOSE The results of a large prospect i ve r and omized trial have shown the efficacy of oral anticoagulation in the secondary prevention of major vascular events in patients with nonrheumatic atrial fibrillation ( NRAF ) ; less well established is the role of antiplatelet agents . The present study compared the effects of indobufen , a reversible inhibitor of platelet cyclooxygenase , with those of warfarin in this setting . METHODS A total of 916 patients with NRAF and a recent ( < or = 15 days ) cerebral ischemic episode were admitted to this multicenter , r and omized study , during which they were treated with either indobufen ( 100 or 200 mg BID ) or warfarin ( to obtain an international normalized ratio of 2.0 to 3.5 ) for 12 months . The two groups ( 462 on indobufen and 454 on warfarin ) were well balanced in terms of their main baseline characteristics . The primary outcome of the study was the combined incidence of nonfatal stroke ( including intracerebral bleeding ) , pulmonary or systemic embolism , nonfatal myocardial infa rct ion , and vascular death . RESULTS At the end of follow-up , the incidence of primary outcome events was 10.6 % in the indobufen group ( 95 % confidence interval , 7.7 % to 13.5 % ) and 9.0 % in the warfarin group ( 95 % confidence interval , 6.3 % to 11.8 % ) , with no statistically significant difference between treatments . The frequency of noncerebral major bleeding complications was low : only four cases ( 0.9 % ) of gastrointestinal bleeding were observed , all of them in the warfarin group . CONCLUSIONS We conclude that , within the limitations of its design , this study may help the medical community in devising appropriate antithrombotic strategies for NRAF patients for whom oral anticoagulants are contraindicated or do not represent a feasible approach to treatment BACKGROUND The risk of venous thromboembolism in patients undergoing total hip replacement is known to be high . However , the optimal duration of prophylaxis with anticoagulant agents after this procedure is unknown . We sought to determine whether one month of anticoagulant therapy with the low-molecular-weight heparin enoxaparin is more effective than enoxaparin therapy given only during the hospitalization for surgery . METHODS Two hundred sixty-two patients undergoing total hip replacement received enoxaparin during their hospitalizations ( average stay , 10 to 11 days ) . They were then r and omly assigned to receive enoxaparin or placebo ( 131 patients each ) . Blinded outpatient therapy ( or placebo ) was continued long enough that the total treatment period , inpatient plus outpatient , was one month for each patient . Bilateral ascending phlebography was performed 19 to 23 days after discharge , with deep-vein thrombosis as the primary end point . Distal and proximal thrombosis , pulmonary embolism , and hemorrhage were also recorded , as were deaths . RESULTS Venography was adequate in 116 patients in the placebo group and 117 in the enoxaparin group . We observed 43 episodes of deep-vein thrombosis and 2 episodes of pulmonary embolism in the placebo group , but only 21 episodes of deep-vein thrombosis and no episodes of pulmonary embolism in the enoxaparin group ( incidence of thromboembolism , 39 percent and 18 percent , respectively ; P<0.001 ) . The difference in the incidence of proximal deep-vein thrombosis was also significant ( 24 percent and 7 percent in the placebo and enoxaparin groups , respectively ; P<0.001 ) . Six enoxaparin groups , respectively ; P<0.001 ) . Six patients in the enoxaparin group and one patient in the placebo group had hematomas at their injection sites . No patients died or had major complications . CONCLUSIONS There were significantly fewer venous thromboembolic complications in patients undergoing elective hip replacement when prophylaxis with enoxaparin was given for a total of one month , rather than only during the hospitalization The optimal long-term treatment of acute venous thromboembolism ( VTE ) in patients with malignancy remains undefined . In particular , based on current evidence , it is uncertain whether secondary prophylaxis using st and ard intensity oral anticoagulant therapy is associated with higher risks of bleeding and recurrent thrombosis in patients with cancer than in those without cancer . This study compared the outcome of  anticoagulation courses  in 95 patients with malignancy with those of 733 patients without malignancy . All patients were participants in a large , nation-wide population study and were prospect ively followed from the initiation of their oral anticoagulant therapy . Based on 744 patient-years of treatment and follow-up , the rates of major ( 5.4 % vs 0.9 % ) , minor ( 16.2 % vs 3.6 % ) and total ( 21.6 % vs 4.5 % ) bleeding were statistically significantly higher in cancer patients compared with patients without cancer . Bleeding was also a more frequent cause of early anticoagulation withdrawal in patients with malignancy ( 4.2 % vs. 0.7 % ; p < 0.01 ; RR 6.2 ( 95 % CI 1.95 - 19.4 ) . There was a trend towards a higher rate of thrombotic complications in cancer patients ( 6.8 % vs. 2.5 % ; p = 0.058 ; RR 2.5 [ CI 0.96 - 6.5 ] ) but this did not achieve statistical significance . In the group of patients with cancer , the bleeding rate was high across the different INR categories and was independent of the temporally associated International Normalized Ratio ( INR ) . In contrast , the bleeding rate was increased only with INR values greater than 4.5 in the group of patients without cancer . The rate of thrombotic events was significantly higher in both cohorts when the INR was less than 2.0 . In conclusion , patients with malignancy treated with oral anticoagulants have a higher rate of bleeding and possibly an increased risk of recurrent thrombosis compared with patients without malignancy . Safer and more effective anticoagulant therapy is needed for this challenging group of patients Context Optimal duration of anticoagulation after pulmonary embolism is uncertain , but physicians commonly prescribe 3 months of therapy for patients with transient risk factors for thrombosis and 6 months for patients with continuing or no known risk factors . Contribution After 3 months of successful anticoagulation , 326 patients were r and omly assigned to stop therapy immediately or extend therapy to 6 months or 1 year . Regardless of duration of anticoagulation , 33 patients had recurrent thromboembolic events but only one event occurred in a patient still receiving therapy . Implication s Extending the duration of anticoagulation does not seem to protect against recurrence once therapy has been discontinued . Patients at high risk for recurrence may require indefinite anticoagulation . The Editors Recent studies have shown that patients with a first episode of venous thromboembolism are protected from a recurrence while they are receiving anticoagulant treatment ( 1 , 2 ) . On the basis of differences in the risk for recurrence when anticoagulant treatment is discontinued , different duration s of oral anticoagulation are currently recommended in different patient categories . A shorter period of anticoagulation is recommended for patients with venous thromboembolism associated with transient risk factors than for patients with idiopathic venous thromboembolism or venous thromboembolism associated with continuing risk factors ( 3 - 5 ) . Current recommendations on the duration of oral anticoagulant treatment for venous thromboembolism are based on studies that mostly included patients presenting with deep venous thrombosis ( 1 , 2 , 5 - 7 ) . Only a limited proportion of patients included in these studies presented with pulmonary embolism . Deep venous thrombosis and pulmonary embolism are generally considered to be two clinical manifestations of the same disease . However , patients presenting with pulmonary embolism are reported to have a higher incidence of fatal recurrent venous thromboembolism than patients presenting with deep venous thrombosis ( 8 , 9 ) . We performed a multicenter r and omized trial to evaluate the long-term clinical benefit of extending a 3-month course of oral anticoagulant therapy to 6 months ( pulmonary embolism associated with temporary risk factors ) or to 1 year ( idiopathic pulmonary embolism ) in patients with a first episode of pulmonary embolism . The primary outcome of the study was symptomatic , objective ly confirmed recurrence of venous thromboembolism . Methods Study Patients Consecutive patients ranging from 15 to 85 years of age with a first episode of symptomatic , objective ly confirmed pulmonary embolism were included in the study if they had completed 3 uninterrupted months of  oral anticoagulant therapy without having a recurrence or bleeding . The diagnosis of pulmonary embolism was confirmed by pulmonary angiography or spiral computed tomography or by a lung scan indicating a high probability of pulmonary embolism or a lung scan indicating an intermediate probability of pulmonary embolism in a patient with objective ly diagnosed deep venous thrombosis . Study patients were categorized as having idiopathic pulmonary embolism or pulmonary embolism associated with transient risk factors . Idiopathic pulmonary embolism was defined as pulmonary embolism occurring in the absence of known cancer , known thrombophilia , or any transient risk factor for venous thromboembolism . Pulmonary embolism associated with transient risk factors was pulmonary embolism occurring after recent trauma with or without bone fracture , recent surgery or childbirth , or prolonged immobilization ( that is , lasting > 7 days ) , or occurring during the use of oral contraceptives or pregnancy . Patients with pulmonary embolism associated with permanent risk factors ( known cancer or known thrombophilia ) were excluded from the study . Systematic screening for occult cancer or thrombophilia was not performed before enrollment . Patients who required prolonged anticoagulant therapy for reasons other than venous thromboembolism were excluded from the study , as were patients with major psychiatric disorders , patients with a life expectancy shorter than 2 years , those who could not return for the follow-up visits , and those who declined to participate . The institutional review boards of the participating hospitals approved the study ; all patients gave informed consent . Study Design and Interventions The Warfarin Optimal Duration Italian Trial in patients with pulmonary embolism ( WODIT-PE ) was a multicenter r and omized , open trial with independent , blinded assessment of the outcome events . The study was design ed to evaluate the clinical benefit of extending the 3-month course of oral anticoagulant therapy after a first episode of pulmonary embolism . Patients who had completed 3 months of warfarin or acenocumarol therapy were r and omly assigned to discontinue anticoagulation or to continue it for 3 additional months ( pulmonary embolism associated with transient risk factors ) or 9 additional months ( idiopathic pulmonary embolism ) . R and omization was performed central ly in permuted blocks of six . The dose of warfarin or acenocumarol was adjusted to achieve a target international normalized ratio ( INR ) between 2.0 and 3.0 . The therapy was monitored in anticoagulant clinics associated with the study centers , all in Italy . Outcome Measures The primary outcome of the study was the recurrence of symptomatic , objective ly confirmed venous thromboembolism after the initial 3 months of anticoagulation . The secondary outcome was the cumulative incidence of adverse outcome events ( recurrence of venous thromboembolism , death , or major bleeding ) . The criteria for the diagnosis of recurrence of pulmonary embolism were a new filling defect revealed by pulmonary angiography or spiral computed tomography or a new high-probability perfusion defect revealed by ventilation-perfusion lung scan . Sudden , otherwise unexplained death was also considered a recurrence of pulmonary embolism . The criteria for the diagnosis of deep venous thrombosis as an outcome for recurrence of venous thromboembolism in patients without deep venous thrombosis at baseline were the presence of a noncompressible proximal vein on ultrasonography or an intraluminal filling defect on venography . In patients with deep venous thrombosis at baseline , the criteria for the diagnosis of recurrent deep venous thrombosis were abnormal results on compression ultrasonography ( proximal veins ) or venography in the contralateral leg or , in the ipsilateral leg , an extension of an intraluminal filling defect on venography ; a newly noncompressible venous segment ; or an increase of 4 mm or more in the diameter of the thrombus ( proximal veins ) on ultrasonography ( 10 ) . Bleeding was defined as major if it was clinical ly overt and associated with either a decrease in the hemoglobin level of at least 20 g/L or the need to transfuse two or more units of red blood cells , if it was retroperitoneal or intracranial , if it warranted the permanent discontinuation of therapy with the study drug , or if it required rehospitalization . Deaths were classified as the result of pulmonary embolism , bleeding , or another identifiable cause or as unexplained . All suspected outcome events ( recurrent thromboembolism and bleeding episodes ) and all deaths were review ed central ly by an independent , external adjudication committee whose members were unaware of the treatment group assignments . Follow-up Patients were instructed to return for follow-up visits at 3 , 6 , and 12 months after r and omization and every 6 months thereafter until the completion of the study . Patients were asked to return to the study center immediately if symptoms suggestive of recurrent venous thromboembolism or bleeding developed . For all patients who died during the follow-up period , the date and cause of death were documented . We attempted to gain permission for autopsies of all patients in whom pulmonary embolism could not be excluded as the cause of death . Statistical Analysis The primary analysis of efficacy was a comparison of the rates of symptomatic , objective ly confirmed recurrence of venous thromboembolism in the two treatment groups . The analysis was performed on an intention-to-treat basis . It was assumed that the rate of recurrence of venous thromboembolism would be 12 % in patients assigned to the discontinue oral anticoagulant therapy in the 2 years after discontinuation . We also assumed that the prolongation of oral anticoagulant therapy would produce a 50 % reduction in the risk for recurrence . Given these assumptions , we needed 312 patients in each group to detect a difference of this magnitude between groups with a power of 80 % and a type I error rate of 5 % . To avoid the exposure of the study patients to an ineffective or dangerous therapeutic regimen , one prespecified interim analysis of efficacy and safety was planned after we r and omly assigned 50 % of planned patients . The following criteria for stopping the trial were defined a priori : an overall rate of recurrence of thromboembolic events lower than 7.5 % , an unequivocal reduction in the rate of recurrent venous thromboembolism in the patients assigned to continue therapy ( P < 0.001 by a one-sided test ) , a risk for recurrence in the continued therapy group that was less than 25 % lower than that in the group assigned to discontinue therapy , or a rate of major bleeding higher than 5 % in the continued therapy group . The cumulative hazard of recurrent venous thromboembolism was calculated according to the Kaplan-Meier life-table method ( 11 ) . Rates of recurrence in the two groups were compared with the use of the log-rank test ( 12 ) . Results Patients Patients were recruited between January 1997 and December 2000 when , after 326 patients were included , the results of the interim analysis showed a difference of less than 25 % in the risk for recurrent venous thromboembolism between the two treatment groups . At the time Aims The r and omized PROTECT AF trial demonstrated non-inferiority of left atrial appendage ( LAA ) closure to oral anticoagulation with warfarin . Current guidelines give a class IIb recommendation for LAA closure . We evaluated the efficacy and safety of LAA closure in a consecutive series of non-valvular atrial fibrillation patients with contraindications to long-term oral anticoagulation or at high bleeding risk . Methods and results 101 consecutive non-valvular atrial fibrillation patients ( age 74.7 ± 7.5 years ) at high risk for stroke ( CHA2DS2-VASc Score 4.4 ± 1.6 ) and high bleeding risk ( HAS-BLED Score 4.2 ± 1.3 ) received LAA closure with either the Watchman closure device ( n = 38 ) or the Amplatzer cardiac plug ( n = 63 ) . Dual antiplatelet therapy with aspirin and clopidogrel was recommended for 3–6 months after device implantation , followed by long-term antiplatelet therapy with aspirin . No anticoagulation was given after device implantation . Mean follow-up was 400 days . One patient ( 1 % ) experienced a transient ischemic attack , and two patients ( 2 % ) suffered from ischemic stroke . While on recommended antiplatelet therapy , bleeding occurred in 12/101 patients ( 12 % ) . Bleeding was significantly reduced with 3 compared with 6 months dual antiplatelet therapy ( 3.0 vs. 16.2 % , p < 0.05 ) while ischemic or thrombotic events were similar . Conclusion Left atrial appendage closure in patients with non-valvular atrial fibrillation and high risk for stroke and bleeding events effectively prevented stroke and reduced cerebral ischemic events compared to expected stroke rate according to CHA2DS2-VASc Score . Dual antiplatelet therapy for 3 months reduced the rate of bleeding events compared to 6 months therapy with no increase of thrombotic events Dabigatran etexilate is a new anticoagulant which has demontstrated as efficient after deep vein thrombosis and atrial fibrilation . In these situation the benefit came from a better anticoagulation with a lower incidence of thrombotic events and with a much lower incidence of non-haemorhagic strokes compared with warfarin . The purpose of this r and omized trial was to demonstrate non-inferiority of 220 mg oral dabigatran etexilate compared to 40 mg subcutaneous enoxaparin administered once daily in terms of safety and efficacy administered in the first day after hip surgery . The primary efficacy end-point was a composite of total venous thromboembolic events and all cause mortality during the treatment period . Safety endpoints include major bleeding events , clinical ly relevant bleeding events , any bleeding events . The trial has been stopped prematurely by the ethics committee . Patients were r and omized to either oral dabigatran 220 mg once daily ( n=1010 ) or 40 mg subcutaneous enoxaparin ( n=1003 ) for an average of 32 days after total hip replacement . Dabigatran was found to be as effective and safe as injected enoxaparin with respect to the trial 's primary end point of total VTE and all-cause mortality ( 7.7 % vs. 8.8 % of patients , respectively with a noninferiority margin statistically significant , p<0.0001 . The most important finding relates to major VTE and VTE-related death . The difference was 2.2 % vs 4.2 % in the dabigatran vs enoxaparin groups , respectively , again statistically significant . Major bleeding events — classified as fatal , in a critical organ , or associated with a 20-mg/L fall in hemoglobin in excess of expected levels — were comparable between both treatment groups , 1.4 % of patients in the dabigatran group vs 0.9 % of those receiving enoxaparin had episodes of major bleeding ( p=0.40 ) . The study opens an opportunity in which the new generation of oral anticoagulant therapy can replace not only old and non predictable oral anticoagulation with warfarine , but also subcutaneous anticoagulation , with similar efficiency , similar bleeding risks and for sure lower costs . OBJECTIVES To assess the effects of acute pressor and depressor blood pressure ( BP ) manipulation on 2-week death and dependency following acute stroke and investigate the safety and efficacy of such treatments . DESIGN A multicentre , prospect i ve , r and omised , double-blind , placebo-controlled titrated-dose trial . SETTING Five hospitals in Engl and . PARTICIPANTS Patients over 18 years admitted to hospital with a clinical diagnosis of suspected stroke and either ( 1 ) symptom onset < 36 hours and hypertension , defined as systolic BP ( SBP ) < 160 mmHg ( depressor arm ) , or ( 2 ) symptom onset < 12 hours and hypotension , defined as SBP < or = 140 mmHg ( pressor arm ) . INTERVENTIONS Patients were allocated to either the pressor or the depressor arm depending on blood pressure at r and omisation . The ratio of allocation to active intervention versus matched placebo was 2:1 for the depressor arm and 1:1 for the pressor arm . MAIN OUTCOME MEASURES The primary end point was death and dependency at 2 weeks , with dependency defined as a modified Rankin score < 3 . Secondary end points were the safety of acute pressor  ( 0 - 12 hours post stroke ) and  depressor  ( 0 - 36 hours post stroke )  BP manipulation  in stroke patients ; whether effects of BP reduction are influenced by stroke type ( ischaemic versus haemorrhagic ) ; whether alternative routes for administration of antihypertensive therapy ( including sublingual and intravenous ) are effective in dysphagic stroke patients ; whether effects of BP manipulation are influenced by the time to treatment ; and the short- and medium-term cost-effectiveness of such therapy in the acute post-stroke period on subsequent disability or death . RESULTS 180 patients were recruited over the 36-month trial period , 179 in the depressor arm and one in the pressor arm ( who received placebo ) . No significant difference was found in death or dependency at 2 weeks between those receiving active depressor treatment with lisinopril or labetalol and those receiving placebo , although numbers recruited to the trial were lower than projected . Active treatment was not associated with an increase in early neurological deterioration despite significantly greater reductions in BP at 24 hours and 2 weeks with active therapy compared with placebo . Active treatment was generally well tolerated and treatment discontinuation rates were similar in active and placebo groups . Survival analysis showed that the active treatment group had a lower mortality at 3 months than the placebo group ( p = 0.05 ) . The pressor arm was closed early because of problems with recruitment , so no conclusions can be drawn regarding this therapy . CONCLUSIONS Oral and sublingual lisinopril and oral and intravenous labetalol are effective BP-lowering agents in acute cerebral infa rct ion and haemorrhage and do not increase the likelihood of early neurological deterioration . The study was not sufficiently powered to detect a difference in disability or death at 2 weeks . However , the 3-month difference in mortality in favour of active treatment is of interest , although care must be taken in interpretation of the results . Further work is needed to confirm this and to assess whether there are differences in the effectiveness of labetalol compared with lisinopril in terms of reducing death or dependency after acute stroke , and whether the introduction of treatment post stroke earlier than was achieved here would be of greater benefit OBJECTIVES The beneficial effect of oral anticoagulants after infrainguinal venous bypass surgery is compromised by bleeding complications . We developed a model to identify patients , treated with anticoagulation  , at risk of major haemorrhage and estimated whether this complication could have been prevented if patients had received aspirin . DESIGN R and omised clinical trial . METHODS Data of patients who participated in the Dutch Bypass Oral Anticoagulation or Aspirin Study were reanalysed using Cox regression . After infrainguinal bypass surgery these patients were r and omised to oral anticoagulants ( n = 1326 ) or aspirin ( n = 1324 ) . RESULTS Predictors of major haemorrhage for patients on oral anticoagulants were increased systolic blood pressure ( > or = 140 mmHg , hazard ratio [ HR ] 1.62 ) , age > or = 75 years ( HR 2.77 ) and diabetes mellitus ( HR 1.60 ) . If the 345 patients in the highest risk quartile had received aspirin , major haemorrhages would have been reduced from 46 to 22 , with no major changes in ischemic events and graft occlusions . In the subgroup with venous bypasses major haemorrhages would have been reduced from 27 to 13 , at the cost of seven more ischemic events ( mostly fatal ) and 17 more graft occlusions . CONCLUSIONS Treating patients at highest risk of major haemorrhage with aspirin instead of oral anticoagulants would have result ed in a reduction of non-fatal haemorrhages , but for venous bypasses this reduction was outweighed by an increase in ischemic events and graft occlusions . We still recommend treatment with oral anticoagulants after peripheral venous bypass surgery This article reports further analyses of the Hypertension Optimal Treatment ( HOT ) Study data with the aim to describe ( 1 ) the value of baseline serum creatinine and its clearance ( estimated by Cockroft and Gault formula ) as predictors of cardiovascular events , ( 2 ) the effects of intensive lowering of BP on cardiovascular events and renal function in patients with reduced renal function , and ( 3 ) the effects on cardiovascular events of adding acetylsalicylic acid to antihypertensive therapy in patients with reduced renal function . The results show that ( 1 ) baseline elevation in serum creatinine and a reduction in estimated creatinine clearance are powerful predictors of cardiovascular events and death . ( 2 ) Reduced renal function at baseline did not preclude the desired control of BP . In contrast to patients with normal renal function , the incidence of major cardiovascular events did not differ in the three groups of patients with mild renal insufficiency r and omized to different diastolic BP targets . No significant changes in serum creatinine were seen at the end of the 3.8-yr treatment period in the great majority of patients . However , there was a small group of patients ( 0.58 % of the total study population ) whose renal function deteriorated ( increase > or = 30 % over baseline and final serum creatinine concentration > or = 2 mg/dl ) despite satisfactory reduction of diastolic BP . ( 3 ) The results of this re analysis of the HOT Study suggest though do not prove that the association of acetylsalicylic acid with intensive antihypertensive therapy offers additional benefit in hypertensive patients with reduced renal function BACKGROUND The optimal intensity of oral anticoagulation for the prevention of recurrent thrombosis in patients with antiphospholipid antibody syndrome is uncertain . Retrospective studies show that only high-intensity oral anticoagulation [ target international normalized ratio ( INR ) > 3.0 ] is effective but a recent r and omized clinical trial comparing high ( INR range 3.0 - 4.0 ) vs. moderate ( INR 2.0 - 3.0 ) intensities of anticoagulation failed to confirm this assumption . METHODS We conducted a r and omized trial in which 109 patients with antiphospholipid syndrome ( APS ) and previous thrombosis were given either  high-intensity warfarin ( INR range 3.0 - 4.5 , 54 patients ) or st and ard antithrombotic therapy ( warfarin , INR range 2.0 - 3.0 in 52 patients or aspirin alone , 100 mg day(-1 ) in three patients ) to determine whether intensive anticoagulation is superior to st and ard treatment in preventing symptomatic thromboembolism without increasing the bleeding risk . RESULTS The 109 patients enrolled in the trial were followed up for a median time of 3.6 years . Mean INR during follow-up was 3.2 ( SD 0.6 ) in the high-intensity warfarin group and 2.5 ( SD 0.3 ) ( P < 0.0001 ) in the conventional treatment patients given warfarin . Recurrent thrombosis was observed in six of 54 patients ( 11.1 % ) assigned to receive high-intensity warfarin and in three of 55 patients ( 5.5 % ) assigned to receive conventional treatment [ hazard ratio for the high intensity group , 1.97 ; 95 % confidence interval ( CI ) 0.49 - 7.89 ] . Major and minor bleeding occurred in 15 patients ( two major ) ( 27.8 % ) assigned to receive high-intensity warfarin and eight ( three major ) ( 14.6 % ) assigned to receive conventional treatment ( hazard ratio 2.18 ; 95 % CI 0.92 - 5.15 ) . CONCLUSIONS High-intensity warfarin was not superior to st and ard treatment in preventing recurrent thrombosis in patients with APS and was associated with an increased rate of minor hemorrhagic complications Background —The optimal duration of oral anticoagulant therapy  after a first episode of venous thromboembolism remains controversial . Methods and Results —We performed an open-label , r and omized trial comparing a short oral anticoagulant course ( 3 months for proximal deep vein thrombosis [ P-DVT ] and /or pulmonary embolism [ PE ] ; 6 weeks for isolated calf DVT [ C-DVT ] ) with a long course of therapy ( 6 months for P-DVT/PE ; 12 weeks for C-DVT ) . The outcome events were recurrences and major , minor , or fatal bleeding complications . A total of 736 patients were enrolled . There were 23 recurrences of venous thromboembolism in the short treatment group ( 6.4 % ) and 26 in the long treatment group ( 7.4 % ) ; the 2 treatment regimens had an equivalent effect . For the hemorrhage end point , the difference between the short and the long treatment groups was not significant : 15.5 % versus 18.4 % for all events ( P = 0.302 ) , 1.7 % versus 2.8 % ( P = 0.291 ) for major events , and 13.9 % versus 15.3 % for minor bleeding . Subgroup analysis demonstrated that the rate of recurrence was lower for C-DVT than for P-DVT or PE . Conclusions —After isolated C-DVT , 6 weeks of oral anticoagulation is sufficient . For P-DVT or PE , we demonstrated an equivalence between 3 and 6 months of anticoagulant therapy . For patients with temporary risk factors who have a low risk of recurrence , 3 months of treatment seems to be sufficient . For patients with idiopathic venous thromboembolism or permanent risk factors who have a high risk of recurrence , other trials are necessary to assess prolonged therapy beyond 6 months OBJECTIVES Optimal antithrombotic/anticoagulation therapy in patients on chronic oral anticoagulation ( OAC ) undergoing drug-eluting stent ( DES ) implantation is unknown . We investigated the efficacy and safety of two regimens of antithrombotic/anticoagulation therapy in patients who present for DES implantation whilst on OAC . METHODS We included a series of 515 patients on OAC who underwent DES implantation between 2002 and 2007 . Based on predefined clinical and echocardiographic criteria , 306 patients continued OAC ( triple therapy )  and 209 patients discontinued OAC ( dual therapy ) for the time they received antiplatelet therapy with clopidogrel and aspirin [ stent-related antithrombotic treatment ( SRAT ) ] . The primary end point was a composite of death , myocardial infa rct ion , stent thrombosis or stroke . RESULTS During SRAT the primary endpoint was observed in 13 patients in the group with triple therapy versus 15 patients in the group with dual therapy [ Kaplan-Meier estimates 4.2 % and 7.2 % , odds ratio ( OR ) = 0.61 , 95 % confidence interval ( CI ) 0.29 - 1.28 ; P = 0.19 ] . At 2 years of follow-up , the primary endpoint was observed in 35 patients in the group with triple therapy versus 36 patients in the group with dual therapy ( Kaplan-Meier estimates 14.1 % and 18.0 % , OR = 0.76 , 95 % CI : 0.48 - 1.21 ; P = 0.25 ) . Two-year incidence of major bleeding was 1.4 % ( n = 4 , triple therapy ) versus 3.1 % ( n = 6 , dual therapy ) ( P = 0.34 ) . CONCLUSIONS In patients on chronic OAC undergoing DES implantation , clinical and echocardiographic criteria help to define postprocedural antithrombotic/anticoagulation therapy . Based on these criteria , both a double antiplatelet therapy ( clopidogrel plus aspirin ) and a triple therapy ( OAC plus clopidogrel plus aspirin ) are associated with favourable safety and efficacy The aim of this study was to assess the effectiveness of low-molecular-weight heparin ( LMWH ) treatment of  deep vein thrombosis ( DVT ) in terms of the evolution of thrombosis , the incidence of adverse events , and compliance with heparin treatment using 2 types of LMWH available on the market administered in therapeutic doses throughout the period of treatment ( Nadroparin ) or at therapeutic doses only during the first month of treatment followed by a prophylactic phase at half dose ( Parnaparin ) . A r and omized prospect i ve study was carried out on patients under observation with a recent diagnosis of DVT . The objectives of the study were to confirm the effectiveness of therapy with LMWH in terms of prevention of the risk of thromboembolism , of relapse of DVT , and of hemorrhagic complications , and to complete an evaluation of venous recanalization and residual valve competence in the 2 groups of patients . From December 2002 to June 2005 , we r and omized a total of 91 patients ( 51 in the Parnaparin group and 40 in the Nadroparin group ) . Overall , there was 1 case of nonfatal pulmonary embolism ( 1.1 % ) at 7 days into therapy with LMWH . There were 3 cases ( 3.3 % ) of progression of thrombosis despite therapy with LMWH , 2 cases ( 5 % ) in the Nadroparin group , and 1 case ( 2 % ) in the Parnaparin group ( P = NS ) , and after suspension of the therapy , there was 1 case of relapse of thrombosis . Three of the 4 thrombotic events occurred in patients with active neoplasia . Moreover , only 1 major hemorrhagic event ( 1.1 % ) required blood transfusion . The Doppler ultrasound in the follow-up showed a complete resolution of 56 % of the vein thromboses at an average of 6.1 ± 4.6 ( mean ± SD ) months . Valve competence recovered in 65.9 % of cases with no significant difference between the 2 heparin groups . Home treatment of sural and femoral-popliteal DVT using LMWH represents a safe and effective method in the prevention of pulmonary embolism and encourages the process of recanalization of the thrombosed vessel , especially in cases of sural and /or popliteal DVT . Administration can be carried out with the same degree of safety at the therapeutic dose throughout the period of treatment or can be halved after the first month of treatment . In patients with active neoplasia , treatment with oral anticoagulant therapy must be considered Eplerenone is a highly selective aldosterone blocking agent , which was recently approved for the treatment of hypertension and has also been shown to reduce mortality in post-myocardial infa rct ion patients with heart failure . To assess its usefulness in patients with essential hypertension , we performed a 12-week , double-blind , placebo-controlled , parallel-arm , fixed-dose study over a range of doses using clinic and ambulatory blood pressure ( BP ) . After single-blind placebo therapy for 3 to 4 weeks to obtain baseline measures , 400 patients were r and omized to receive placebo or 1 of 4 doses of eplerenone ( 25 , 50 , 100 , and 200 mg once daily ) . In addition , changes from baseline in serum potassium , active renin activity , and serum aldosterone were assessed . After 12 weeks of therapy , reductions in clinic BP showed a significant dose response in which 25 mg of eplerenone achieved statistical significance compared with placebo for systolic BP ; maximum clinic BP reduction was achieved with the 100 mg dose . Ambulatory BP monitoring showed that all doses of eplerenone ( 25 to 200 mg/day ) lowered BP significantly greater than placebo with a significant dose response . The 24-hour mean BP reductions ranged from 6.4/4.4 to 10.3/5.7 mm Hg on eplerenone compared with 1.3/0.8 mm Hg on placebo . One patient on placebo and 1 patient on 200 mg of eplerenone had episodes of elevated serum potassium levels ( > 5.5 mEq/L ) . Increases in serum aldosterone were related to dose but not to reductions in 24-hour BP . Side effects and withdrawal rates attributed to eplerenone were similar to those of placebo . These data show that eplerenone is an effective antihypertensive agent at doses as low as 25 mg/day . The top effective dose in stage 1 to 3 hypertension based on clinic and ambulatory BP was 100 mg once daily . The incidence of elevated serum potassium levels was not increased across doses of eplerenone in this study The objectives of the study were to clarify the relationship between blood pressure and mortality from stroke , heart disease , cardiovascular diseases and all causes of death among representative population of Japanese and to estimate category-specific excess mortality from stroke due to blood pressure ( BP ) level . The study design comprised a retrospective cohort study using the 1980 National Survey on Cardiovascular Diseases and identification of underlying causes of death using national vital statistics data . In 1994 , a 14-year follow-up cohort study was conducted among participants of the National Survey on Cardiovascular Diseases in 1980 , r and omly selected from the Japanese population . With a collaboration of 300 public health centres , which had conducted the original survey in 1980 , 91.4 % of the participants of the original survey could be followed up . Total observed person-years were 53 948 for men and 70 932 for women . During follow-up , 1327 deaths were observed . BP levels were significantly related to mortality from strokes , cardiovascular diseases and all causes of death for both sexes ( P<0.001 ) . Heart disease mortality was significantly related to BP levels among men ( P<0.05 ) while not among women . Estimated excess mortality was 130 % for men and 42 % for women and chiefly observed among moderate hypertensives ( 48 % for men and 16 % for women ) . In conclusion , high blood pressure was a risk factor for mortality from all causes as well as those from cardiovascular diseases , stroke and heart disease among Japanese . Since the major part of excess mortality was due to mild hypertension , a population strategy to reduce blood pressure should be encouraged INTRODUCTION Prothrombin complex concentrates ( PCCs ) are used for the urgent reversal of oral vitamin K antagonists in patients with life-threatening bleeding or prior to urgent procedures /surgery . PCCs offer rapid and complete reversal without the disadvantages of volume overload and adverse reactions seen with fresh frozen plasma ( FFP ) . There is concern about the risk of thrombosis associated with the use PCCs ; data on this is limited at present . OBJECTIVES To determine the incidence of objective ly confirmed arterial or venous thromboembolism within 30 days following the administration of PROTHROMBINEX ® -VF ( PTX-VF ) to acutely reverse a prolonged INR . MATERIAL S/ METHODS A prospect i ve observational study was conducted at two teaching hospitals in Auckl and , NZ . All patients who received PTX-VF  for the acute reversal of prolonged INR were eligible . Baseline patient demographics and reasons for PTX-VF administration were recorded . Patients were review ed at days 7 and 30 , to confirm/exclude thromboembolism or adverse events . RESULTS 173 patients were enrolled from August 2008 to March 2009 . The most frequent indication for reversal was acute bleeding . At 30 days 4.6 % ( 8/173 ) patients had a definite/probable thrombotic event , and 16.7 % had died either due to the presenting bleed ( intracranial haemorrhage ) or a complication of their presenting complaint ( e.g. sepsis , renal failure ) . CONCLUSIONS Acute reversal of anticoagulant therapy with PTX-VF is associated with a significant rate of thromboembolism ( 4.6 % ) within 30 days . These events can be explained by ongoing cessation of anticoagulant therapy in patients with ongoing risk factors for arterial or venous thrombosis , rather than directly attributable to PTX-VF therapy OBJECTIVES We studied the rate of thromboembolism in patients undergoing bioprosthetic replacement of the aortic or mitral valve , or both , at serial intervals after operation and the effects of anticoagulant or antiplatelet treatment  and risk factors . BACKGROUND Thromboembolism appears to occur early after operation , but the incidence , timing and risk factors for thromboembolism and the role , timing , adequacy , effectiveness , duration and risk of anticoagulation and antiplatelet agents are uncertain . METHODS The rate of thromboembolism was studied at three time intervals after operation ( 1 to 10 , 11 to 90 and > 90 days ) in 816 patients who underwent bioprosthetic replacement of the aortic or mitral valve , or both , at the Mayo Clinic from January 1975 to December 1982 . The effect of antithrombotic therapy ( warfarin , aspirin or dipyridamole , alone or in combination ) was evaluated . RESULTS Median follow-up of surviving patients was 8.6 years . The rate of thromboembolism ( % /year ) decreased significantly ( p < 0.01 ) at each time interval after operation ( 1 to 10 , 11 to 90 and > 90 days ) for mitral valve replacement ( 55 % , 10 % and 2.4%/year , respectively ) and over the first time interval for aortic valve replacement ( 41 % , 3.6 % and 1.9%/year , respectively ) . During the first 10 days , 52 % to 70 % of prothrombin time ratios were low ( < 1.5 x control ) . Patients with mitral valve replacement who received anticoagulation had a lower rate of thromboembolism for the entire follow-up period ( 2.5%/year with vs. 3.9%/year without anticoagulation , p = 0.05 ) . Of 112 patients with a first thromboembolic episode , permanent disability occurred in 38 % and death in 4 % . Risk factors for emboli were lack of anticoagulation , mitral valve location , history of thromboembolism and increasing age . Only 10 % of aortic , 44 % of mitral and 17 % of double valve recipients had anticoagulation at the time of an event . Patients with bleeding episodes ( 2.3%/year ) were older and usually underwent anticoagulation . Blood transfusions were required in 60 of 111 patients ( 1.2%/year ) , and 13 patients ( 0.3%/year ) died . CONCLUSIONS Thromboembolic risk was especially high for aortic and mitral valve replacement for 90 days after operation , and overall was increased with lack of anticoagulation , mitral valve location , previous thromboembolism and increasing age . Anticoagulation reduced thromboemboli and appears to be indicated in all patients as early as possible for 3 months and thereafter in those with risk factors , but needs prospect i ve testing BACKGROUND Bleeding is the most serious complication of the use of oral anticoagulation in the prevention and treatment of thromoboembolic complications . We studied the frequency of bleeding complications in out patients treated routinely in anticoagulation clinics . METHODS In a prospect i ve cohort from thirty-four Italian anticoagulation clinics , 2745 consecutive patients were studied from the start of their oral anticoagulation ( warfarin in 64 % , acenocourmarol in the rest ) . The target anticoagulation-intensity was low ( international normalised ratio [ INR ] < or = 2.8 ) in 71 % of the patients and high ( > 2.8 ) in the remainder . We recorded demographic details and the main indication for treatment and , every 3 - 4 months , INR and outcome events . Such events included all complications ( bleeding , thrombosis , other ) , although only bleeding events are reported here , and deaths . We divided bleeding into major and minor categories . FINDINGS 43 % of the patients were women . Nearly three-fifths of the patients were aged 60 - 79 ; 8 % were over 80 . The main indication for treatment was venous thrombolism ( 33 % ) , followed by non-ischaemic heart disease ( 17 % ) . Mean follow-up was 267 days . Over 2011 patient-years of follow-up , 153 bleeding complications occurred ( 7.6 per 100 patient-years ) . 5 were fatal ( all cerebral haemorrhages , 0.25 per 100 patient-years ) , 23 were major ( 1.1 ) , and 125 were minor ( 6.2 ) . The rate of events was similar between sexes , coumarin type , size of enrolling centre , and target INR . The rate was higher in older patients : 10.5 per 100 patient-years in those aged 70 or over , 6.0 in those aged under 70 ( relative risk 1.75 , 95 % Cl 1.29 - 2.39 , p < 0.001 ) . The rate was also higher when the indication was peripheral and /or cerebrovascular disease than venous thromboembolism plus other indications ( 12.5 vs 6.0 per 100 patient-years ) ( 1.80 , 1.2 - 2.7 , p < 0.01 ) , and during the first 90 days of treatment compared with later ( 11.0 vs 6.3 , 1.75 , 1.27 - 2.44 , p < 0.001 ) . A fifth of the bleeding events occurred at low anticoagulation intensity ( INR < 2 , rate 7.7 per 100 patient-years of follow-up ) . The rates were 4.8 , 9.5 , 40.5 , and 200 at INRs 2.0 - 2.9 , 3 - 4.4 , 4.5 - 6.9 , and over 7 , respectively ( relative risks for INR > 4.5 , 7.91 , 5.44 - 11.5 , p < 0.0001 ) . INTERPRETATION We saw fewer bleeding events than those recorded in other observational and experimental studies . Oral anticoagulation has become safer in recent years , especially if monitored in anticoagulation clinics . Caution is required in elderly patients and anticoagulation intensity should be closely monitored to reduce periods of overdosing Background Half of all lower limb deep vein thrombi ( DVT ) in symptomatic ambulatory patients are located in the distal ( calf ) veins . While proximal disease warrants therapeutic anticoagulation to reduce the associated risks , distal DVT often goes untreated . However , a proportion of untreated distal disease will undoubtedly propagate or embolize . Concern also exists that untreated disease could lead to long-term post thrombotic changes . Currently , it is not possible to predict which distal thrombi will develop such complications . Whether these potential risks outweigh those associated with unrestricted anticoagulation remains unclear . The Anticoagulation of Calf Thrombosis ( ACT ) trial aims to compare therapeutic anticoagulation against conservative management for patients with acute symptomatic distal deep vein thrombosis . Methods ACT is a pragmatic , open-label , r and omized controlled trial . Adult patients diagnosed with acute distal DVT will be allocated to either therapeutic anticoagulation or conservative management . All patients will undergo 3 months of clinical and assessor blinded sonographic follow-up , followed by 2-year final review . The project will commence initially as an external pilot study , recruiting over a 16-month period at a single center to assess feasibility measures and clinical event rates . Primary outcome measures will assess feasibility endpoints . Secondary clinical outcomes will be collected to gather accurate data for the design of a definitive clinical trial and will include : ( 1 ) a composite endpoint combining thrombus propagation to the popliteal vein or above , development of symptomatic pulmonary embolism or sudden death attributable to venous thromboembolic disease ; ( 2 ) the incidence of major and minor bleeding episodes ; ( 3 ) the incidence of post-thrombotic leg syndrome at 2 years using a vali date d screening tool ; and ( 4 ) the incidence of venous thromboembolism ( VTE ) recurrence at 2 years . Discussion The ACT trial will explore the feasibility of comparing therapeutic anticoagulation to conservative management in acute distal DVT , within a modern cohort . We also aim to provide contemporary data on clot propagation , bleeding rates and long-term outcomes within both groups . These results will inform the conduct of a definitive study if feasibility is established . Trial registration Current Controlled Trials IS RCT Context Doctors typically treat deep venous thrombosis with anticoagulants for 3 to 6 months to prevent recurrence . Patients at high risk for recurrence may benefit from longer treatment . Can we identify them with ultrasonography that detects persistent thrombosis ? Contribution Three hundred thirteen patients with deep venous thrombosis had ultrasonography  every 6 to 12 months for 3 years . Recurrent thromboembolism , assessed over 6 years , was more frequent among those showing persistent residual thrombosis rather than early vein recanalization . Implication s We now need trials that evaluate prolonged anticoagulation in patients with and without residual thrombosis to see whether tailoring treatment on the basis of serial ultrasonography is beneficial . The Editors Patients with deep venous thrombosis ( DVT ) of the lower extremities are usually treated with an initial course of unfractionated or low-molecular-weight heparin followed by at least 3 months of oral anticoagulant therapy . This treatment regimen reduces the risk for short-term thromboembolic complications to approximately 5 % ( 1 , 2 ) . Although the short-term outcome of this disease has been extensively documented , only a few studies have addressed the risk for late recurrent venous thromboembolism . These studies suggest that this risk persists for years and is related to patient characteristics at initial presentation ( 1 , 2 ) . It has been documented that patients with continuous risk factors , such as cancer or the antiphospholipid antibody syndrome , and those with idiopathic thrombosis have a two- to threefold increased risk for recurrence compared with patients who developed a thrombotic event in association with a transient risk factor ( 3 - 5 ) . As a consequence , longer anticoagulant treatment ( up to several years ) has been evaluated in patients with idiopathic DVT , with the aim of decreasing recurrences in patients with idiopathic DVT ( 6 , 7 ) . Although long-term anticoagulant therapy is effective in preventing recurrences , it is inconvenient and carries a risk for bleeding ( 8 - 11 ) . It would be beneficial to further improve our ability to identify patients who are at higher risk for recurrent events . The absolute incidence of recurrent venous thromboembolism decreases over time ( 3 , 5 ) . Residual thrombus mass also decreases over time in patients with proximal venous thrombosis , according to recent studies that used repeated ultrasonographic imaging ( 12 , 13 ) . If vein recanalization indicates a lower risk for recurrent disease , ultrasonographic imaging might help clinicians adjust the duration of oral anticoagulant therapy on an individual basis in patients who have had an episode of DVT . To estimate whether the risk for recurrent venous thromboembolism is higher in the presence of residual thrombosis , we performed repeated ultrasonography in a large number of patients with proximal venous thrombosis who were followed prospect ively for up to 6 years . Methods Study Design We performed a prospect i ve cohort follow-up study to assess the potential effect of residual venous thrombosis on the risk for recurrent venous thromboembolism in patients with a first episode of symptomatic DVT . The institutional review board of Padua University , Padua , Italy , approved the study . Inception Cohort All consecutive out patients who were referred to the Department of Medical and Surgical Sciences of the University of Padua between 1993 and 1996 for clinical suspicion of a first episode of DVT and who met inclusion criteria were eligible . Inclusion criteria were proximal venous thrombosis on compression ultrasonography , absence of diseases requiring indefinite anticoagulation ( such as atrial fibrillation , active cancer , chronic medical illnesses , or other permanent risk factors for venous thrombosis ) , life expectancy of more than 6 months , and ability to return to the study center for follow-up visits . Eligible patients received conventional anticoagulation ( full doses of unfractionated or low-molecular-weight heparin followed by 3 months of oral anticoagulant therapy ) . Patients who completed the initial 3 months of treatment without a recurrent thrombotic episode and who gave informed consent were recruited for the current study . On the basis of laboratory results and clinical characteristics , patients were divided into three categories : those who had thrombophilia , those who had secondary DVT , and those who had idiopathic DVT . Tests for thrombophilia ( antithrombin , protein C or S defect , factor V Leiden mutation , prothrombin G20210 gene mutation , and lupus-like anticoagulants ) were performed before anticoagulation was started or at least 2 weeks after its conclusion . On the basis of test results , patients were categorized as being with or without thrombophilia . Patients without thrombophilia were further classified as having idiopathic DVT or DVT secondary to transient risk factors , according to a st and ardized form for clinical data collection completed at referral . Secondary thrombosis was defined as that occurring during pregnancy or childbirth ; during estrogen use for contraception or hormone replacement therapy ( ongoing or interrupted for < 1 month ) ; or after recent trauma , fracture , or surgery ( within <3 months ) . If thrombophilia screening could not be performed , patients were classified as having idiopathic or secondary DVT on the basis of clinical presentation . Ultrasonographic Assessment s The first ultrasonographic assessment was performed 3 months after the initial event . Patients found to have residual thrombosis were scheduled for repeated assessment 6 , 12 , 24 , and 36 months after the initial event . Independent experts who were unaware of patients ' clinical details or of previous ultrasonographic findings performed assessment s according to a st and ardized procedure . Only the common femoral vein at the saphenofemoral junction and the popliteal vein in the midpopliteal fossa were scanned for residual venous thrombosis . Vein compression was performed in the transverse plane ; vein diameter was measured during maximal compression and was expressed in millimeters . Veins were considered recanalized if they were 2.0 mm or less in diameter on a single test or 3.0 mm or less in diameter on two consecutive tests . This definition was based on ultrasonographic findings from a separate group of 145 patients with proven proximal DVT who were followed prospect ively at our institution in the early 1990s ; fewer than 2.0 % of these patients developed recurrent thromboembolism in the 2 years after vein recanalization ( 12 ) . Follow-up and Recurrent Venous Thromboembolism All recruited patients were instructed to interrupt oral anticoagulant therapy when they were included in the current study . Patients were followed to document the incidence of symptomatic recurrent DVT or pulmonary embolism . Patients were educated about the main signs and symptoms of recurrent venous thromboembolism and received a card with the telephone numbers of the thrombosis clinic . They were instructed to return to the study center if they noted clinical manifestations suggestive of recurrent venous thrombosis ( edema , redness , tenderness , pain , or swelling ) in either leg or suggestive of pulmonary embolism ( dyspnea , chest pain , or tachycardia ) . Patients were also seen at the time of ultrasonographic assessment s and were contacted at least twice yearly to ascertain whether signs and symptoms had occurred . If they had , patients were invited to come to the study center for additional diagnostic procedures . Recurrent DVT was diagnosed by compression ultrasonography , followed by ascending phlebography in case of indeterminate findings , or a strong discrepancy between clinical suspicion and negative results on ultrasonography ( 14 ) . Patients with suspected pulmonary embolism had ventilationperfusion lung scanning , which was followed by pulmonary angiography if findings were inconclusive ( 15 ) . Fatal pulmonary embolism was diagnosed on the basis of autopsy findings or the opinion of an independent physician . Statistical Analysis The first 3 months of initial anticoagulant treatment were not included in any of our analyses . For the remaining months , KaplanMeier estimates and 95 % CIs were calculated to assess the risk for recurrent venous thromboembolism . Time-dependent multivariate Cox proportional-hazards models were then used to calculate hazard ratios for recurrent venous thromboembolism in patients with residual thrombosis versus those without . For this analysis , patients who did not have a recurrence were censored at the end of the available follow-up or at death . In addition , the clinical categorization of patients was evaluated by using two dummy variables to indicate the presence of idiopathic DVT or thrombophilia . Secondary thrombosis was therefore used as the reference group , and in each case , the duration of oral anticoagulant treatment was used as a time-dependent covariate . Finally , all of these variables , as well as age and sex , were introduced in a stepwise hierarchical Cox model ( 16 , 17 ) . The results of these analyses were expressed as risk ratios and 95 % CIs . In addition , incidence density of recurrent venous thromboembolism ( events per observation-year ) was calculated for the various combinations of clinical characteristics . All calculations were performed by using SAS software , version 6.10 ( SAS Institute , Inc. , Cary , North Carolina ) . Results Patients Of 1250 patients who were referred for clinical suspicion of first DVT , 389 ( 31.1 % ) received a diagnosis of proximal venous thrombosis on compression ultrasonography ( Figure 1 ) . Forty-nine of these 389 patients were excluded because of poor life expectancy ( n = 29 ) , diseases requiring permanent anticoagulation ( n = 14 ) , or inability to attend follow-up visits ( n = 6 ) . Of the remaining 340 eligible patients , 25 developed a recurrent thromboembolic event during initial anticoagulation . Therefore , 315 patients completed an uneventful 3-month period of anticoagulation The PIONEER AF-PCI trial ( Open-Label , R and omized , Controlled , Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with AF who Undergo Percutaneous Coronary Intervention ) is an ambitious , open-label comparison of 3 regimens , almost exclusively in Caucasians , all of whom had coexisting atrial fibrillation and atherosclerotic coronary artery disease requiring stenting ( PCI-S ) . These 2 conditions when they coexist pose a clinical challenge , necessitating concurrent usage of dual antiplatelet and anticoagulation therapy , a cocktail which presents major bleeding risks . Because anticoagulation therapy is suboptimal in preventing stent thrombosis and dual anti platelet therapy is inadequate in averting embolic stroke in atrial fibrillation , neither treatment is sufficient and they must be combined . The study has a unique design and consists of 2 treatment arms and a control ( see Figure 1 for trial design ) , each with about 700 patients and a 20 % dropout rate in groups 1 and 2 but a statistically greater rate of 29 % in group 3 . Both treatment arms are modeled upon previous studies , which involved patients with the need for both antiplatelet therapy and anticoagulation ( see Figure 2 for derivation of trial from WOEST and ATLAS-TIMI 51 ) . The control arm , design ated group 3 in the trial , consists of the US st and ard of practice regimen , in this situation , called “ triple therapy , ” consisting of aspirin 100 mg/d , clopidogrel 75 mg/d , and warfarin maintaining the INR between 2 and 3 . About 7 % of patients in groups 1 and 2 received a different P2Y12 inhibitor , either prasugrel or ticagrelor , and about 4 % in group 3 . Prominent among the numerous exclusions were patients with a previous stroke and a creatinine clearance of under 30 mL/min . In arm 1 , patients with a creatinine clearance between 30 and 60 mL/min received a lower dose of 10 mg of rivaroxaban . The first treatment arm , called arm 1 , is a reprisal of the treatment arm of the Belgian 2013 WOEST trial which showed that clopidogrel 75 mg and warfarin , maintaining an INR of 2 to 3 , were associated with less combined TIMI major and minor bleeding as well as no increase in cardiac or neurological thrombotic complications when compared to the same control arm as is in this study . Despite having studied only 573 patients for just a year , WOEST was influential in generating the recommendation ( level B ) from the European Society of Cardiology to use this regimen in some people at high risk for bleeding with stents who also require anticoagulation . Furthermore in PIONEER , arm 1 , rivaroxaban 15 mg has been substituted for warfarin ; otherwise , the other trial drugs are identical to those in WOEST . A compelling question posed by this arm of the study , although not the primary end point of the study , is whether equivalent stent patency or prevention of atherosclerotic or thromboembolic complications can be achieved with only a single antiplatelet drug throughout the entire 12 months of treatment , including the vital first month poststent . Also addressed is whether the WOEST results can be replicated substituting rivaroxaban , a drug that offers several advantages over warfarin . In treatment group 1 , one would intuitively expect confirmation of the bleeding advantage observed in WOEST , since it contains 2 drugs versus the 3 in the control group , and therefore would be expected to be associated with less bleeding in group 1 versus group 3 . The second treatment group is based on the 2012 ATLAS ACS 2-TIMI 51 trial and consists of very-low-dose rivaroxaban 2.5 mg twice a day along with clopidogrel 75 mg/d and aspirin 100 mg/d . An interesting point of arm 2 versus 3 , although again not the primary end point , is if a dosage of rivaroxaban , which is only 25 % of the FDA -approved dose of that needed to treat atrial fibrillation , would be adequate in preventing embolic strokes . One would anticipate in group 2 that the dual antiplatelet therapy would be equally effective in preventing stent occlusion and recurrent coronary events as the Background and purpose It is unknown what the optimal anticoagulant level is to prevent thromboembolic stroke in patients with left ventricular assist device ( LVAD ) support . We aim ed to evaluate the relation between coagulation status and the occurrence of thromboembolic stroke in HeartMate-II LVAD assisted patients . Methods Thirty-eight consecutive patients with a HeartMate-II LVAD were included . Coagulation status was classified according to INR and aPTT ratio at : 1 ) the moment of first thromboembolic stroke ; and 2 ) during the two weeks preceding the first thromboembolic stroke to assess long-term coagulation status . In patients without stroke , coagulation status was determined just before heart transplant , VAD explantation or death , whichever came first , and at two weeks preceding these surrogate endpoints . Based on coagulation status , patients were divided in two groups : Group I ( reference group ) was defined as INR below 2 and aPTT ratio below 1.5 ; Group II ( adequate anticoagulation ) as INR above 2 or aPTT ratio above 1.5 . Logistic regression analysis was performed to assess the odds ratio for developing stroke for patients with adequate anticoagulation compared to the reference Group . Results Thromboembolic stroke occurred in six ( 16 % ) patients , none within 2 weeks after LVAD implantation . Considering coagulation status at the time of event , patients in coagulation Group II had no decreased risk for thromboembolic stroke ( OR 0.78 ; 95 % CI 0.12–5.0 ) . Results for coagulation status 2 weeks prior of event could not be calculated as all six strokes occurred in Group II . Conclusion In our experience anticoagulation within predefined targets is not associated with a reduced thromboembolic stroke risk in patients with a HeartMate-II LVAD on antiplatelet therapy . However , no firm statement about the effect of either anticoagulant or antiaggregant therapy can be made based on our study . A larger r and omized study is needed to support the hypothesis that there may be no additional benefit of coumarin or heparin therapy compared with antiplatelet therapy alone Background The post‐thrombotic syndrome frequently develops in patients with proximal deep‐vein thrombosis despite treatment with  anticoagulant therapy . Pharmacomechanical catheter‐directed thrombolysis ( hereafter “ pharmacomechanical thrombolysis ” ) rapidly removes thrombus and is hypothesized to reduce the risk of the post‐thrombotic syndrome . Methods We r and omly assigned 692 patients with acute proximal deep‐vein thrombosis to receive either anticoagulation alone ( control group ) or anticoagulation plus pharmacomechanical thrombolysis ( catheter‐mediated or device‐mediated intrathrombus delivery of recombinant tissue plasminogen activator and thrombus aspiration or maceration , with or without stenting ) . The primary outcome was development of the post‐thrombotic syndrome between 6 and 24 months of follow‐up . Results Between 6 and 24 months , there was no significant between‐group difference in the percentage of patients with the post‐thrombotic syndrome ( 47 % in the pharmacomechanical‐thrombolysis group and 48 % in the control group ; risk ratio , 0.96 ; 95 % confidence interval [ CI ] , 0.82 to 1.11 ; P=0.56 ) . Pharmacomechanical thrombolysis led to more major bleeding events within 10 days ( 1.7 % vs. 0.3 % of patients , P=0.049 ) , but no significant difference in recurrent venous thromboembolism was seen over the 24‐month follow‐up period ( 12 % in the pharmacomechanical‐thrombolysis group and 8 % in the control group , P=0.09 ) . Moderate‐to‐severe post‐thrombotic syndrome occurred in 18 % of patients in the pharmacomechanical‐thrombolysis group versus 24 % of those in the control group ( risk ratio , 0.73 ; 95 % CI , 0.54 to 0.98 ; P=0.04 ) . Severity scores for the post‐thrombotic syndrome were lower in the pharmacomechanical‐thrombolysis group than in the control group at 6 , 12 , 18 , and 24 months of follow‐up ( P<0.01 for the comparison of the Villalta scores at each time point ) , but the improvement in quality of life from baseline to 24 months did not differ significantly between the treatment groups . Conclusions Among patients with acute proximal deep‐vein thrombosis , the addition of pharmacomechanical catheter‐directed thrombolysis to anticoagulation did not result in a lower risk of the post‐thrombotic syndrome but did result in a higher risk of major bleeding . ( Funded by the National Heart , Lung , and Blood Institute and others ; ATTRACT Clinical Trials.gov number , NCT00790335 . Patients receiving chemotherapy for metastatic breast cancer are at high risk of thromboembolic disease . Long-term oral anticoagulant therapy is needed but increases the risk of haemorrhagic complications . We have assessed the safety and efficacy of warfarin in very low doses as prophylaxis . Women receiving chemotherapy for metastatic breast cancer were r and omly assigned either very-low-dose warfarin ( 152 patients ) or placebo ( 159 ) . The warfarin dose was 1 mg daily for 6 weeks and was then adjusted to maintain the prothrombin time at an international normalised ratio ( INR ) of 1.3 to 1.9 . Study treatment continued until 1 week after the end of chemotherapy . The average daily dose from initiation of titration was 2.6 ( SD 1.2 ) mg for the warfarin group and the mean INR was 1.52 . The mean time at risk of thrombosis was 199 ( 126 ) days for warfarin-treated patients and 188 ( 137 ) days for placebo recipients ( p = 0.45 ) . There were 7 thromboembolic events ( 6 deep-vein thrombosis , 1 pulmonary embolism ) in the placebo group and 1 ( pulmonary embolism ) in the warfarin group , a relative risk reduction of about 85 % ( p = 0.031 ) . Major bleeding occurred in 2 placebo recipients and 1 warfarin-treated patient . There was no detectable difference in survival between the treatment groups . Very-low-dose warfarin is a safe and effective method for prevention of thromboembolism in patients with metastatic breast cancer who are receiving chemotherapy Background Blood pressure ( BP ) within pre-hypertensive levels confers higher cardiovascular risk and is an intermediate stage for full hypertension , which develops in an annual rate of 7 out of 100 individuals with 40 to 50 years of age . Non-drug interventions to prevent hypertension have had low effectiveness . In individuals with previous cardiovascular disease or diabetes , the use of BP-lowering agents reduces the incidence of major cardiovascular events . In the absence of higher baseline risk , the use of BP agents reduces the incidence of hypertension . The PREVER-prevention trial aims to investigate the efficacy , safety and feasibility of a population -based intervention to prevent the incidence of hypertension and the development of target-organ damage . Methods This is a r and omized , double-blind , placebo-controlled clinical trial , with participants aged 30 to 70 years , with pre-hypertension . The trial arms will be chlorthalidone 12.5 mg plus amiloride 2.5 mg or identical placebo . The primary outcomes will be the incidence of hypertension , adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG . The secondary outcomes will be fatal or non-fatal cardiovascular events : myocardial infa rct ion , stroke , heart failure , evidence of new sub- clinical atherosclerosis , and sudden death . The study will last 18 months . The sample size was calculated on the basis of an incidence of hypertension of 14 % in the control group , a size effect of 40 % , power of 85 % and P alpha of 5 % , result ing in 625 participants per group . The project was approved by the Ethics committee of each participating institution . Discussion The early use of blood pressure-lowering drugs , particularly diuretics , which act on the main mechanism of blood pressure rising with age , may prevent cardiovascular events and the incidence of hypertension in individuals with hypertension . If this intervention shows to be effective and safe in a population -based perspective , it could be the basis for an innovative public health program to prevent hypertension in Brazil . Trial Registration Clinical Trials NCT00970931 Background Long-term oral anticoagulation treatment is associated with potential morbidity . Insufficient patient education is linked to poorly controlled anticoagulation . However the impact of a specific educational program on anticoagulation related morbidity remains unknown . Objective To evaluate the effect of an oral anticoagulation patient education program in reducing both hemorrhagic and recurrent thrombotic complications . Design / Participants We conducted a prospect i ve , multicenter open r and omized study , comparing an interventional group who received a specific oral anticoagulation treatment educational program with a control group . Eligible patients were older than 18 and diagnosed as having deep vein thrombosis or pulmonary embolism requiring therapy with a vitamin K antagonist for 3 months or more . Our primary outcome was the occurrence of hemorrhagic or thromboembolic events . Results During the 3-month follow-up the main outcome criteria were observed 20 times ( 6.6 % of patients ) , 5 ( 3.1 % ) in the experimental and 15 ( 10.6 % ) in the control group . Consequently , in multivariate analysis , the cumulative risk reduction in the experimental group was statistically significant ( OR 0.25 , 95 % CI 0.1 – 0.7 , p < 0.01 ) . Conclusions Patient education using an educational program reduced VKA-related adverse event rates PURPOSE The efficacy and safety of new antiplatelet therapies , as well as antiplatelet therapies in development , are review ed . SUMMARY Variability in the response to treatment with aspirin has been recognized for more than 40 years . Thienopyridine antiplatelet agents are now a st and ard pharmacologic component in the management of patients undergoing percutaneous coronary intervention ( PCI ) and stent placement . However , investigators have recently described wide inter-individual variability in the level of platelet inhibition following treatment with the thienopyridine clopidogrel , with a small number of patients classified as " non-responders " or " resistant . " Such variability in response is likely to have important clinical implication s , because antiplatelet therapy plays a key role in the prevention and treatment of cardiovascular disease , For example , recent studies have demonstrated that diminished response to clopidogrel may be associated with increased cardiac events after PCI . Even with larger-than-approved loading doses , clopidogrel requires several hours to reach a steady-state effect , and therapy must be discontinued for several days prior to surgery in order to avoid major bleeding events . Clinical trials of prasugrel , a new oral thienopyridine with a more rapid onset of platelet inhibition , have demonstrated significant reductions in adverse cardiovascular outcomes and stent thrombosis ; however , there is an increased risk for major bleeding events with prasugrel in some subgroups of the study population s. These limitations have led to development of agents that may potentially overcome such clinical challenges . AZD6140 , a novel , potent oral P2Y12 antagonist , demonstrated more effective platelet inhibition versus clopidogrel in a large r and omized trial of patients with acute coronary syndrome . However , patients taking AZD6140  reported dyspnea significantly more frequently than those taking clopidogrel . Cangrelor , a novel intravenous P2Y(12 ) receptor antagonist with a rapid onset of action and complete reversibility of platelet inhibition within 20 - 50 minutes of administration , may offer advantages over currently approved antiplatelet therapies . A new oral antiplatelet thrombin-receptor antagonist , TRA-SCH 530348 , is in early clinical trials . Unlike currently available drugs , TRA-SCH 530348 effectively prevents thrombin-induced activation of platelets . CONCLUSION Each new class of antiplatelet therapies has the potential for specific benefits and adverse effects in clinical use No r and omized study comparing the effect of combined ticlopidine and aspirin therapy versus each drug alone in reducing poststenting thrombotic complications has been performed . To compare these three antiplatelet regimens versus placebo , we conducted a double-blind r and omized study using an ex vivo model of thrombosis . Sixteen healthy male volunteers were assigned to receive for 8 days the following four regimens separated by a 1-month period : aspirin 325 mg/d , ticlopidine 500 mg/d , aspirin 325 mg/d + ticlopidine 500 mg/d , and placebo . At the end of each treatment period , native nonanticoagulated blood was drawn directly from an antecubital vein over collagen- or tissue factor (TF)-coated coverslips positioned in a parallel-plate perfusion chamber at an arterial wall shear rate ( 2 , 600 s-1 ) for 3 minutes . Thrombus , which formed on collagen in volunteers treated by placebo , were rich in platelets and poor in fibrin . As compared with placebo , aspirin and ticlopidine alone reduced platelet thrombus formation by only 29 % and 15 % , respectively ( P > .2 ) . In contrast , platelet thrombus formation was blocked by more than 90 % in volunteers treated by aspirin + ticlopidine ( P < .01 v placebo or each treatment alone ) . Furthermore , the effect of the drug combination therapy was significantly larger than the sum of the two active treatments ( P < .05 ) . Thrombus , which formed on TF-coated coverslips in volunteers treated by placebo , were rich in fibrin and platelets . Neither of the three antiplatelet treatments significantly inhibited fibrin deposition and platelet thrombus formation on this surface ( P > .2 ) . Thus , the present study shows that combined aspirin and ticlopidine therapy dramatically potentiates the antithrombotic effect of each drug alone , but that the antithrombotic effect of the combined treatment depends on the nature of the thrombogenic surface PURPOSE The thrombogenicity of newer anticancer agents and the challenges associated with managing cancer patients on warfarin have led to the evaluation of the low-molecular-weight heparins ( LMWHs ) for primary and secondary prophylaxis in this high-risk patient population . SUMMARY The first published trial of LMWH in cancer compared three months of warfarin therapy with enoxaparin in cancer patients with proximal deep venous thrombosis ( DVT ) , pulmonary embolism ( PE ) , or both . All patients received four days of enoxaparin 1.5 mg/kg and were then r and omized to continue receiving enoxaparin or begin warfarin therapy . Due to inadequate patient enrollment , no statistically significant differences were detected between the two treatment groups . In a similar patient population , the Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer ( CLOT ) trial evaluated the use of long-term dalteparin for the prevention of recurrent venous thromboembolism ( VTE ) in patients with cancer . Cancer patients with proximal DVT , PE , or both were r and omized to initial treatment with dalteparin followed by either six months of oral anticoagulant therapy or dalteparin monotherapy . The primary outcome was symptomatic , recurrent VTE , and secondary outcomes were bleeding events and survival time . The cumulative risk of recurrent VTE at six months was reduced from 17 % in the oral anticoagulant group to 9 % in the dalteparin group , a risk reduction of 52 % ( p=0.002 ) . No significant differences in bleeding events or overall mortality occurred between the groups . Recent recommendations from the American College of Chest Physicians on the treatment of cancer-associated thrombosis are based in part on data from the CLOT trial and support the use of dalteparin and tinzaparin in the long-term treatment of patients with DVT and cancer . Finally , results of recent trials support the concept that antithrombotic therapy with dalteparin or nadroparin may have an antineoplastic effect , result ing in improved survival time . However , these results require further validation . CONCLUSION Despite the absence of oncology-specific guidelines for cancer-associated thrombosis , pharmacists now have a number of new tools available for selecting an anticoagulant , including results from several clinical trials with LMWHs and recent reports from national meetings BACKGROUND In the elderly the impact of atrial fibrillation on mortality and morbidity is substantial . Oral anticoagulant therapy reduces the risk of stroke by 70 % ; nevertheless , it remains largely underused . We evaluated , in a community prospect i ve study , the factors associated with embolic events and death and the feasibility of oral anticoagulant therapy managed by general practitioners . METHODS We enrolled at the Trieste Cardiovascular Center 229 patients aged > or = 65 years with non-rheumatic atrial fibrillation . At baseline , each patient underwent a transesophageal echocardiography and received instructions about oral anticoagulation . Patients were regularly followed by their general practitioner and finally evaluated at the Center . RESULTS At baseline , the mean age was 73 years , 14 % of patients were free of heart disease , 27 % had had a previous embolic event , and 33 % had an atrial thrombus . After a 5-year follow-up , 85 % of the patients had been admitted to hospital , 17 % had suffered an embolic event , and 35 % were dead . Diabetes and the presence of a low flow in the left atrial appendage were predictive of embolic events . Heart failure , spontaneous echocontrast and aortic plaques were predictive of death . Anticoagulant therapy increased from 14 to 34 % but the incidence of major bleeding did not change . The patients on anticoagulant therapy at follow-up constituted the group with the worst cardiovascular profile and embolic rate , but had a lower death rate ( 19 % ) compared with those on antiplatelet therapy ( 32 % ) and with those without antithrombotic therapy ( 67 % ) . The hospitalization rates were respectively 78 , 83 and 100 % . CONCLUSIONS In a group of elderly patients followed by their general practitioner with the support of a specialized cardiologic unit , oral anticoagulant therapy was well tolerated and associated with a significant decrease in mortality and hospitalization Objective : To assess the role of the intravascular ultrasound ( IVUS ) during implantation of Drug‐eluting stents ( DES ) on long‐term outcome in patients with complex coronary artery disease and high clinical risk profile with special attention to the development of late stent thrombosis ( LST ) . Methods : Two hunderd and ten patients were r and omly assigned to receive DES either with ( N = 105 ) or without ( N = 105 ) the IVUS guidance . Dual antiplatelet treatment was administered for 6 months in all patients . At 18‐month follow‐up , the rates of Major adverse cardiac events ( MACEs ) ( death , myocardial infa rct ion , and reintervention ) were assessed in both groups with special attention to possible LST . Stent thrombosis was classified according to Academic Research Consortium ( ARC ) . Results : At the 18‐month follow‐up , there was no significant difference between both groups regarding MACE ( 11 % vs. 12 % ; P = NS ) . Stent thrombosis has occurred in four patients ( 3.8 % ) in the group with and in 6 patients ( 5.7 % ; P = NS ) in the group without the IVUS guidance . Conclusions : In our r and omized trial we failed to demonstrate the superiority of the IVUS guidance during DES implantation over st and ard high‐pressure postdilatation . However we confirmed worrisome results concerning DES thrombosis after discontinuation of dual antiplatelet‐treatment with documented stent thrombosis related events in almost 5 % of patients with 50 % of mortality in this high‐risk clinical scenario . © 2009 Wiley‐Liss , Elevated blood pressure ( BP ) is a causal risk factor for cardiovascular disease ( CVD ) . Epidemiological analyses have established the grade d and continuous association between higher BP and CVD . Moreover , r and omized clinical trials among individuals with hypertension have demonstrated , in aggregate , a reduction in CVD events by 20 % , coronary heart disease ( CHD ) by 17 % , stroke by 27 % , and heart failure by 28 % for every 10 mm Hg systolic BP ( SBP ) lowering with medical therapy.1 Therefore , prevention , detection , treatment , and control of elevated BP , and its clinical correlate hypertension , is an important public health priority and a primary target for CVD prevention . Although national health surveys have demonstrated improvements in hypertension awareness and treatment , strategic opportunities to improve the efficiency and efficacy of applying BP-lowering therapy in patients most likely to benefit remain.2 Global CVD risk assessment , using multivariable prediction models that estimate absolute CVD risk from routinely measured clinical variables , has been promulgated in several CVD prevention guidelines for cholesterol management to target the most intensive preventive therapies to those at highest absolute CVD risk.3–5 Hypertension guidelines , however , have instead relied solely on isolated BP thresholds and BP goals to guide treatment initiation and intensity . In this review , we provide a rationale for incorporating global CVD risk assessment in BP treatment decision-making and propose a framework to guide its implementation in future CVD prevention guidelines . Epidemiological analyses have firmly established that CVD is a multifactorial condition and that modest increases of several CVD risk factors can often lead to greater overall risk than a severe elevation of a
Acetylsalicylic acid ( ASA ) did not reduce stroke or ‘ all cardiovascular events ’ compared to placebo in primary prevention patients with elevated BP and no prior cardiovascular disease .
To conclude for primary prevention in patients with elevated BP , antiplatelet therapy with ASA can not be recommended since the magnitude of benefit , a reduction in myocardial infa rct ion , is negated by a harm of similar magnitude , an increase in major haemorrhage .
Although elevated systemic blood pressure ( BP ) results in high intravascular pressure , the main complications of hypertension are related to thrombosis rather than haemorrhage .
It therefore seemed plausible that use of antithrombotic therapy may be useful in preventing thrombosis-related complications of elevated BP .
The objectives were to conduct a systematic review of the role of antiplatelet therapy and anticoagulation in patients with BP , to address the following hypotheses : ( i ) antiplatelet agents reduce total deaths and /or major thrombotic events when compared to placebo or other active treatment ; and ( ii ) oral anticoagulants reduce total deaths and /or major thromboembolic events when compared to placebo or other active treatment .