title: Pharmacologic control of thromboembolic complications of cardiac-valve replacement. [Coumarin combined with low-dose acetylsalicylic acid in the prevention of thromboembolic complications in patients with mitral and aortic valve prostheses]. Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: danger of aspirin compared with dipyridamole. Low-intensity oral anticoagulation plus low-dose aspirin versus high-intensity oral anticoagulation alone: a randomized trial in patients with mechanical prosthetic heart valves. Triflusal versus oral anticoagulation for primary prevention of thromboembolism after bioprosthetic valve replacement (trac): prospective, randomized, co-operative trial. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. [Significance of combined use of anticoagulants and antiplatelet agents in the early stage after prosthetic valve replacement]. Early and long-term (one-year) effects of the association of aspirin and oral anticoagulant on thrombi and morbidity after replacement of the mitral valve with the St. Jude medical prosthesis: a clinical and transesophageal echocardiographic study. Quantitative Synthesis in Systematic Reviews Combined warfarin and antiplatelet therapy after St. Jude Medical valve replacement for mitral valve disease. Prevention of arterial thromboembolism with acetylsalicylic acid. A controlled clinical study in patients with aortic ball valves. Thromboembolic risk in prosthetic valve carriers. Prevention trial. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial Ticagrelor versus clopidogrel in patients with acute coronary syndromes. Effect of Dipyridamole on the Incidence of Arterial Emboli After Cardiac Valve Replacement Comparison of two levels of anticoagulant therapy in patients with substitute heart valves. Anticoagulation therapy with combined low dose aspirin and warfarin following mechanical heart valve replacement. Low-Intensity Oral Anticoagulant Plus Low-Dose Aspirin During the First Six Months Versus Standard-Intensity Oral Anticoagulant Therapy After Mechanical Heart Valve Replacement: A Pilot Study of Low-Intensity Warfarin and Aspirin in Cardiac Prostheses (LIWACAP)
abstract: Abstract Either dipyridamole , a vasodilator known to reduce platelate adhesiveness and aggregation , or a placebo was given in a daily dose of 400 mg as a r and om , blind trial to 70 patients who had undergone prosthetic cardiac-valve replacement . Patients in both groups were given anticoagulation with warfarin sodium . Of 36 patients in the placebo group followed for 557 months systemic arterial embolism occurred in 17 per cent . Twenty-seven patients in the dipyridamole group followed for 393 months gave no clinical evidence of arterial embolism .  Dipyridamole was discontinued shortly after surgery in seven patients , and these were followed for 110 months . In two of them cerebral emboli developed six months after treatment was discontinued . It is tentatively concluded that the addition of dipyridamole to a program of anticoagulation reduces the frequency of postoperative arterial emboli originating on prosthetic cardiac valves in patients who can tolerate the drug Authors studied the effect of coumarin , and its combination with low-dose ( 125 mg/day ) acetylsalicylic acid in the prevention of thromboembolic complication during a 10-year period ( average 4.7 years ) in a r and omized trial of 296 patients aged 18 - 60 year with tilting disc type prosthetic heart valve ( 159 mitral and 137 aortic ) in sinus rhythm . In the group treated with coumarin ( 152 patients , 743.4 patient-years ) 4 cases ( 2 of them fatal ) of valve thrombosis , 12 cases of peripheral embolism and 9 cases ( 3 intracranial , 3 among them fatal ) of major bleeding were observed ; in the group treated with coumarin plus acetylsalicylic acid ( 144 patients , 638.7 patient-years ) 2 cases ( 1 of them fatal ) of valve thrombosis , 4 cases of peripheral embolism and 14 cases ( 3 of them fatal ) of major bleeding were observed . In the case of valve thromboses the difference between the two groups was non-significant but still clinical ly remarkable ; peripheral embolism occurred in significantly higher number ( p < 0.05 ) . There was no statistically significant difference of bleeding complications between the two groups . The results suggest that the combination of coumarin plus low-dose acetylsalicylic acid is more effective in the prevention of thromboembolic complications in patients with mitral and aortic prosthetic heart valve than coumarin alone ; the danger of bleeding complications seems to be acceptable with adequate control Despite the use of oral anticoagulation in patients with prosthetic heart valves , persistent thromboembolism over time warrants a search for improved methods of prevention . Thus , patients receiving 1 or more mechanical prosthetic heart valves were r and omized to therapy with warfarin plus dipyridamole ( 400 mg/day ) or warfarin plus aspirin ( 500 mg/day ) on the basis of location and type of valve and surgeon , and followed up with a concurrent , nonr and omized control group taking warfarin alone . In 534 patients followed up 1,319 patient-years ,  excessive bleeding ( necessitating blood transfusion or hospitalization ) was noted in the warfarin plus aspirin group ( 23 of 170 [ 14 % ] , or 6.0/100 patient-years ) compared with warfarin plus dipyridamole ( 7 of 181 [ 4 % ] , or 1.6/100 patient-years , p less than 0.001 ) , or warfarin alone ( 9 of 183 [ 5 % ] , or 1.8/100 patient-years , p less than 0.001 ) . A trend was evident toward a reduction in thromboembolism in the warfarin plus dipyridamole group ( 2 of 181 [ 1 % ] , or 0.5/100 patient-years ) as compared with warfarin plus aspirin ( 7 of 170 [ 4 % ] , or 1.8/100 patient-years ) , or warfarin alone ( 6 of 183 [ 4 % ] , or 1.2/100 patient-years ) . Adequacy of anticoagulation ( based on 12,720 prothrombin time determinations ) was similar in all 3 groups with 65 % of prothrombin times in the therapeutic range ( 1.5 less than or equal to prothrombin time/control less than or equal to 2.5 ) , 30 % too low , and 5 % too high . Warfarin plus aspirin therapy result ed in excessive bleeding and is contraindicated . Longer follow-up study is needed to determine whether further separation of the incidence of thromboembolism can be detected BACKGROUND Mechanical heart valve replacement requires lifelong anticoagulant treatment . Aspirin has proved useful in further reducing thromboembolic events when added to oral anticoagulants . However , increased ( gastrointestinal ) bleeding was observed at the doses previously tested for this combination in heart valve prostheses . METHODS We performed a prospect i ve r and omized trial to compare the combination of low-intensity oral anticoagulants ( international normalized ratio 2.5 to 3.5 ) plus aspirin ( 100 mg/day ) ( arm A ) versus high-intensity oral anticoagulants alone ( arm B ) ( international normalized ratio 3.5 to 4.5 ) . Arm A included 258 patients and arm B 245 patients . The two groups were comparable for all baseline characteristics . RESULTS The outcomes of the study were embolism , valve thrombosis , and major hemorrhage . The median follow-up was 23 months . The two treatments offered similar antithrombotic protection . The incidence of embolic episodes was 1.32 per 100 patient-years ( 95 % confidence interval 0.53 to 2.7 ) for arm A and 1.48 per 100 patient-years ( 95 % confidence interval 0.59 to 3.03 ) for arm B. Major hemorrhage occurred in 1.13 per 100 patient-years ( 95 % confidence interval 0.41 to 2.45 ) for arm A and 2.33 per 100 patient-years ( 95 % confidence interval 1.17 to 4.14 ) for arm B. Gastrointestinal bleeding was not increased by this combined reduced dose of aspirin and coumarin OBJECTIVE Antiplatelet agents are used for prevention of thromboembolism in surgical patients and in patients with chronic atrial fibrillation . Up to date , however , results of r and omized studies comparing antiplatelet agents and oral anticoagulation have not been reported . The aim of this study was to compare the efficacy and safety of triflusal ( an antiplatelet agent ) versus acenocoumarol for primary prevention of thromboembolism in the early postoperative period after implantation of a bioprosthesis . METHODS In this prospect i ve , multicentric , r and omized , open pilot trial , patients were assigned to treatment with triflusal ( 600mg/d ) or acenocoumarol ( target INR 2.0 - 3.0 ) . Study medication was started 24 - 48h after valve replacement with a bioprosthesis , and continued for 3 months . Four follow-up visits were scheduled : baseline , and at 1 , 3 and 6 months thereafter . The primary end-point was a composite of the rate of thromboembolism , severe hemorrhage and valve-related mortality . RESULTS A total of 193 patients were included ( 97 received triflusal and 96 acenocoumarol ) , with a mean age of 72.5 years . Half were men . Aortic valve replacement was performed in 181 patients ( 93.8 % ) , mitral valve replacement in 10 patients ( 5.2 % ) and double valve replacement in 2 ( 1.0 % ) . Hospital mortality was 11 ( 5.7 % ) . Primary outcome was recorded in 9 patients with triflusal ( 9.4 % ) and in 10 patients with acenocoumarol ( 11 % ) . There were nine episodes ( 4.7 % ) of thromboembolism , six in the triflusal group and three in the acenocoumarol group , and three episodes of permanent neurological deficits , one in the triflusal group and two in the acenocoumarol group . Severe hemorrhage : nine episodes , six in the acenocoumarol group and three in the triflusal group . None of the observed differences in efficacy were statistically significant . Regarding safety , three patients in triflusal group reported at least one hemorrhage , compared to 10 in acenocoumarol group ( P=0.048 ) . CONCLUSIONS There were no significant differences in efficacy between both groups , however , triflusal showed a significantly lower incidence of bleeding episodes BACKGROUND Despite the use of warfarin , major systemic embolism remains an important complication in patients with heart-valve replacement . Although the addition of antiplatelet agents has the potential to reduce this complication , their efficacy and safety when given in combination with warfarin are uncertain . METHODS In a r and omized , double-blind , placebo-controlled trial , we assessed the efficacy and safety of adding aspirin ( 100 mg per day ) to warfarin treatment ( target international normalized ratio , 3.0 to 4.5 ) in 370 patients with mechanical heart valves or with tissue valves plus atrial fibrillation or a history of thromboembolism . RESULTS A total of 186 patients were r and omly assigned to aspirin  and 184 to placebo  , and they were followed for up to 4 years ( average , 2.5 ) . Major systemic embolism or death from vascular causes occurred in 6 aspirin-treated patients ( 1.9 percent per year ) and 24 placebo-treated patients ( 8.5 percent per year ) ( risk reduction with aspirin , 77 percent ; 95 percent confidence interval , 44 to 91 percent ; P < 0.001 ) . Major systemic embolism , nonfatal intracranial hemorrhage , or death from hemorrhage or vascular causes occurred in 12 patients assigned to aspirin ( 3.9 percent per year ) and 28 patients assigned to placebo ( 9.9 percent per year ) ( risk reduction , 61 per cent ; 95 percent confidence interval , 24 to 80 percent ; P = 0.005 ) ; major systemic embolism or death from any cause occurred in 13 patients ( 4.2 percent ) and 33 patients ( 11.7 percent ) , respectively ( risk reduction , 65 percent ; 95 percent confidence interval , 33 to 82 percent ; P < 0.001 ) ; and death from all causes occurred in 9 patients ( 2.8 percent ) and 22 patients ( 7.4 percent ) , respectively ( risk reduction , 63 percent ; 95 percent confidence interval , 19 to 83 percent ; P = 0.01 ) . Bleeding occurred in 71 patients in the aspirin group ( 35.0 percent ) , as compared with 49 patients in the placebo group ( 22.0 percent ) ( increase in risk , 55 percent ; 95 percent confidence interval , 8 to 124 percent ; P = 0.02 ) ; major bleeding occurred in 24 and 19 patients , respectively ( increase in risk , 27 percent ; 95 percent confidence interval , -30 to 132 percent ; P = 0.43 ) . CONCLUSIONS In patients with mechanical heart valves and high-risk patients with prosthetic tissue valves , the addition of aspirin to warfarin therapy reduced mortality , particularly mortality from vascular causes , together with major systemic embolism . Although there was some increase in bleeding , the risk of the combined treatment was more than offset by the considerable benefit Patients who had undergone prosthetic valve replacement were treated with warfarin ( anticoagulant ) alone or in combination of ticlopidine ( 200 mg/day ) or aspirin ( 81 mg/day ) ( anti-platelet agents ) . The study of blood coagulation factors and platelet aggregation were carried out with these cases . 1 ) The patients ( n = 24 ) receiving  warfarin for 21 days after prosthetic valve replacement revealed marked increases in PIVKA-II and vitamin K1-epoxide . The protein C activity was significantly lower than that before the operation . High levels of more than 5 ng/ml of TAT were found before operation and after warfarin administration for 21 days . 2 ) Warfarin did not affect platelet aggregation , whereas ticlopidine inhibited ADP-induced platelet aggregation and aspirin inhibited both collagen-induced and arachidonic acid-induced aggregation . In conclusion , combined use of anticoagulants and antiplatelet agents after prosthetic valve replacement will suppress not only the blood coagulation but also the platelet aggregation systems OBJECTIVES The aim of the study was to test the value of low dose aspirin associated with st and ard oral anticoagulants ( OAC )  after mechanical mitral valve replacement ( MMRV ) to reduce str and s , thrombi and thromboembolic events . BACKGROUND Str and s and thrombi are thought to increase the risk of embolic events after MMVR , particularly in the immediate postoperative period . METHODS Two hundred twenty-nine patients were prospect ively recruited : 109 patients ( group A+ ) were r and omly assigned to aspirin ( 200 mg per day ) with OAC and 120 patients ( group A- ) to OAC alone ( international normalized ratio 2.5 to 3.5 ) . All patients were subjected to multiplane transesophageal echocardiography at nine days and five months and were followed up for one year . RESULTS At nine days and five months , there was a high and comparable incidence of str and s in the two groups ( group A+ : 44 % , 58 % ; group A- : 49 % , 63 % ) . However , the incidence of nonobstructive periprosthetic valve thrombi was significantly lower in group A+ at 9 days : 5 % versus 13 % , p = 0.03 . Total thromboembolic events were reduced in group A+ ( 9 % vs. 25 % , p = 0.004 ) although there was an increased incidence of gastrointestinal hemorrhage ( 7 % vs. 0 % ) . Overall mortality was 9 % in group A+ and 4 % in group A- . Valve-related events were similar in both groups . Early thrombi , but not str and s , were associated with higher morbidity , especially thromboembolic events ( 30 % vs. 13 % , p = 0.003 ) . CONCLUSIONS One year after MMVR , the association of aspirin with OAC reduced thrombi and thromboembolic events , but not morbidity , due to an increase in hemorrhagic complications A quantitative systematic review , or meta- analysis , uses statistical methods to combine the results of multiple studies . Meta-analyses have been done for systematic review s of therapeutic trials , diagnostic test evaluations , and epidemiologic studies . Although the statistical methods involved may at first appear to be mathematically complex , their purpose is simple : They are trying to answer four basic questions . Are the results of the different studies similar ? To the extent that they are similar , what is the best overall estimate ? How precise and robust is this estimate ? Finally , can dissimilarities be explained ? This article provides some guidance in underst and ing the key technical aspects of the quantitative approach to these questions . We have avoided using equations and statistical notations ; interested readers will find implementations of the described methods in the listed references . We focus here on the quantitative synthesis of reports of r and omized , controlled , therapeutic trials because far more meta-analyses on therapeutic studies than on other types of studies have been published . For practical reasons , we present a stepwise description of the tasks that are performed when statistical methods are used to combine data . These tasks are 1 ) deciding whether to combine data and defining what to combine , 2 ) evaluating the statistical heterogeneity of the data , 3 ) estimating a common effect , 4 ) exploring and explaining heterogeneity , 5 ) assessing the potential for bias , and 6 ) presenting the results . Deciding Whether To Combine Data and Defining What To Combine By the time one performs a quantitative synthesis , certain decisions should already have been made about the formulation of the question and the selection of included studies . These topics were discussed in two previous articles in this series [ 1 , 2 ] . Statistical tests can not compensate for lack of common sense , clinical acumen , and biological plausibility in the design of the protocol of a meta- analysis . Thus , a reader of a systematic review should always address these issues before evaluating the statistical methods that have been used and the results that have been generated . Combining poor- quality data , overly biased data , or data that do not make sense can easily produce unreliable results . The data to be combined in a meta- analysis are usually either binary or continuous . Binary data involve a yes/no categorization ( for example , death or survival ) . Continuous data take a range of values ( for example , change in diastolic blood pressure after antihypertensive treatment , measured in mm Hg ) . When one is comparing groups of patients , binary data can be summarized by using several measures of treatment effect that were discussed earlier in this series [ 3 ] . These measures include the risk ratio ; the odds ratio ; the risk difference ; and , when study duration is important , the incidence rate . Another useful clinical measure , the number needed to treat ( NNT ) , is derived from the inverse of the risk difference [ 3 ] . Treatment effect measures , such as the risk ratio and the odds ratio , provide an estimate of the relative efficacy of an intervention , whereas the risk difference describes the intervention 's absolute benefit . The various measures of treatment effect offer complementary information , and all should be examined [ 4 ] . Continuous data can be summarized by the raw mean difference between the treatment and control groups when the treatment effect is measured on the same scale ( for example , diastolic blood pressure in mm Hg ) , by the st and ardized mean difference when different scales are used to measure the same treatment effect ( for example , different pain scales being combined ) , or by the correlation coefficients between two continuous variables [ 5 ] . The st and ardized mean difference , also called the effect size , is obtained by dividing the difference between the mean in the treatment group and the mean in the control group by the SD in the control group . Evaluating the Statistical Heterogeneity of the Data This step is intended to answer the question , Are the results of the different studies similar ( homogeneous ) ? It is important to answer this question before combining any data . To do this , one must calculate the magnitude of the statistical diversity ( heterogeneity ) of the treatment effect that exists among the different sets of data . Statistical diversity can be thought of as attributable to one or both of two causes . First , study results can differ because of r and om sampling error . Even if the true effect is the same in each study , the results of different studies would be expected to vary r and omly around the true common fixed effect . This diversity is called the within- study variance . Second , each study may have been drawn from a different population , depending on the particular patients chosen and the interventions and conditions unique to the study . Therefore , even if each study enrolled a large patient sample , the treatment effect would be expected to differ . These differences , called r and om effects , describe the between- study variation with regard to an overall mean of the effects of all of the studies that could be undertaken . The test most commonly used to assess the statistical significance of between- study heterogeneity is based on the chi-square distribution [ 6 ] . It provides a measure of the sum of the squared differences between the results observed and the results expected in each study , under the assumption that each study estimates the same common treatment effect . A large total deviation indicates that a single common treatment effect is unlikely . Any pooled estimate calculated must account for the between- study heterogeneity . In practice , this test has low sensitivity for detecting heterogeneity , and it has been suggested that a liberal significance level , such as 0.1 , should be used [ 6 ] . Estimating a Common Effect The questions that this step tries to answers are , 1 ) To the extent that data are similar , what is their best common point estimate of a therapeutic effect , and 2 ) how precise is this estimate ? The mathematical process involved in this step generally involves combining ( pooling ) the results of different studies into an overall estimate . Compared with the results of individual studies , pooled results can increase statistical power and lead to more precise estimates of treatment effect . Each study is given a weight according to the precision of its results . The rationale is that studies with narrow CIs should be weighted more heavily than studies with greater uncertainty . The precision is generally expressed by the inverse of the variance of the estimate of each study . The variance has two components : the variance of the individual study and the variance between different studies . When the between- study variance is found to be or assumed to be zero , each study is simply weighted by the inverse of its own variance , which is a function of the study size and the number of events in the study . This approach characterizes a fixed-effects model , as exemplified by the Mantel-Haenszel method [ 7 , 8 ] or the Peto method [ 9 ] for dichotomous data . The Peto method has been particularly popular in the past . It has the advantage of simple calculation ; however , although it is appropriate in most cases , it may introduce large biases if the data are unbalanced [ 10 , 11 ] . On the other h and , r and om-effects models also add the between- study variance to the within- study variance of each individual study when the pooled mean of the r and om effects is calculated . The r and om-effects model most commonly used for dichotomous data is the DerSimonian and Laird estimate of the between- study variance [ 12 ] . Fixed- and r and om-effects models for continuous data have also been described [ 13 ] . Pooled results are generally reported as a point estimate and CI , typically a 95 % CI . Other quantitative techniques for combining data , such as the Confidence Profile Method [ 14 ] , use Bayesian methods to calculate posterior probability distributions for effects of interest . Bayesian statistics are based on the principle that each observation or set of observations should be viewed in conjunction with a prior probability describing the prior knowledge about the phenomenon of interest [ 15 ] . The new observations alter this prior probability to generate a posterior probability . Traditional meta- analysis assumes that nothing is known about the magnitude of the treatment effect before r and omized trials are performed . In Bayesian terms , the prior probability distribution is noninformative . Bayesian approaches may also allow the incorporation of indirect evidence in generating prior distributions [ 14 ] and may be particularly helpful in situations in which few data from r and omized studies exist [ 16 ] . Bayesian analyses may also be used to account for the uncertainty introduced by estimating the between- study variance in the r and om-effects model , leading to more appropriate estimates and predictions of treatment efficacy [ 17 ] . Exploring and Explaining Heterogeneity The next important issue is whether the common estimate obtained in the previous step is robust . Sensitivity analyses determine whether the common estimate is influenced by changes in the assumptions and in the protocol for combining the data . A comparison of the results of fixed- and r and om-effects models is one such sensitivity analysis [ 18 ] . Generally , the r and om-effects model produces wider CIs than does the fixed-effects model , and the level of statistical significance may therefore be different depending on the model used . The pooled point estimate per se is less likely to be affected , although exceptions are possible [ 19 ] . Other sensitivity analyses may include the examination of the residuals and the chi-square components [ 13 ] and assessment of the effect of deleting each study in turn . Statistically significant results that depend on a single study may require further exploration . Cumulative Meta- Analysis OBJECTIVES The clinical effect of combined warfarin and antiplatelet therapy on the incidence of stroke and postoperative complications after mitral ( plus aortic ) valve replacement was studied and compared with that observed with warfarin therapy alone . BACKGROUND It has been reported that combined warfarin and antiplatelet therapy may be effective but may be associated with an increased hemorrhagic risk . Therefore , definite benefits of the treatment in patients with an implanted prosthetic valve have not been clearly documented . METHODS Between January 1980 and December 1992 , 195 patients with a St. Jude Medical valve at the mitral ( plus aortic ) position were assigned to receive treatment with either warfarin alone ( 125 patients ) or warfarin plus antiplatelet agents ( 70 patients ) , such as dipyridamole ( 150 or 300 mg daily , 14 patients ) or ticlopidine ( 200 or 400 mg daily , 56 patients ) . A minimal dose of aspirin ( 10 to 40 mg ) was added ( 29 patients ) if the maximal platelet aggregation rate by collagen was not reduced . The target thrombotest level was 10 % to 20 % . RESULTS The two treatment groups were similar with regard to gender and age distribution . The number of patients with atrial fibrillation , left atrial thrombus , history of previous stroke , simultaneous aortic valve operation and previously performed valve procedures were comparable in the two groups . Actuarial survival rate at 10 years was 98.3 + /- 1.7 % ( mean + /- SD ) in the warfarin plus antiplatelet group and 90.3 + /- 3.2 % in the warfarin group ( p < 0.05 at 1 and 9 to 12 years ) . The actuarial stroke-free rate at 10 years was 95.3 + /- 3.4 % and 84.3 + /- 3.8 % , respectively ( p < 0.05 by the generalized Wilcoxon test ) . The actuarial complication-free rate at 10 years was 89.4 + /- 4.3 % and 67.9 + /- 4.8 % , respectively ( p < 0.05 by the generalized Wilcoxon test ) . No hemorrhagic complications were seen in the warfarin plus antiplatelet group . CONCLUSIONS The results strongly indicate the effectiveness and safety of combined warfarin plus antiplatelet treatment after St. Jude Medical valve replacement for mitral ( plus aortic ) valve disease Prevention of arterial thromboembolism with acetylsalicylic acid ( ASA ) was studied in 148 patients with single Starr-Edwards aortic ball-valve prostheses . These patients are suitable for such a study because they have a high incidence of arterial emboli derived mainly from thrombi formed on the valves . They were given either 1 Gm . of ASA daily or placebo in combination with anticoagulants , and were observed for 2 years . Only two emboli occurred in patients receiving ASA , none of them severe . In the placebo group 12 thromboembolic episodes were diagnosed in 10 patients , and three with cerebral emboli died ; in one a subdural hematoma unrelated to the embolus was found . In addition , one fatal and the one nonfatal intracranial bleeding occurred in each group , whereas gastrointestinal complications were seen more frequently in patients taking ASA . It is concluded that ASA combined with anticoagulants offered a significantly better protection against arterial thromboembolism than did anticoagulant therapy alone SUMMARY The long-term thromboembolic risk ( TER ) was estimated in a series of 1096 prosthesis carriers review ed by the same group between 1963 and 1980 , and in which the following points were particularly studied : the 376 first subjects operated upon with a mean follow-up of 6 + 3 years , involving all types of prostheses , but more particularly Starr-Edwards 1260 and 6120 valves . selected groups of patients : 60 aortic B jork valves , 50 aortic xenografts , 18 late thromboses of surgical or anatomic valves BACKGROUND Mechanical reperfusion with stenting for ST-elevation myocardial infa rct ion ( STEMI ) is supported by dual antiplatelet treatment with aspirin and clopidogrel . Prasugrel , a potent and rapid-acting thienopyridine , is a potential alternative to clopidogrel . We aim ed to assess prasugrel versus clopidogrel in patients undergoing percutaneous coronary intervention ( PCI ) for STEMI . METHODS We undertook a double-blind , r and omised controlled trial in 707 sites in 30 countries . 3534 participants presenting with STEMI were r and omly assigned by interactive voice response system either prasugrel ( 60 mg loading , 10 mg maintenance [ n=1769 ] ) or clopidogrel ( 300 mg loading , 75 mg maintenance [ n=1765 ] ) and were unaware of the allocation . The primary endpoint was cardiovascular death , non-fatal myocardial infa rct ion , or non-fatal stroke . Efficacy analyses were by intention to treat . Follow-up was to 15 months , with secondary analyses at 30 days . This trial is registered with Clinical Trials.gov , number NCT00097591 . FINDINGS At 30 days , 115 ( 6.5 % ) individuals assigned prasugrel had met the primary endpoint compared with 166 ( 9.5 % ) allocated clopidogrel ( hazard ratio 0.68 [ 95 % CI 0.54 - 0.87 ] ; p=0.0017 ) . This effect continued to 15 months ( 174 [ 10.0 % ] vs 216 [ 12.4 % ] ; 0.79 [ 0.65 - 0.97 ] ; p=0.0221 ) . The key secondary endpoint of cardiovascular death , myocardial infa rct ion , or urgent target vessel revascularisation was also significantly reduced with prasugrel at 30 days ( 0.75 [ 0.59 - 0.96 ] ; p=0.0205 ) and 15 months ( 0.79 [ 0.65 - 0.97 ] ; p=0.0250 ) , as was stent thrombosis . Treatments did not differ with respect to thrombolysis in myocardial infa rct ion ( TIMI ) major bleeding unrelated to coronary-artery bypass graft ( CABG ) surgery at 30 days ( p=0.3359 ) and 15 months ( p=0.6451 ) . TIMI life-threatening bleeding and TIMI major or minor bleeding were also similar with the two treatments , and only TIMI major bleeding after CABG surgery was significantly increased with prasugrel ( p=0.0033 ) . INTERPRETATION In patients with STEMI undergoing PCI , prasugrel is more effective than clopidogrel for prevention of ischaemic events , without an apparent excess in bleeding BACKGROUND Ticagrelor is an oral , reversible , direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel . METHODS In this multicenter , double-blind , r and omized trial , we compared ticagrelor ( 180-mg loading dose , 90 mg twice daily thereafter ) and clopidogrel ( 300-to-600-mg loading dose , 75 mg daily thereafter ) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome , with or without ST-segment elevation . RESULTS At 12 months , the primary end point -- a composite of death from vascular causes , myocardial infa rct ion , or stroke -- had occurred in 9.8 % of patients receiving ticagrelor as compared with 11.7 % of those receiving clopidogrel ( hazard ratio , 0.84 ; 95 % confidence interval [ CI ] , 0.77 to 0.92 ; P<0.001 ) . Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points , as well as myocardial infa rct ion alone ( 5.8 % in the ticagrelor group vs. 6.9 % in the clopidogrel group , P=0.005 ) and death from vascular causes ( 4.0 % vs. 5.1 % , P=0.001 ) but not stroke alone ( 1.5 % vs. 1.3 % , P=0.22 ) . The rate of death from any cause was also reduced with ticagrelor ( 4.5 % , vs. 5.9 % with clopidogrel ; P<0.001 ) . No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups ( 11.6 % and 11.2 % , respectively ; P=0.43 ) , but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting ( 4.5 % vs. 3.8 % , P=0.03 ) , including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types . CONCLUSIONS In patients who have an acute coronary syndrome with or without ST-segment elevation , treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes , myocardial infa rct ion , or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding . ( Clinical Trials.gov number , NCT00391872 . Dipyridamole is a vasodilator known to reduce platelet adhesiveness and aggregation . Either dipyridamole or a placebo was given in a daily dose of 400 mg as a r and om , blind trial to 100 patients who had undergone prosthetic cardiac valve replacement . Patients in both groups were anticoagulated with warfarin sodium . Fifty patients of the placebo group followed for 695 months had 18 % incidence of systemic arterial embolism . Forty-two patients in the dipyridamole group were followed for 553 months . One patient exhibited clinical evidence of arterial embolism .  Dipyridamole was discontinued shortly after surgery in eight patients followed for 119 months . Two of these patients developed cerebral emboli six months after discontinuation of treatment . It is tentatively concluded that the addition of dipyridamole to a program of anticoagulation reduces the incidence of postoperative arterial emboli originating on prosthetic cardiac valves in those patients who can tolerate the drug After cardiac valve replacement patients were blindly r and omized into two groups , both receiving aspirin ( 330 mg ) and dipyridamole ( 75 mg ) twice daily and the oral anticoagulant acenocoumarol ( Sintrom ) . An international normalized ratio of 2.0 to 2.99 was assigned to group A and 3.0 to 4.5 to group B ; both groups were subsequently analyzed for thromboembolic and hemorrhagic complications .  Final evaluation included 51 and 48 patients , respectively . The follow-up was 626 months for group A ( 12.3 months/patient ) and 486 months for group B ( 10.1 months/patient ) . The frequency of thromboembolism was equal in both groups : one transient ischemic attack in group A ( a rate of 1.92/100 patient-years ) and two transient ischemic attacks in group B ( a rate of 4.94/100 patient-years ) . There was , however , a statistical difference in bleeding complications between the two groups ( p less than 0.02 ) . Two patients bled in group A , a rate of 3.9 % ( 3.8/100 patient-years ) , which represents an incidence of one episode each 25.6 years of treatment ; 10 patients bled in group B , a rate of 20.8 % ( 24.7/100 patient-years ) representing an incidence of one episode each 4 years of treatment . We conclude that an international normalized ratio of 2 to 3 is safer than a ratio of 3 to 4.5 and confers good protection from thromboembolism when oral anticoagulant therapy is used conjointly with platelet function-inhibiting drugs in patients with mechanical substitute heart valves INTRODUCTION This study was design ed to evaluate safety and efficacy of combined low dose aspirin and warfarin therapy following mechanical heart valve replacement . METHODS A total of 1496 patients ( 686 males , mean age 35±8.5 years ) undergoing mechanical heart valvular replacement were r and omly divided into study ( warfarin plus 75 - 100 mg aspirin ) or control ( warfarin only ) group . International normalized ratio ( INR ) and prothrombin time was maintained at 1.8 - 2.5 and 1.5 - 2.0 times of the normal value , respectively . Thromboembolic events and major bleedings were registered during follow up . RESULTS Patients were followed up for 24±9 months . The average dose of warfarin in the study and control group was 2.92±0.87 mg and 2.89±0.79 mg , respectively ( p>0.05 ) . The overall thromboembolic events in study group were lower than in control group ( 2.1 % vs. 3.6 % , p=0.044 ) . No statistically significant differences were found in hemorrhage events ( 3.5 % vs. 3.7 % , p>0.05 ) or mortality ( 0.3 % vs 0.4 % , p>0.05 ) between the two groups . CONCLUSIONS Following mechanical valve replacement , combined low dose aspirin and warfarin therapy was associated with a greater reduction in thromboembolism events  than warfarin therapy alone . This combined treatment was not associated with an increase in the rate of major bleeding or mortality The objective of this study was to evaluate the safety and efficacy of low-intensity warfarin treatment plus aspirin during the first 6 months after surgery in patients undergoing heart valve substitution with mechanical prostheses .  Vitamin K antagonists ( VKA ) are able to reduce but not eliminate thrombosis and systemic embolism in patients with mechanical heart valves . The intensity of treatment and additional use of aspirin in these patients is still controversial . Consecutive patients undergoing aortic or mitral valve replacement ( or a combination of the two ) with mechanical prostheses were invited to participate in the study . After stratifying for site of prosthesis , patients were r and omized to receive low intensity VKA treatment ( target INR 2.5 ) plus aspirin ( 100 mg/day ) for the first six months ( Group A ) or st and ard-intensity ( INR target 3.7 ) VKA treatment ( Group B ) . Mean follow-up was 1.5 years . Principal outcome events were systemic embolism , major bleeding , and vascular death . A total of 94 patients in Group A and 104 in Group B were r and omized and followed up for 144 and 163 patient years , respectively . There were 5 ( 5 % ) events in Group A ( 4 major bleeding events and 1 vascular death ) and 4 ( 4 % ) in group B ( 2 major bleeding events and 2 ischemic stroke ) . All the events except 1 occurred within the first 6 months after surgery . Cumulative incidence of primary outcome events was 5.8 % ( 95 % CI 0.9 to 10.7 ) in Group A and 4.3 % ( 95 % CI 0,2 to 8.4 ) in Group B ( p=0.6 ) . Low-intensity treatment plus aspirin during the first six months after surgery appears to be as effective and safe as moderate-high-intensity anticoagulation
target: A lower daily dose of aspirin ( < 100 mg ) may be associated with a lower major bleeding risk than higher doses .
  Adding antiplatelet therapy , either dipyridamole or low-dose aspirin , to oral anticoagulation decreases the risk of systemic embolism or death among patients with prosthetic heart valves .
  The risk of major bleeding is increased with antiplatelet therapy .
  These results apply to patients with mechanical prosthetic valves or those with biological valves and indicators of high risk such as atrial fibrillation or prior thromboembolic events .
  The effectiveness and safety of low-dose aspirin ( 100 mg daily ) appears to be similar to higher-dose aspirin and dipyridamole .
background: BACKGROUND Patients with prosthetic heart valves are at increased risk for valve thrombosis and arterial thromboembolism .
  Oral anticoagulation alone , or the addition of antiplatelet drugs , has been used to minimise this risk .
  An important issue is the effectiveness and safety of the latter strategy .
  OBJECTIVES This is an up date of our previous review ; the goal was to create a valid synthesis of all available , method ologically sound data to further assess the safety and efficacy of combined oral anticoagulant and antiplatelet therapy versus oral anticoagulant monotherapy in patients with prosthetic heart valves .