Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. [A clinical trial of using antiplatelet therapy to prevent restenosis following peripheral artery angioplasty and stenting]. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial fibrillation: a randomized multicenter study. Intensifying platelet inhibition with tirofiban in poor responders to aspirin, clopidogrel, or both agents undergoing elective coronary intervention: results from the double-blind, prospective, randomized Tailoring Treatment with Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel study. Antiplatelet agents in thrombotic thrombocytopenic purpura (TTP). Results of a randomized multicenter trial by the Italian Cooperative Group for TTP. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. A comparison of dual vs. triple antiplatelet therapy in patients with non-ST-segment elevation acute coronary syndrome: results of the ELISA-2 trial. Glycoprotein IIb/IIIa inhibitors improve outcome after coronary stenting in clopidogrel nonresponders: a prospective, randomized study. Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy.
To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events.
                Collaborative meta-analyses (systematic overviews).
                Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another in high risk patients (with acute or previous vascular disease or some other predisposing condition) from which results were available before September 1997. Trials had to use a method of randomisation that precluded prior knowledge of the next treatment to be allocated and comparisons had to be unconfounded-that is, have study groups that differed only in terms of antiplatelet regimen.
                287 studies involving 135 000 patients in comparisons of antiplatelet therapy versus control and 77 000 in comparisons of different antiplatelet regimens.
                "Serious vascular event": non-fatal myocardial infarction, non-fatal stroke, or vascular death.
                Overall, among these high risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). Absolute reductions in the risk of having a serious vascular event were 36 (SE 5) per 1000 treated for two years among patients with previous myocardial infarction; 38 (5) per 1000 patients treated for one month among patients with acute myocardial infarction; 36 (6) per 1000 treated for two years among those with previous stroke or transient ischaemic attack; 9 (3) per 1000 treated for three weeks among those with acute stroke; and 22 (3) per 1000 treated for two years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01)). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 (4) vascular events per 1000 (P<0.0001) but caused 23 major (but rarely fatal) extracranial bleeds per 1000.
                Aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation. Low dose aspirin (75-150 mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required. Adding a second antiplatelet drug to aspirin may produce additional benefits in some clinical circumstances, but more research into this strategy is needed. To evaluate the clinical effect and restenosis rate of antiplatelet therapy following peripheral artery angioplasty and stenting.
                After successful placement of peripheral artery stents to 103 patients with peripheral arterial occlusive disease (PAOD) in were randomized assigned to 2 groups: antiplatelet therapy group receiving clopidogrel 75 mg plus aspirin 100 mg (n = 56) and control group (n = 47) receiving anticoagulation therapy low molecular weight heparin (LWMH) for 7 d plus long-term warfarin. The patients were followed up 1 day, and 1, 6, 12, and 18 months after the operation to undergo color Doppler ultrasonography, and examinations of blood routine, bleeding time, coagulation time, and ankle-brachial Index. The primary endpoint events included major bleeding rate, and composite rate of restenosis and reocclusion. The secondary endpoint events included cardiovascular events, death, and adverse drug reaction.
                There were no significant differences in the baseline data between these two groups. The thrombotic occlusion rate was 1.8% in the antiplatelet group and 0% in control group, and the restenosis rate was 14.3% in the antiplatelet group and 25.5% in control group (both P > 0.05). The bleeding complication rate of the antiplatelet group was 1.8%, significantly lower than that of the anticoagulation group (19.1%, P < 0.01). There were not significant differences in cardiovascular event rate and mortality 18 months after operation between these two groups.
                Antiplatelet therapy combined with clopidogrel plus aspirin is effective and safe in preventing restenosis following peripheral artery angioplasty and stenting. This trial evaluated the efficacy and safety of the combination of antiplatelet and moderate-intensity anticoagulation therapy in patients with atrial fibrillation associated with recognized risk factors or mitral stenosis.
                Warfarin was more effective than aspirin in preventing stroke in these patients; combined therapy with low anticoagulant intensity was ineffective. Mitral stenosis patients were not investigated.
                We performed a multicenter randomized trial in 1,209 patients at risk. The intermediate-risk group included patients with risk factors or age >60 years: 242 received the cyclooxygenase inhibitor triflusal, 237 received acenocumarol, and 235 received a combination of both. The high-risk group included patients with prior embolism or mitral stenosis: 259 received anticoagulants and 236 received the combined therapy. Median follow-up was 2.76 years. Primary outcome was a composite of vascular death and nonfatal stroke or systemic embolism.
                Primary outcome was lower in the combined therapy than in the anticoagulant arm in both the intermediate- (hazard ratio [HR] 0.33 [95% confidence interval (CI)0.12 to 0.91]; p = 0.02) and the high-risk group (HR 0.51 [95% CI 0.27 to 0.96]; p = 0.03). Primary outcome plus severe bleeding was lower with combined therapy in the intermediate-risk group. Nonvalvular and mitral stenosis patients had similar embolic event rates during anticoagulant therapy.
                The combined antiplatelet plus moderate-intensity anticoagulation therapy significantly decreased the vascular events compared with anticoagulation alone and proved to be safe in atrial fibrillation patients. Inhibition of platelet aggregation after aspirin or clopidogrel intake varies greatly among patients, and previous studies have suggested that poor response to oral antiplatelet agents may increase the risk of thrombotic events, especially after coronary angioplasty. Whether this reflects suboptimal platelet inhibition per se, which might benefit from more potent antiplatelet agents such as tirofiban, is unknown.
                We screened 1277 patients to enroll 93 aspirin, 147 clopidogrel, and 23 dual poor responders, based on a point-of-care assay, who underwent elective coronary angioplasty at 10 European sites for stable or low-risk unstable coronary artery disease. Patients were randomly assigned in a double-blind manner to receive either tirofiban (n=132) or placebo (n=131) on top of standard aspirin and clopidogrel therapy. The primary end point, consisting of troponin I/T elevation at least 3 times the upper limit of normal, was attained in 20.4% (n=27) in the tirofiban group compared with 35.1% (n=46) in the placebo group (relative risk, 0.58; 95% confidence interval, 0.39 to 0.88; P=0.009). The rate of major adverse cardiovascular events within 30 days in the tirofiban group also was reduced (3.8% versus 10.7%; P=0.031). The overall incidence of bleeding was low, likely explained by a substantial use of the transradial approach, and did not differ between the 2 groups.
                In low-risk patients according to clinical presentation who had poor responsiveness to standard oral platelet inhibitors via a point-of-care assay, intensified platelet inhibition with tirofiban lowers the incidence of myocardial infarction after elective coronary intervention. Antiplatelet agents are often included in plasma exchange-based regimens for thrombotic thrombocytopenic purpura (TTP) patients; however, the opportuneness of their use in TTP is still controversial. The italian Cooperative Group for TTP carried out a randomized trial to investigate their actual effectiveness, both in acute TTP and as maintenance treatment.
                Seventy-two TTP patients were randomized to receive plasma exchange and steroids with (group B) or without (group A) aspirin and dipyridamole. Treatment efficacy was evaluated after 15 days and salvage treatments were also considered for non-responders. Upon disease remission, the patients already treated with antiplatelet agents received ticlopidine for one year.
                Regarding the treatment of acute phase TTP, similar overall response rates were observed in the two groups (91.4% in group B vs. 75.6% in group A), but lower mortality rates were observed at 15 days in the patients treated with antiplatelet agents; as a matter of fact, 5 patients from arm A died in the first 15 days (13.5%) versus only one in arm B (2.8%). These figures, while not statistically significant, seem to suggest that antiplatelet agents might be useful in preventing deaths in acute TTP; moreover, bleeding did not worsen in antiplatelet agent-treated patients. As for the role of maintenance treatment, our results support the efficacy and safety of one-year ticlopidine therapy since the current relapse rate is significantly higher in non-treated patients; as a matter of fact, 6 patients (21.4%) in the non-ticlopidine group and only 2 (6.25%) in the ticlopidine group relapsed (P = .0182 in favor of maintenance treatment).
                Our results suggest the usefulness of antiplatelet agents in the treatment of acute phase TTP patients. Moreover, one-year ticlopidine maintenance therapy appears to be beneficial in preventing TTP relapses; however, only the completion of an adequate follow-up for all patients will definitively confirm this observation. The clinical benefit of coronary-artery stenting performed in conjunction with coronary angioplasty is limited by the risk of thrombotic occlusion of the stent as well as hemorrhagic and vascular complications of intensive anticoagulation. We compared antiplatelet therapy with conventional anticoagulant therapy with respect to clinical outcomes 30 days after coronary-artery stenting.
                After successful placement of Palmaz-Schatz coronary-artery stents, 257 patients were randomly assigned to receive antiplatelet therapy (ticlopidine plus aspirin) and 260 to receive anticoagulant therapy (intravenous heparin, phenprocoumon, and aspirin). The primary cardiac end point was a composite measure reflecting death from cardiac causes or the occurrence of myocardial infarction, aortocoronary bypass surgery, or repeat angioplasty. The primary noncardiac end point comprised death from noncardiac causes, cerebrovascular accident, severe hemorrhage, and peripheral vascular events.
                Of the patients assigned to antiplatelet therapy, 1.6 percent reached a primary cardiac end point, as did 6.2 percent of those assigned to anticoagulant therapy (relative risk, 0.25; 95 percent confidence interval, 0.06 to 0.77). With antiplatelet therapy, there was an 82 percent lower risk of myocardial infarction than in the anticoagulant-therapy group, and a 78 percent lower need for repeat interventions. Occlusion of the stented vessel occurred in 0.8 percent of the antiplatelet-therapy group and in 5.4 percent of the anticoagulant-therapy group (relative risk, 0.14; 95 percent confidence interval, 0.02 to 0.62). A primary noncardiac end point was reached by 1.2 percent of the antiplatelet-therapy group and 12.3 percent of the anticoagulant-therapy group (relative risk, 0.09; 95 percent confidence interval, 0.02 to 0.31). Hemorrhagic complications occurred only in the anticoagulant-therapy group (in 6.5 percent). An 87 percent reduction in the risk of peripheral vascular events was observed with antiplatelet therapy.
                As compared with conventional anticoagulant therapy, combined antiplatelet therapy after the placement of coronary-artery stents reduces the incidence of both cardiac events and hemorrhagic and vascular complications. To compare dual vs. triple antiplatelet pre-treatment in patients with non-ST-elevation acute coronary syndrome (NSTE ACS) who were planned for early catheterization.
                A total of 328 consecutive patients with NSTE ACS were included and were randomized to pre-treatment with dual (n = 166, aspirin, clopidogrel 600 mg) or triple antiplatelet therapy (n = 162, aspirin, clopidogrel 300 mg, and Tirofiban). The primary endpoint was enzymatic infarct size, defined as cumulative LDH release (LDHQ(48)). Initial TIMI flow of the culprit vessel was a pre-specified secondary endpoint. Angiography was performed in 98% of patients at a median of 23 h after admission. Enzymatic infarct size (median, 25-75%) was 166 (60-349) IU/L in the triple group compared with 193 (75-466) IU/L in the dual group (P = 0.2). Initial TIMI 3 flow of the culprit vessel was significantly more often observed after triple antiplatelet therapy (67 vs. 47%, P = 0.002). At 30 days follow-up, myocardial infarction (MI) occurred in 46% of patients in the triple antiplatelet group, compared with 57% in the dual antiplatelet group, P = 0.052. No significant difference in bleeding was present.
                This study showed that in patients with NSTE ACS, triple antiplatelet pre-treatment was associated with a non-significant reduction in enzymatic infarct size, a significantly better initial perfusion of the culprit vessel, and a trend towards a better survival without death or MI. Further, large-scale studies should be performed to find whether the beneficial trend in favour of triple antiplatelet pre-treatment can be reproduced. The aim of this study was to assess, in clopidogrel nonresponders undergoing elective percutaneous coronary intervention (PCI), the benefit of adjusted antiplatelet therapy with glycoprotein (GP) IIb/IIIa antagonist administration during PCI for 1-month clinical outcome.
                Numerous biological studies have reported interindividual variability in platelet response to clopidogrel with clinical relevance, and high post-treatment platelet reactivity (adenosine diphosphate-induced aggregation >70%) has been proposed to define nonresponse to clopidogrel. These nonresponders might benefit from tailored antiplatelet therapy.
                One hundred forty-nine clopidogrel nonresponders referred for elective PCI were prospectively included and randomized to "conventional group" (n = 75) or "active group" with GP IIb/IIIa antagonist (n = 74). All patients received 250-mg aspirin and 600-mg clopidogrel before PCI and platelet testing.
                The rate of cardiovascular events at 1 month was significantly lower in the "active group" than in the "conventional group": 19% (n = 14) versus 40% (n = 30), p = 0.006, odds ratio: 2.8; 95% confidence interval: 1.4 to 6.0. No patient in either group had post-procedural Thrombolysis In Myocardial Infarction major bleeding or required transfusions.
                The present study suggested benefit of tailored antiplatelet therapy during elective PCI with GP IIb/IIIa antagonist for clopidogrel nonresponders without increased bleeding risk. Angiotensin-converting enzyme (ACE) inhibitors and AT1-receptor antagonists (ARAs) are widely administered to reduce urinary protein loss and slow the progression of proteinuric nephropathy to end-stage renal failure. Our group recently observed that the combination of ACE inhibitors and ARAs may have an additive antiproteinuric effect, which may occur because ACE inhibitors do not completely reduce angiotensin II (Ang II) production. Ang II is also produced by chymase. Thus, combination therapy better antagonizes the effects of Ang II. The purpose of this study is to ascertain whether the additive antiproteinuric effect of ACE inhibitors plus ARAs is dose dependent and related to the drug-induced reduction in systemic blood pressure. Therefore, enalapril (E; 10 mg/d) and losartan (LOS; 50 mg/d) were randomly administered alone and then in association; initial dosages were doubled when drugs were administered alone and in association. To determine the influence of the drug-dependent effect on reducing blood pressure and the reduction in urinary proteinuria, both ambulatory and office blood pressures were recorded. E and LOS administered alone reduced proteinuria by the same extent; no further reduction was observed when E and LOS alone were administered at a doubled dose. When E and LOS were coadministered, proteinuria decreased by a greater extent compared with E and LOS alone; an additional reduction in proteinuria was observed when combined therapy doses were doubled. The reduction in proteinuria was not correlated with clinical through blood pressure; however, reductions in diastolic and mean ambulatory blood pressures significantly correlated with the decrease in proteinuria, as well as with creatinine clearance. In conclusion, this study shows that combination therapy with E and LOS has an additive dose-dependent antiproteinuric effect that is likely induced by the drug-related reduction in systemic blood pressure. In normotensive proteinuric patients, it is likely that even a small reduction in systemic blood pressure may affect intraglomerular hemodynamics by a great extent because efferent arteriole regulation is hampered more completely by the coadministration of ACE inhibitors and ARAs.
Antiplatelet therapy with ASA for primary prevention in patients with elevated blood pressure provides a benefit, reduction in myocardial infarction, which is negated by a harm of similar magnitude, increase in major haemorrhage. 
The benefit of antiplatelet therapy for secondary prevention in patients with elevated blood pressure is many times greater than the harm. 
Benefit has not been demonstrated for warfarin therapy alone or in combination with aspirin in patients with elevated blood pressure. Ticlopidine, clopidogrel and newer antiplatelet agents such as prasugrel and ticagrelor have not been sufficiently evaluated in patients with high blood pressure. Newer antithrombotic oral drugs such as dabigatran, rivaroxaban, apixaban and endosaban are yet to be tested in patients with high blood pressure.
Further trials of antithrombotic therapy including with newer agents and complete documentation of all benefits and harms are required in patients with elevated blood pressure.