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. Anticoagulant vs anti-platelet therapy as prophylactic against cerebral infarction in transient ischemic attacks. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. The effect of prophylactic epsilon-aminocaproic acid on bleeding, transfusions, platelet function, and fibrinolysis during coronary artery bypass grafting. Glycoprotein IIb/IIIa inhibitors improve outcome after coronary stenting in clopidogrel nonresponders: a prospective, randomized study. Does pre-treatment with aspirin and loading dose clopidogrel obviate the need for glycoprotein IIb/IIIa antagonists during elective coronary stenting? A focus on peri-procedural myonecrosis. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (fantastic) study. Antiplatelet agents in thrombotic thrombocytopenic purpura (TTP). Results of a randomized multicenter trial by the Italian Cooperative Group for TTP. Antiplatelet therapy: an alternative to heparin for blunt carotid injury. Preoperative platelet dysfunction increases the benefit of aprotinin in cardiopulmonary bypass. [Reducing bleeding during extracorporeal circulation interventions by high doses of aprotinin]. Aprotinin significantly decreases bleeding and transfusion requirements in patients receiving aspirin and undergoing cardiac operations. A comparison of dual vs. triple antiplatelet therapy in patients with non-ST-segment elevation acute coronary syndrome: results of the ELISA-2 trial. Aprotinin and dipyridamole for the safe reduction of postoperative blood loss. 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. Low doses of aprotinin in aortocoronary bypass surgery--advantages and disadvantages. Aspirin is beneficial in hypertensive patients with chronic kidney disease: a post-hoc subgroup analysis of a randomized controlled trial. Frequent reocclusion of patent infarct-related arteries between 4 weeks and 1 year: effects of antiplatelet therapy. The efficacy and safety of short- and long-term dual antiplatelet therapy in patients with mild or moderate chronic kidney disease: results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Long-term follow-up after extracranial internal carotid artery dissection. Glycoprotein IIB/IIIA inhibitor to reduce postpercutaneous coronary intervention myonecrosis and improve coronary flow in diabetics: the 'OPTIMIZE-IT' pilot randomized study. Safety and efficacy of the platelet glycoprotein IIb/IIIa inhibitor abciximab in Chinese patients undergoing high-risk angioplasty. Intraoperative plateletpheresis and autologous platelet gel do not reduce chest tube drainage or allogeneic blood transfusion after reoperative coronary artery bypass graft. Platelet-rich plasma sequestration, with therapeutic platelet yields, reduces allogeneic transfusion in complex cardiac surgery. Aprotinin prevents cardiopulmonary bypass-induced platelet dysfunction. A scanning electron microscope study. [Comparison of the effects of epsilon-aminocaproic acid and aprotinin on intra- and postoperative bleeding in heart surgery]. Epsilon-aminocaproic acid in coronary artery bypass graft surgery: preincision or postheparin? Randomized, double-blind, placebo-controlled dose-ranging study of tirofiban (MK-383) platelet IIb/IIIa blockade in high risk patients undergoing coronary angioplasty. Platelet inhibition with Ticlopidine in atherosclerotic intermittent claudication. Antiplatelet drugs in femoropopliteal vein bypasses: a multicenter trial. A randomized clinical trial investigating the relationship between aprotinin and hypercoagulability in off-pump coronary surgery. The prophylactic effect of aprotinin on intraoperative bleeding in liver transplantation: a randomized clinical study. Aprotinin and epsilon aminocaproic acid are effective in reducing blood loss after primary total hip arthroplasty--a prospective randomized double-blind placebo-controlled study. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. The RESTORE Investigators. Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis. Reduction of bleeding after heart operations through the prophylactic use of epsilon-aminocaproic acid. Autologous platelet-rich plasma does not reduce transfusion of homologous blood products in patients undergoing repeat valvular surgery. Acute platelet inhibition with abciximab does not reduce in-stent restenosis (ERASER study). The ERASER Investigators.
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. 156 patients with transient ischemic attacks (TIA) or reversible ischemic neurological deficit (RIND) were given prophylactic anticoagulant (AC) treatment against cerebral infarction in a prospective multicenter study from 5 hospitals in southern Sweden. After 2 months of AC treatment, 135 patients remained in the study and were randomized into 2 groups; one continued with AC treatment and one changed to anti-platelet therapy. The patients were followed for 12 months. No significant difference was seen between the 2 groups but 3 completed cerebral infarctions occurred during anti-platelet therapy against one during AC treatment. One cerebral hemorrhage was seen during AC treatment. All completed strokes occurred in men who initially had carotid symptoms. The number of patients with TIA/RIND was somewhat higher in the anti-platelet group whereas myocardial infarctions occurred more often during AC treatment. Compared to the natural history of untreated TIA/RIND both treatments were found to have a prophylactic effect against cerebral infarction. 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. Antifibrinolytic medications administered before skin incision decrease bleeding after cardiac surgery. Numerous case reports indicate thrombus formation with administration of epsilon-aminocaproic acid (epsilon-ACA). The purpose of this study was to examine the efficacy of epsilon-ACA administered after heparinization but before cardiopulmonary bypass in reducing bleeding and transfusion requirements after primary coronary artery bypass surgery.
                Seventy-four adult patients undergoing primary coronary artery bypass surgery were randomized to receive 125 mg/kg epsilon-ACA followed by an infusion of 12.5 mg x kg(-1) x h(-1) or an equivalent volume of saline. Coagulation studies, thromboelastography, and platelet aggregation tests were performed preoperatively, after bypass, and on the first postoperative day. Mediastinal drainage was recorded during the 24 h after surgery. Homologous blood transfusion triggers were predefined and transfusion amounts were recorded.
                One patient was excluded for surgical bleeding and five patients were excluded for transfusion against predefined criteria One patient died from a dysrhythmia 2 h postoperatively. Among the remaining 67, the epsilon-ACA group had less mediastinal blood loss during the 24 h after surgery, 529+/-241 ml versus 691+/-286 ml (mean +/- SD), P < 0.05, despite longer cardiopulmonary bypass times and lower platelet counts, P < 0.05. Platelet aggregation was reduced in both groups following cardiopulmonary bypass but did not differ between groups. Homologous blood transfusion was similar between both groups.
                Prophylactic administration of epsilon-ACA after heparinization but before cardiopulmonary bypass is of minimal benefit for reducing blood loss postoperatively in patients undergoing primary coronary artery bypass grafting. 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. Although full platelet inhibition with aspirin and thienopyridines before coronary stenting has significantly reduced the risk of acute stent thrombosis, peri-procedural myonecrosis still occurs frequently and is associated with increased death rate. Whether further inhibition of platelet aggregation by a glycoprotein IIb/IIIa antagonist may provide an additional cardioprotection is unknown.
                A total of 200 patients pre-treated with aspirin and a loading dose of clopidogrel (450 mg) were randomized just before coronary intervention (percutaneous coronary intervention, PCI) to treatment with or without abciximab. Platelet aggregation was assessed in samples collected during the procedure and the degree of platelet aggregation inhibition was correlated with cardiac enzyme release post-PCI. Abciximab treatment achieved a more complete inhibition of aggregation than dual oral antiplatelet therapy alone (median value of 1 vs. 50%, normal 100%). Any pathological increase in creatinine kinase-MB (CK-MB) post-PCI was present in 21% of the abciximab group and in 22% of the no-abciximab group (P = 0.9). Also the occurrence of clinically relevant myonecrosis [myocardial infarction (MI) = CK-MB > 3x upper limit of normal] was not significantly influenced by treatment assignment: 9 vs. 10% (P = 0.9). In a multiple logistic regression model including clinical, angiographic, and procedural characteristics, post-PCI myonecrosis was not correlated with the degree of platelet aggregation inhibition but with procedural features (such as long inflation time) and with the presence of multi-vessel disease. There were no cases of acute or subacute stent thrombosis. At 6 months, major adverse cardiac events, including cardiac death, non-fatal MI, or target lesion revascularization occurred in 13% of abciximab patients and in 16% of the control patients (P = 0.6).
                In the studied patients scheduled for elective coronary stenting and pre-treated with aspirin and a loading dose of clopidogrel, further inhibition of platelet aggregation by abciximab does not afford additional cardioprotection. Our data suggest that distal athero-embolization rather than thrombo-embolization is involved in the phenomenon of myonecrosis post-elective stenting. Dual therapy with ticlopidine and aspirin has been shown to be as effective as or more effective than conventional anticoagulation in patients with an optimal result after implantation of intracoronary metallic stents. However, the safety and efficacy of antiplatelet therapy alone in an unselected population has not been evaluated.
                Patients were randomized to conventional anticoagulation or to treatment with antiplatelet therapy alone. Indications for stenting were classified as elective (decided before the procedure) or unplanned (to salvage failed angioplasty or to optimize the results of balloon angioplasty). After stenting, patients received aspirin and either ticlopidine or conventional anticoagulation (heparin or oral anticoagulant). The primary end point was the occurrence of bleeding or peripheral vascular complications; secondary end points were cardiac events (death, infarction, or stent occlusion) and duration of hospitalization.
                In 13 centers, 236 patients were randomized to anticoagulation and 249 to antiplatelet therapy. Stenting was elective in 58% of patients and unplanned in 42%. Stent implantation was successfully achieved in 99% of patients. A primary end point occurred in 33 patients (13.5%) in the antiplatelet group and 48 patients (21%) in the anticoagulation group (odds ratio=0.6 [95% CI 0.36 to 0.98], P=0.03). Major cardiac-related events in electively stented patients were less common (odds ratio=0.23 [95% CI 0.05 to 0.91], P=0.01) in the antiplatelet group (3 of 123, 2.4%) than the anticoagulation group (11 of 111, 9.9%). Hospital stay was significantly shorter in the antiplatelet group (4.3+/-3.6 versus 6. 4+/-3.7 days, P=0.0001).
                Antiplatelet therapy after coronary stenting significantly reduced rates of bleeding and subacute stent occlusion compared with conventional anticoagulation. 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. Blunt carotid injuries (BCIs) are uncommon. Most single-center studies are small and highlight the use of anticoagulation for treatment. In a retrospective review, we identified 22 patients who presented with BCI and assessed neurologic and survival outcomes on the basis of injury grade and treatment with anticoagulation or antiplatelet therapy.
                Patient demographics were identified using the trauma registry at a single Level I trauma center. Chart reviews assessed neurologic function, modalities used for diagnosis, and treatment. Neurologic outcomes were graded good (minimal to no deficit), fair (moderate deficit needing some assistance), poor (requiring institutionalization), and dead.
                Twenty-two adult trauma patients were diagnosed with BCI, for an incidence of 0.45% in the 8-year study period. All BCI patients underwent head computed tomography and four-vessel cerebral arteriography. Eight patients were not anticoagulated, five because of intracranial injuries, two who had surgical CCA repairs, and one with an aortic injury. Full anticoagulation with heparin was attempted in seven patients, with four major bleeding complications requiring cessation of heparin and blood transfusions. Seven patients received antiplatelet therapy. No difference in neurologic outcome was observed between those receiving anticoagulation and those receiving antiplatelet therapy. Bleeding complications from full anticoagulation were higher than with antiplatelet agents (p = 0.05).
                Contrary to previous reports, we did not observe improved outcomes with full anticoagulation compared with antiplatelet therapy. Anticoagulation was associated with increased extracranial bleeding complications. The risks and possible benefits, as well as timing, of anticoagulation or antiplatelet therapy for BCI should be carefully weighed by the major care providers of the patient with multiple injuries. This study was designed to determine the benefit of aprotinin therapy in reducing bleeding during and after cardiopulmonary bypass in patients with preoperative platelet dysfunction. Platelet function involvement in the mechanism by which aprotinin acts was also investigated.
                In a double-blind, randomized study, patients received high-dose aprotinin (n = 54) or placebo (n = 52). Whole blood aggregation was measured preoperatively. Platelet function and activation in both groups were assessed intraoperatively and postoperatively at five times.
                Aprotinin significantly reduced perioperative bleeding and postoperative blood transfusion. Placebo-treated patients with reduced preoperative platelet aggregation bled more postoperatively, but aprotinin reduced the bleeding in patients with normal or reduced platelet function to similar levels. Any cardiopulmonary bypass-induced changes in platelet aggregation, platelet activation as measured by P-selectin expression, and von Willebrand factor antigen and function were similar in aprotinin-treated and placebo-treated groups.
                The mechanism by which aprotinin reduced bleeding was independent of any effect on platelet function. However, aprotinin produced a greater reduction in bleeding among patients whose condition was hemostatically compromised by preoperative platelet dysfunction. The great risk of severe infectious diseases transmission through blood transfusion, has increased during the last years the effort to reduce the bank blood and its derivates use. Many techniques have proposed to achieve this purpose during and post cardiopulmonary bypass: normovolemic hemodilution, perioperative blood autotransfusion, postoperative return of extra corporeal circuit and chest drains blood and the particular use of some drugs. In the last few years several reports have been presented in the literature concerning the reduction of intra and postoperative bleeding in cardiac surgery by high dose Aprotinin administration. A randomized study with the use of this pharmacologic agent is presented: a group of patients was treated with Aprotinin (shared in two subgroups receiving respectively a different dose of the drug) and a control group. The results were highly encouraging both because of the reduction of peri and postoperative bleeding and because of the bank blood use important reduction. Patients with heart disease are frequently maintained on a regimen of aspirin because of its ability to decrease thrombotic complications and reduce the prevalence of unstable angina and myocardial infarction. Aspirin-induced platelet acetylation also increases bleeding caused by impairment of platelet function during cardiac surgery.
                Between October 1990 and November 1991 this double-blind, randomized, placebo-controlled, parallel group interventional study examined the efficacy of high-dose aprotinin administration (up to 7 million KIU) to decrease blood loss and transfusion requirements in patients receiving aspirin within 48 hours of undergoing coronary bypass or valvular heart operations. Primary outcome measures in this study were total volume of blood loss (intraoperative blood loss plus postoperative chest tube drainage) and volume of transfusion during hospitalization.
                Patients treated with aprotinin (n = 29) had significantly lower total blood loss (1409 +/- 232 ml versus 2765 +/- 248 ml; p = 0.0002), intraoperative blood loss (503 +/- 53 ml versus 1055 +/- 199 ml; p = 0.0001), postoperative blood loss (906 +/- 204 ml versus 1710 +/- 202 ml; p = 0.0074), and prevalence of transfusion (59% versus 88% of patients; p = 0.016) than the placebo group (n = 25). The prevalence of complications including myocardial infarction was similar in the two groups.
                High-dose aprotinin significantly reduces blood loss and red blood cell transfusions in patients receiving aspirin who undergo cardiac operations. 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. Aprotinin (APR) reduces postoperative blood loss but may induce thrombosis. Dipyridamole (DIP) limits platelet aggregation and may reduce the thrombotic complications associated with APR.
                To evaluate the safety and effectiveness of combined APR and DIP, we undertook a prospective randomized trial in patients undergoing cardiac operations. Patients were stratified according to risk for bleeding (low or high), and received either DIP with placebo (DIP group; n = 59) or DIP with APR (DIP + APR group; n = 56). Blood samples were obtained for the measurement of hematologic and biochemical parameters. Blood loss and transfusion requirements were documented postoperatively.
                Postoperative blood loss and transfusion requirements were significantly lower in the DIP + APR group at 6, 12, and 24 hours after bypass (p < 0.01). No significant differences were found between groups in the incidence of perioperative mortality (DIP, 0%; DIP + APR, 3%), myocardial infarction (DIP, 0%; DIP + APR, 3%), stroke (DIP, 1%; DIP + APR, 1%), or potential thrombotic events (death, myocardial infarction, and stroke: DIP, 2%; DIP + APR, 5%). In addition, these rates did not differ from those of nonparticipating matched control patients.
                Administration of both drugs simultaneously was more effective than DIP alone in reducing postoperative blood loss. A platelet inhibitor may be required to reduce the thrombotic complications associated with APR. Further studies evaluating graft patency and perioperative ischemia are necessary to confirm the potential benefits of the combination of a platelet inhibitor and APR. 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. Excessive blood loss, as a result of augmented postoperative drainage, is considered one of the most serious cardiosurgical complications. The compounding constitutive anemia seems particularly harmful for patients with coronary artery disease. Aprotinin (Trasylol), a non-specific serine protease inhibitor, is successfully used to reduce excessive postoperative bleeding in such patients. The aim of our study was to verify the hypothesis whether aprotinin used during cardiopulmonary bypass procedure affects hemostatic parameters, which might be crucial for the elevated risk of thromboembolic complications.
                The group of 54 patients subjected to coronary artery surgical treatment included 30 patients, who were given intraoperatively 3 million KIU aprotinin each, and 24 subjects non-treated with aprotinin. Aliquots of blood were withdrawn at several time intervals, until the 5th day after the operation. Whole blood platelet activation and reactivity (the expressions of P-selectin and glycoprotein Ib) were monitored by means of flow cytometry. In addition, several plasma parameters, like PAI-1, t-PA, D-dimers, prothrombin fragment F1 + 2, fibrinogen, ATIII activity, troponin I and CK-MB, as well as platelet count were determined at each time point.
                In this study we confirmed the essential advantage of the use of aprotinin: both the postoperative blood drainage and the blood units to be transfused postoperatively to cardiosurgical patients were vastly reduced in the aprotinin-treated subjects. The enhanced overall frequency of perioperative myocardial infarction events was not attributed to this group of patients, nor the non Q-wave infarctions were observed more often in patients treated with aprotinin. In these patients, fibrinolysis parameters tended to be depressed (with increased PAI-1 dominating over elevated t-PA) on the first day after the operation, and no significant differences with regard to fibrinogen, prothrombin fragment F1 + 2, troponin I and platelet count. There was a continuous rise in D-dimers in all the postoperative patients, which lasted until the third day and tended to reach plateau at the 5th day after the operation. We failed to reveal the preventive effects of aprotinin on platelet function: both platelet activation and reactivity remained apparently unchanged. Overall, our results rather support the reasoning on the advantageous effects of low doses of aprotinin. The use of this inhibitor reduces the risk of postoperative undesirable bleeding and results in a decreased postoperative drainage and reduced transfused blood units. On the other hand, however, a higher incidence of perioperative Q-wave infarction in the aprotinin-treated patients, although purely apparent and not statistically significant, might question the unlimited safety of the use of aprotinin in cardiovascular operations. The purpose of this study was to determine the benefit and risk associated with antiplatelet therapy in the chronic kidney disease (CKD) population.
                Cardiovascular and possibly bleeding risks are elevated in patients with CKD. The balance of benefit and harm associated with antiplatelet therapy remains uncertain.
                The HOT (Hypertension Optimal Treatment) study randomly assigned participants with diastolic hypertension to aspirin (75 mg) or placebo. Study treatment effects were calculated using univariate proportional hazards regression models stratified by baseline estimated glomerular filtration rate (eGFR) with trends tested by adding interaction terms. End points included major cardiovascular events, total mortality, and major bleeding.
                The study included 18,597 participants treated for 3.8 years. Baseline eGFR was < 60 ml/min/1.73 m(2) in 3,619 participants. Major cardiovascular events were reduced by 9% (95% confidence interval [CI]: -9% to 24%), 15% (95% CI: -17% to 39%), and 66% (95% CI: 33% to 83%) for patients with baseline eGFR of ≥ 60, 45 to 59, and < 45 ml/min/1.73 m(2), respectively (p trend = 0.03). Total mortality was reduced by 0% (95% CI: -20% to 17%), 11% (95% CI: -31% to 40%), and 49% (95% CI: 6% to 73%), respectively (p trend = 0.04). Major bleeding events were nonsignificantly greater with lower eGFR (hazard ratio [HR]: 1.52 [95% CI: 1.11 to 2.08], HR: 1.70 [95% CI: 0.74 to 3.88], and HR: 2.81 [95% CI: 0.92 to 8.84], respectively; p trend = 0.30). Among every 1,000 persons with eGFR < 45 ml/min/1.73 m(2) treated for 3.8 years, 76 major cardiovascular events and 54 all-cause deaths will be prevented while 27 excess major bleeds will occur.
                Aspirin therapy produces greater absolute reduction in major cardiovascular events and mortality in hypertensive patients with CKD than with normal kidney function. An increased risk of major bleeding appears to be outweighed by the substantial benefits.
                Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved. This study assessed the effect of the combination of aspirin and dipyridamole on patency of the infarct-related artery between 4 weeks and 1 year after myocardial infarction.
                Patency of the infarct-related artery is an important determinant of prognosis after myocardial infarction. The incidence of late reocclusion and the effects of antiplatelet therapy are unknown.
                To investigate the importance of antiplatelet therapy for the prevention of late reocclusion, 215 patients who had a patent infarct-related artery 4 weeks after myocardial infarction were randomized in a double-blind manner to receive either a combination of 25 mg of aspirin and 200 mg of dipyridamole twice daily or placebo. One hundred fifty-four patients underwent further coronary arteriography 1 year later.
                At 1 year, 38 (25%) of 154 patients had reocclusion of the infarct-related artery; 18 (23%) of 79 patients receiving aspirin and dipyridamole had late reocclusion versus 20 (27%) of 75 who received placebo (p = NS). The rate of reocclusion was related to the severity of the residual coronary artery stenosis at 4 weeks (< 50% stenosis 9.2%; 50% to 69% stenosis 11.6%; 70% to 89% stenosis 30.4%; > or = 90% stenosis 70%, p < 0.01). The majority of reocclusions were silent, and only 17 (45%) of 38 were clinically associated with further infarction. There were no differences for a hierarchic end point of cardiac death, myocardial infarction or revascularization (14.8% aspirin and dipyridamole vs. 17.8% placebo).
                Late reocclusion of the patent infarct-related artery is a frequent event, occurring in 25% of patients. Antiplatelet therapy with the combination of aspirin and dipyridamole does not alter the overall rate of late reocclusion. Other strategies are required to reduce late reocclusion. Mild and moderate chronic kidney disease (CKD) is associated with decreased survival and increased adverse events after a percutaneous coronary intervention (PCI). Therapy with clopidogrel decreases adverse events in large patient populations. Therefore, we sought to determine the efficacy and safety of long-term clopidogrel therapy in patients with CKD.
                Two thousand two patients from the CREDO trial in whom an elective PCI of a single or multiple vessels was planned were analyzed. Patients were randomly assigned to a 300-mg loading dose of clopidogrel before PCI followed by clopidogrel 75 mg/d for a year versus a placebo loading dose at the time of the PCI procedure and clopidogrel 75 mg/d for 28 days and placebo for the remainder of a year. Patients were categorized by their estimated creatinine clearance (>90 [normal, n = 999], 60-89 [mild CKD, n = 672], <60 mL/min [moderate CKD, n = 331]).
                Diminished renal function was associated with worse outcomes. Patients with normal renal function who received 1 year of clopidogrel had a marked reduction in death, myocardial infarction, or stroke compared with those who received placebo (10.4% vs 4.4%, P < .001), whereas patients with mild and moderate CKD did not have a significant difference in outcomes with clopidogrel therapy versus placebo (mild: 12.8% vs 10.3%, P = .30; moderate: 13.1% vs 17.8%, P = .24). Clopidogrel use was associated with an increased relative risk of major or minor bleeding, but this increased risk was not different based on renal function (relative risk 1.2, 1.3, 1.1).
                Clopidogrel in mild or moderate CKD patients may not have the same beneficial effect as it does in patients with normal renal function, but was not associated with a greater relative risk of bleeding based on renal function. Further studies are needed to define the role of clopidogrel therapy in patients with CKD. To evaluate long-term outcome after extracranial internal carotid artery dissection (eICAD) in consideration of the applied antithrombotic therapy.
                Among 33 consecutive eICAD patients initially treated either with anticoagulation (n = 25) or with antiplatelets (n = 8), a standardized interview was performed after 28 +/- 22.1 months to analyze risks and benefits of both agents. Ischemic and hemorrhagic complications, occurrence of seizure and rates of arterial recanalization were compared and long-term clinical outcome was assessed using the modified Rankin Scale (mRS) and Barthel Index (BI).
                Among anticoagulated patients, 1 died due to brain herniation. In 3 patients stroke (n = 2) or TIA (n = 1) recurred. In the antiplatelet group, none died and no subsequent ischemic events happened. Hemorrhagic complications were noted in neither treatment group. Functional outcome among anticoagulated patients was BI 92 +/- 21.6 and mRS 1.48 +/- 1.50, which did not differ from patients initially treated with antiplatelets (BI 89 +/- 18.9, mRS 1.50 +/- 1.41, p > 0.05). Four anticoagulated patients developed seizures, compared to 2 patients with antiplatelets (p > 0.05). Arterial recanalization occurred in 16 of 22 antico- agulated patients with ultrasound follow-up, compared to 6 of 6 patients with antiplatelets (p > 0.05).
                In the absence of iatrogenic side effects, both anticoagulation and antiplatelets seem to be safe for eICAD. The rates for death and stroke were low and outcome ratings did not differ between both agents. These findings may indicate that a controlled randomized trial comparing anticoagulation and antiplatelets is ethically justified.
                Copyright 2000 S. Karger AG, Basel Subgroup analyses of trials enrolling acute coronary syndrome patients suggest that inhibition of glycoprotein IIb/IIIa can improve the outcome of diabetic patients undergoing percutaneous coronary interventions (PCIs), possibly by improving microvascular perfusion. However, the efficacy of small-molecule IIb/IIIa receptor inhibitors to improve microvascular perfusion in stable diabetic patients undergoing elective PCI has not been specifically investigated.
                We randomized consecutive stable diabetic patients, undergoing elective PCI, to tirofiban or placebo groups along with double antiplatelet therapy. High-dose bolus (25 microg/kg per 3 min) of tirofiban was administered immediately before PCI followed by 8 h continuous infusion (0.15 microg/kg per min). Postprocedural myonecrosis was assessed prospectively by measurement of cardiac troponin T (cTnT) at 6 and 24 h after PCI. The primary end-points were post-PCI coronary flow estimated by corrected thrombolysis in myocardial infarction frame count and post-PCI myocardial infarction. Platelet aggregation was measured by platelet function analyser-100 values.
                Forty-six patients entered the study (22 randomized to placebo and 24 randomized to tirofiban). The study drug was associated with a significant increase of platelet function analyser-100 values that peaked immediately after PCI and was maintained at 6 h (pre-PCI: 131 +/- 65 s; post-PCI: 222 +/- 49 s; after 6 h: 219 +/- 55 s).Post-PCI corrected thrombolysis in myocardial infarction frame count was similar in tirofiban and in placebo groups (10.2 +/- 3.6 vs. 12.0 +/- 7.6, P = 0.30, respectively). The prevalence of raised cTnT levels was similar in the two groups (25 vs. 30%, P = 0.56, respectively). At multivariate analysis, direct stenting (associated with reduced myonecrosis) and postdilatation (associated with increased myonecrosis) predicted cTnT elevation.
                A high-dose bolus of tirofiban in stable diabetic patients undergoing elective PCI, along with double antiplatelet therapy, was associated with a significant further inhibition of platelet aggregation which, however, did not translate in a lower incidence of post-PCI distal embolization. Platelets are believed to play a role in the ischemic complications of coronary angioplasty, such as abrupt closure of coronary vessels during or soon after the procedure. Accordingly, we evaluated the effect of a chimeric monoclonal antibody abciximab, directed against the platelet glycoprotein IIb/IIIa receptor, in patients undergoing angioplasty who were at high risk for ischemic complications. This receptor is the final common pathway for platelet aggregation.
                In a prospective, double-blind trial, we randomly assigned 42 patients to receive a bolus and an infusion of placebo or a bolus and an infusion of abciximab. Low-dose, weight-adjusted heparin (initial dose of 70 U/kg of body weight) was used in both groups. Patients underwent coronary angioplasty for high-risk clinical situations involving unstable angina or high-risk coronary morphologic characteristics. The primary study end-point consisted of any of the following: death, nonfatal myocardial infarction, unplanned surgical revascularization, unplanned repeat percutaneous procedure, unplanned implantation of a coronary stent, or insertion of an intra-aortic balloon pump for refractory ischemia within 30 days of randomization.
                Compared with placebo, the abciximab resulted in a trend toward reduction in periprocedural myocardial infarction from 15% to 0%, although the differences were not statistically significant (p = 0.099). There were no significant differences between the two groups in the risk of major and minor bleeding and the need for blood transfusion.
                Inhibition of platelet glycoprotein IIb/IIIa receptor with abciximab, together with low-dose, weight-adjusted heparin, had a favorable trend toward the reduction of periprocedural myocardial infarction in patients undergoing high-risk angioplasty, without increasing the risk of hemorrhage. Platelet-rich plasma (PRP) is postulated to decrease postoperative mediastinal chest tube drainage (MCTD) and allogeneic blood transfusions (ABT) after surgery with cardiopulmonary bypass. However, recent metaanalysis of the literature reveals that few good quality (therapeutic yield) trials that show a benefit have been published. The potential hemodynamic instability caused by plateletpheresis has not been emphasized. We studied the effect of plateletpheresis on MCTD, ABT, and hemodynamic stability in reoperative coronary artery bypass graft patients, a group perceived to be at high risk for ABT. Ninety patients were randomly assigned to Pheresis or Control groups. epsilon-Aminocaproic acid was given to all patients. Hemodynamic instability was assessed by degree of volume and inotrope resuscitation required. Part of the sequestered platelet volume was used to make autologous platelet gel, which was applied as a wound sealant. Mean pheresis yield was 30% +/- 7% of the circulating platelet mass or 6.4 +/- 2.2 allogeneic platelet unit equivalents. Total MCTD did not differ between the groups. There were no differences in mean packed red blood cell, platelet, and plasma transfusion rates. Overall, 52% of the Pheresis group received ABT, versus 55% of the Control group. Fifty-three percent of the Pheresis group patients exhibited significant hemodynamic instability, versus 27% of the Control group (P < 0.05). This study was unable to show any reduction in MCTD or ABT, although the plateletpheresis technique may offset platelet dysfunction caused by aspirin or increased blood exposure to nonbiologic surfaces, or it may compensate for lack of antifibrinolytic use. The significantly increased incidence of hemodynamic instability in the Pheresis group means that the risk/benefit ratio must be determined for individual cardiac surgical units. Platelet dysfunction is the most common cause of nonsurgical bleeding after cardiopulmonary bypass (CPB). We hypothesized that reinfusion of a therapeutic quantity of platelets sequestered before CPB would decrease the need for allogeneic platelet transfusion, as well as decrease bleeding and total allogeneic transfusion, in cardiac surgery patients at moderately high risk for bleeding. Fifty-five patients undergoing either reoperative coronary artery bypass (CABG) or combined CABG and valve replacement were randomized to control or platelet-rich plasma sequestration (pheresis) groups. All patients received intraoperative epsilon-aminocaproic acid infusions. There was no significant difference between groups with respect to preoperative characteristics, duration of CPB, or target postoperative hematocrit. Mean platelet yields were 6.2 +/- 2.1 units (3.1 x 10(11) platelets). Mean pheresis time was 44 min. Allogeneic platelets (range = 6-12 units) were transfused to 28% of control patients, compared with 0% of pheresis patients (P < 0.01). Allogeneic packed red blood cells were transfused to 45% of control patients (1.2 units per patient) versus 31% of pheresis patients (0. 7 unit per patient) (P = 0.35). Total allogeneic units transfused were significantly reduced in the pheresis group (P < 0.02). Mediastinal chest tube drainage was not significantly decreased in the pheresis group. In this prospective, randomized study, therapeutic platelet yields were obtained before CPB. In contrast with recent studies with low platelet yields, these data support the conclusion that platelet-rich plasma sequestration is effective in reducing allogeneic platelet transfusions and total allogeneic units transfused in cardiac surgery patients at moderately high risk for post-CPB coagulopathy and bleeding.
                Transfusion of allogeneic blood products, including platelets, is common during complex cardiac surgical procedures. In the present prospective, randomized study, a significant reduction in allogeneic platelet transfusion and total allogeneic units transfused was observed after the reinfusion of a therapeutic quantity of autologous platelets sequestered before cardiopulmonary bypass. Administration of aprotinin during extracorporeal circulation reduces blood loss and improves platelet function.
                To evaluate the protective effect of aprotinin on platelets, 50 patients undergoing cardiopulmonary bypass were randomized before surgery to one of three groups. Seventeen patients (group A) received continuous high-dose aprotinin (7 x 10(6) KIU) during cardiopulmonary bypass, 17 (group B) received a single bolus of aprotinin in the pump prime (2 x 10(6) KIU), and 16 (group C) received placebo. Scanning electron microscopy was used to evaluate platelet aggregation on extracellular matrix. The platelet function was graded from 1 to 4, with grade 4 being normal aggregation. Immediately after cardiopulmonary bypass, 16 patients in group A (94%) reached preoperative aggregation grade (mean grade, 3.4 +/- 0.7) compared with nine of 17 in group B (52%) (mean grade, 2.9 +/- 1.2), and none in group C (0%) (mean grade, 1.4 +/- 0.5; p < 0.001). Postoperative platelet count did not differ significantly among the three groups. After surgery, group A bled less than groups B and C (395 +/- 120 versus 488 +/- 135 and 780 +/- 408 ml, respectively; p < 0.01). Patients in the aprotinin groups received fewer red blood cell units (0.9 +/- 1.2 and 1.9 +/- 1.2 versus 3.4 +/- 1.9, respectively; p < 0.01) and were exposed to less homologous blood products (1.3 +/- 1.7 and 2.1 +/- 1.1 versus 6.1 +/- 5, respectively; p < 0.001).
                By preserving platelet function, aprotinin improves postoperative hemostasis in all patients who receive high dose and in most who receive low dose. Excessive bleeding during and after cardiac surgery with cardiopulmonary bypass is a real problem in this kind of surgery. The use of prophylactic high doses of aprotinin (APROT) reduces blood loss in this context but this treatment is expensive. Some investigators have advocated that epsilon-aminocaproic acid (EACA), a cheaper antifibrinolytic drug, could reduce blood loss in cardiac surgery. The goal of this prospective study was to determine if EACA is as effective as APROT for this clinical condition. Sixty patients undergoing elective surgery for cardiac disease were randomly allocated to one of the two groups. Drugs were administered after induction of anesthesia at a dose of 2.10(6) UIK in the APROT group or 5 g in the EACA group. The same dose was added to the priming of the cardiopulmonary bypass circuit. Until the skin closure the patients received 5.10(5) UIK/h of APROT or 2 g/h of EACA. Bleeding during and after surgery was not different between the two groups. No complication, directly due to the treatment administered, was observed. EACA seems to be as effective as APROT to reduce intra and post cardiac surgery blood loss. EACA has the advantage of being cheaper (treatment is approximately 200 times cheaper), therefore allowing a wider use. Epsilon-aminocaproic acid (epsilon-ACA), an antifibrinolytic agent, is used in cardiac surgery to decrease postoperative bleeding. Theoretical concerns exist about the potential for epsilon-ACA to contribute to thrombotic complications. For this reason epsilon-ACA administration is sometimes delayed until after heparinization. This study investigated the impact of the timing of epsilon-ACA administration on its efficacy.
                In this double-blind study, 90 patients undergoing primary coronary artery bypass graft surgery were prospectively randomized to receive either epsilon-ACA commencing prior to skin incision (bolus 150 mg/kg, followed by an infusion at 15 mg x kg(-1) x hr(-1), epsilon-ACA commencing after heparin (same doses), or placebo. All infusions were terminated at the end of cardiopulmonary bypass. Criteria for the transfusion of blood products were standardized. Postoperative chest tube drainage (at 6 h, 12 h, and at chest tube removal) and blood transfusion requirements of the three groups were compared.
                At all time intervals, the placebo group had significantly greater chest tube drainage than either of the two epsilon-ACA groups (P < 0.005). At no time did a significant difference exist between the two epsilon-ACA groups. A trend existed for the placebo group to require more blood products than either epsilon-ACA group.
                Epsilon-ACA produces a reduction in chest tube drainage in patients undergoing primary coronary artery bypass graft surgery. This effect is similar whether the drug is given prior to incision or following anticoagulation. Given the similar hemostatic efficacy and the theoretical potential for thrombotic complications, it may be prudent to administer epsilon-ACA following anticoagulation. The objectives of this double-blind, placebo-controlled, randomized dose-ranging study were 1) to examine the safety and tolerability of tirofiban (MK-383), a new nonpeptide platelet IIb/IIIa receptor antagonist, on a background of intravenous heparin and aspirin therapy; 2) to study the pharmacodynamics and pharmacokinetics of tirofiban; and 3) to evaluate the incidence of adverse cardiac outcomes (urgent repeat revascularization, myocardial infarction and death) with tirofiban versus placebo in a high risk subset of patients undergoing coronary angioplasty.
                Abrupt vessel closure complicates 4% to 8% of angioplasty procedures. Recent data have suggested that agents that antagonize the platelet glycoprotein IIb/IIIa receptor may reduce the incidence of adverse ischemic outcomes after coronary angioplasty.
                Seventy-three patients received tirofiban in three sequential dose panels and 20 patients received placebo. Patients within each panel were randomized to receive either tirofiban or placebo in a 3:1 randomization design. Bolus doses of 5, 10 and 10 microg/kg and continuous infusion (16 to 24 h) doses of 0.05, 0.10 and 0.15 microg/kg per min were administered in panels I, II and III, respectively. Patients received concomitant heparin and aspirin for the angioplasty procedure. Data on patients receiving placebo (heparin and aspirin only) were pooled across panels for comparisons. The pharmacodynamic effect of tirofiban on ex vivo platelet aggregation to 5 micromol/liter adenosine diphosphate (ADP) and bleeding times were measured. Clinical outcomes were assessed in all patients, but the power to detect clinically meaningful differences (a one-third reduction in clinical events) between groups was limited (5%).
                Tirofiban was associated with a dose-dependent inhibition of ex vivo ADP-mediated platelet aggregation that was sustained during intravenous infusion and resolved rapidly after drug cessation. Adverse bleeding events, largely related to vascular access site hemorrhage, were slightly increased at the highest dose. Adverse clinical outcomes were infrequent in all patients and were not different among the small number of patients within each group.
                This study establishes a rational and generally well tolerated dosing regimen for administration of tirofiban as adjunctive therapy in high risk angioplasty patients. The impact of tirofiban on adverse clinical outcomes after angioplasty awaits definition by a larger clinical trial. Fifty-one men with atherosclerotic intermittent claudication and haemorheological abnormalities completed a double-blind, one-year randomised trial of Ticlopidine (500 mg/day), a new antiplatelet agent. Ticlopidine caused significant inhibition of platelet aggregation but did not fully correct abnormalities of coagulation, viscosity, and fibrinolysis. There was no significant improvement in walking ability, Doppler ankle-pressure indices, or calf blood flow. Sustained platelet inhibition for 12 months was insufficient to correct the prothrombotic abnormality of extensive atherosclerosis. To evaluate the influence of antiplatelet drugs on patency in femoropopliteal vein bypasses, 48 vascular surgeons recruited 549 patients to a randomized double-blind trial of aspirin (300 mg) + dipyridamole (150 mg) or placebo twice daily starting 2 days before surgery and continuing indefinitely. Graft occlusion measured objectively by independent coordinators and cardiovascular events (myocardial infarction or stroke) were studied, expressed by life table, and analyzed statistically by log rank and confidence intervals (95% CI). Randomization achieved comparable groups with 60% of grafts inserted for rest pain or gangrene. Operative complications on aspirin plus dipyridamole included 18 reoperations for bleeding and 12 hematomas compared with 9 and 14, respectively, on placebo (NS). Most of the 172 graft failures occurred early with failure rates of 43/1000 patient-months in the first 3 months, reducing to 17/1000 at 6 to 12 months, and under 10/1000 in subsequent years. Cumulative graft patency on placebo was 72%, 62%, and 60% at 1, 2, and 3 years, respectively, compared with 78%, 70%, and 61% on aspirin plus dipyridamole. The difference in patency of 6.1% (95% CI, -3% to 15.5%) at 1 year and 8.0% (95% CI, -5% to 21%) at 2 years failed to achieve significance (p = 0.43). On mean follow-up of 34 months, 53 (132/1000 patient-years) cardiovascular events (myocardial infarction or cerebrovascular accident) occurred in patients on placebo compared with only 35 (73/1000) on aspirin plus dipyridamole, a significant difference of 59/1000 (p = 0.004). Antiplatelet therapy had little influence on femoropopliteal vein patency, but subsequent myocardial infarction and stroke was reduced in these patients with peripheral vascular disease. Off-pump coronary artery bypass (OPCAB) surgery is associated with a hypercoagulable state in which the platelet thrombin receptor, protease-activated receptor-1 (PAR-1), helps propagate a thrombin burst within saphenous vein grafts. Aprotinin, used in cardiothoracic surgery mainly for its antifibrinolytic properties, also spares platelet PAR-1 activation due to thrombin. We hypothesized that this PAR-1 antagonistic property provides an antithrombotic benefit during OPCAB surgery.
                Patients were randomly assigned to receive saline (n = 38) or a modified full-dose regimen of aprotinin (n = 37) IV during OPCAB surgery. Blood sampled perioperatively from the coronary sinus, skin wounds, and systemic circulation was analyzed to test coagulation and platelet function. Major adverse cardiovascular events were monitored by obtaining troponin I at 24 h (myocardial infarction), predischarge computed tomography angiography (vein graft thrombosis), and by clinical examination for stroke.
                Coronary sinus blood obtained immediately after OPCAB surgery showed significantly less activation in the aprotinin group, as judged by reduced formation of platelet-leukocyte conjugates (P < 0.02) and platelet-derived microparticles (P < 0.05). The aprotinin group showed inhibition of platelet aggregation induced by thrombin (P = 0.007) but not adenosine diphosphate. Thrombin generation, defined by F1.2 levels, was significantly reduced by aprotinin in the coronary sinus but not in skin wound incisions. Major adverse cardiovascular events were significantly reduced in aprotinin-treated patients (5.4% vs 29.7%, P < 0.05). Aprotinin also demonstrated antifibrinolytic properties through diminished red blood cell transfusion (P < 0.04) and reduced blood loss postoperatively (603 +/- 330 vs 810 +/- 415 mL, P < 0.004).
                This study demonstrates that aprotinin protects patients undergoing OPCAB surgery from a hypercoagulable state by diminishing thrombin-induced platelet activation and thrombin generation within saphenous vein grafts, while maintaining systemic hemostatic and antifibrinolytic benefits. These results support further investigation of aprotinin and other PAR-1 antagonists in OPCAB surgery. Fibrinolysis has been recognized as an important cause of intraoperative bleeding during orthotopic liver transplantation (OLT). Several investigators have used prophylactic administration of aprotinin in patients to inhibit fibrinolysis and to decrease transfusion requirements, morbidity, and mortality. Nevertheless, the role of aprotinin in this situation is not yet clear. The goal of this study was to determine the effects of prophylactic administration of aprotinin on intraoperative bleeding and blood requirements, and on hemostatic changes during OLT. Eighty consecutive patients were included in a double-blind, prospective study and were randomized in two groups. In group A (n = 39), an initial dose of 2 x 10(6) kallikrein inactivator units (KIU) of aprotinin was administered in the induction of anesthesia followed by infusion of 5 x 10(5) KIU/h until the end of the procedure. The control group (n = 41) received an identical volume of saline solution. The majority of the operations were performed with vena cava preservation (piggy-back technique) without venovenous bypass. During the anhepatic phase, a significant increase in levels of tissue plasminogen activator, thrombin-antithrombin complexes (TAT) and D-dimers (DD) was noted in both groups. A significant increment of TAT was observed in group A during reperfusion. The remaining hemostatic parameters were similar in both groups. Intraoperative requirements of packed red cells, fresh-frozen plasma (FFP), platelets, and cryoprecipitate were similar in the two groups. Our results suggest that prophylactic administration of aprotinin is not useful in reducing bleeding and blood product requirements during OLT. A prospective randomized double-blind placebo-controlled study was undertaken to determine the efficacy and mechanism of action of two antifibrinolytic drugs aprotinin and epsilon aminocaproic acid (EACA) in reducing blood loss in primary unilateral total hip arthroplasty (THA). Aprotinin was administered as a bolus of 2 x 10(6) kallikrein inhibitor units (KIU) followed by 0.5 x 10(6) KIU h(-1) for 3 h, EACA was given as 10 g over 30 min followed by 5 g over 3 h. The median postoperative blood loss 24 h postoperatively was reduced from 450 mL in the placebo group to 180 mL for aprotinin (60% reduction, P < 0.001) and to 210 mL for EACA (53% reduction, P < 0.01). In this population, there was no reduction in the perioperative transfusion requirements. The mechanism of both drugs was independent of platelets as indicated by flow cytometric measurement of change of their expression of P-selectin, platelet-monocyte aggregates, V/Va and CD40 ligand. There were no thrombotic or infective complications and no adverse events were attributable to use of either drug. Infusion of either aprotinin or EACA at the doses described is a safe and effective means of reducing blood loss after THA. These therapies provide a means of reducing blood loss in THA patients. Adverse cardiovascular events associated with thrombotic occlusion occur in 4% to 12.8% of patients after coronary angioplasty. Recently, potent antiplatelet agents have been used to reduce those thrombotic complications. Tirofiban is a highly selective, short-acting inhibitor of fibrinogen binding to platelet glycoprotein (GP) IIb/IIIa that inhibits ex vivo platelet aggregation in response to a variety of agonists.
                The RESTORE trial (Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis) was a randomized, double-blind, placebo-controlled trial of tirofiban in patients undergoing coronary interventions (balloon angioplasty or directional atherectomy) within 72 hours of presentation with an acute coronary syndrome (unstable angina pcctoris or acute myocardial infarction). The end points of the study were death from any cause, myocardial infarction, coronary bypass surgery due to angioplasty failure or recurrent ischemia, repeat target-vessel angioplasty for recurrent ischemia, and insertion of a stent due to actual or threatened abrupt closure of the dilated artery, and the primary end point was a composite representing the occurrence of any of these events. The prespecified primary hypothesis of the study was that tirofiban, administered as a bolus of 10 microg/kg over a 3-minute period and followed by a 36-hour infusion of 0.15 microg x kg(-1) x min(-1), would result in a reduction in the 30-day composite end point compared with placebo. Patients (n=2139) who were already receiving treatment with aspirin and heparin were randomized to receive tirofiban or placebo. The primary composite end point at 30 days was reduced from 12.2% in the placebo group to 10.3% in the tirofiban group, a 16% relative reduction (P=.160). However, 2 days after angioplasty, the tirofiban group had a 38% relative reduction in the composite end point (P< or =.005), and at 7 days there was a 27% relative reduction (P=.022), largely because of a reduction in nonfatal myocardial infarction and the need for repeat angioplasty. When repeat angioplasty or coronary artery bypass surgery procedures were included in the composite only if performed on an urgent or emergency basis, the composite 30-day event rates were 10.5% for the placebo group and 8.0% for the tirofiban group, a relative reduction of 24% (P=.052). Major bleeding, including transfusion, was not significantly different between the two groups (3.7% in the placebo group and 5.3% in the tirofiban group; P=.096). When the Thrombolysis In Myocardial Infarction (TIMI) criteria for major bleeding were used, the incidence was 2.1% in the placebo group compared with 2.4% in the tirofiban group (P=.662). Thrombocytopenia was similar in the placebo and tirofiban groups (0.9% for the placebo group versus 1.1% for the tirofiban group; P=.709).
                In patients undergoing coronary angioplasty for acute coronary syndromes, tirofiban protects against early adverse cardiac events related to thrombotic closure. At 30 days, however, the reduction in adverse cardiac events was no longer statistically significant. The bleeding observed with tirofiban was not statistically different from that observed with placebo. Excessive postoperative bleeding after heart operations continues to be a source of morbidity. This prospective double-blind study evaluated epsilon-aminocaproic acid as an agent to reduce postoperative bleeding and investigated its mode of action. One hundred three patients were randomly assigned to receive either 30 gm epsilon-aminocaproic acid (51 patients) or an equivalent volume of placebo (52 patients). In a subset of these patients (14 epsilon-aminocaproic acid, 12 placebo), tests of platelet function and fibrinolysis were performed.
                By multivariate analysis, three factors were associated with decreased blood loss in the first 24 hours after operation: epsilon-aminocaproic acid versus placebo (647 ml versus 839 ml, p = 0.004), surgeon 1 versus all other surgeons (582 ml versus 978 ml, p = 0.002), and no intraaortic balloon versus intraaortic balloon pump use (664 ml versus 1410 ml, p = 0.02). No significant differences in platelet function could be demonstrated between the two groups. Inhibited fibrinolysis, as reflected by less depression of the euglobulin clot lysis and no rise in D-dimer levels, was significant in the epsilon-aminocaproic acid group compared with the placebo group.
                The intraoperative use of epsilon-aminocaproic acid reduces postoperative cardiac surgical bleeding. Patients undergoing cardiac surgery employing cardiopulmonary bypass frequently require transfusion of homologous blood products and, therefore, are exposed to the risk of transfusions. Autologous platelet-rich plasma administration may reduce homologous transfusion and attendant risks.
                In a blinded, randomized fashion, patients undergoing repeat sternotomy and valvular surgery received either a sham product (n = 28) or autologous platelet-rich plasma (n = 28) at the conclusion of cardiopulmonary bypass. Perioperative blood loss, coagulation profiles, and transfusion requirements were compared between the two groups.
                In the first 24 h postoperatively, both the platelet-rich plasma and sham groups received a median of 10.5 units of homologous blood products. Total median perioperative homologous transfusion requirements were 13 and 11.5 units for the platelet-rich plasma and sham groups, respectively. There was no significant difference in intraoperative or postoperative bleeding between the groups.
                Autologous platelet-rich plasma did not reduce perioperative bleeding or transfusion requirements in repeat valvular surgery. Although stents reduce restenosis compared with balloon angioplasty, their long-term efficacy is limited by neointimal hyperplasia. Platelet and alpha(v)beta(3) integrin receptor inhibition limits neointimal proliferation in animal models of arterial injury.
                We tested whether the dual beta(3) integrin blocking agent abciximab, administered for 12 or 24 hours at the same intravenous dose as that shown to reduce adverse clinical events (death, infarction, and revascularization) after angioplasty, would reduce restenotic tissue volume, as measured by intravascular ultrasound at 6 months. Two hundred twenty-five patients were randomly allocated to placebo or abciximab before coronary intervention. Of the 215 patients who received stents and study drug, 191 (88.8%) returned for late (>/=4 months) coronary evaluation. Tissue volume, expressed as a percentage of stent volume, did not differ: 25+/-15%, 27+/-15%, and 29+/-14% for the patients in the placebo and the 12- and 24-hour abciximab groups, respectively. Lack of abciximab benefit was confirmed by quantitative coronary angiography (dichotomous restenosis: 11.6%, 18. 9%, and 19.4%; loss index: 0.33, 0.52, and 0.47, respectively, P=NS).
                Potent platelet inhibition with abciximab, as administered in this study, does not reduce in-stent restenosis. The interrelationship between stents, platelets, and neointimal proliferation requires further study.
Antiplatelet agents reduce myocardial infarction but increase major bleeding. Risks may outweigh benefits among people with low annual risks of cardiovascular events, including those with early stages of CKD who do not have clinically-evident occlusive cardiovascular disease.