Clopidogrel does not suppress blood markers of coagulation activation in aspirin-treated patients with non-ST-elevation acute coronary syndromes.

AIMS: The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Study demonstrated that clopidogrel plus aspirin was superior to aspirin alone for prevention of recurrent vascular events in patients with acute coronary syndromes. The aim of this study was to compare the effect of these two regimens on biochemical markers of platelet and coagulation activation. METHODS AND RESULTS: We studied 485 patients with non-ST-elevation acute coronary syndrome who were randomized to clopidogrel (300 mg loading dose followed by 75 mg daily) or placebo for a period of 3-12 months. All patients also received aspirin (recommended dose 75-325 mg daily). Blood levels of P-selectin, prothrombin fragment F1.2, D-dimer, and von Willebrand factor were measured at baseline, day 7 (or hospital discharge), and at day 30 after randomization. Patients receiving clopidogrel plus aspirin compared with aspirin alone had similar baseline geometric mean plasma levels of P-selectin (50.2 vs 51.7 ng.ml(-1), P=0.45), prothrombin fragment F1.2 (1.13 vs 1.12 nmol.l(-1), P=0.94), D-dimer (467 vs 460 ng.ml(-1), P=0.85), and von Willebrand factor levels (1.89 vs 1.85 U.ml(-1), P=0.59) and there also were no significant differences at day 7, or day 30. However, compared with baseline, there was a significant rise in prothrombin fragment F1.2 at day 7 (from 1.12 to 1.39 nmol.l(-1), P<0.0001) and day 30 (from 1.12 to 1.44 nmol.l(-1), P<0.0001), and D-dimer at day 7 (from 464 to 539 nmol.l(-1), P<0.0001) and day 30 (from 464 to 576 nmol.l(-1), P<0.0001). The magnitude of this rise appeared to be greatest in patients who experienced the primary outcome, a composite of cardiovascular death, myocardial infarction, stroke, or refractory ischaemia by the end of the study. P-selectin levels were not elevated at any time point but von Willebrand factor values were elevated at baseline and remained elevated at days 7 and 30. CONCLUSION: Our results indicate that the clinical benefits of clopidogrel are not associated with a parallel reduction in markers of coagulation activation. Early suppression of coagulation markers most likely reflects the effects of heparin. The persistence of thrombin generation despite long-term clopidogrel and aspirin therapy suggests that even more intensive antithrombotic therapy may be required in these patients.     

Myocardial ischemia and ventricular tachycardia on continuous electrocardiographic monitoring and risk of cardiovascular outcomes after non-ST-segment elevation acute coronary syndrome (from the MERLIN-TIMI 36 Trial)

Among patients with non-ST-segment elevation acute coronary syndromes, recurrent ischemia and ventricular arrhythmias detected on continuous electrocardiographic monitoring remain common events that are associated with worse outcomes. The relative clinical significance of both events together is not well described. We determined the risk associated with ischemia (≥1 mm ST depression lasting ≥1 minutes) and ventricular tachycardia (VT) (≥4 beats) detected on 7-day continuous electrocardiographic monitoring in 6,355 patients with non-ST-segment elevation acute coronary syndromes from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-elevation Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction (MERLIN-TIMI) 36 trial. The patients were categorized into 4 groups according to the presence or absence of VT and ischemia. Cardiovascular death, sudden cardiac death (SCD), myocardial infarction, and recurrent ischemia were assessed during a median follow-up of 348 days. A total of 60.0% patients had no VT or ischemia, 20.0% had VT alone, 14.7% had ischemia alone, and 5.3% had both. The patients with either VT or ischemia were at increased risk of cardiovascular outcomes. The combination of ischemia and VT identified a particularly high-risk population for cardiovascular death (10.1% vs 3.0%, p <0.001), SCD (7.8% vs 0.9%, p <0.001), and myocardial infarction (15.4% vs 6.2%, p <0.001) compared to patients with neither. The addition of arrhythmia and ischemia significantly improved the clinical model for predicting cardiovascular death or SCD (p <0.001). In patients with both ischemia and VT, 66.6% of SCD occurred within 90 days of the non-ST-segment elevation acute coronary syndromes. In conclusion, in >6,300 patients with non-ST-segment elevation acute coronary syndromes, the presence of myocardial ischemia or VT alone, and particularly in combination, was independently associated with poor cardiovascular outcomes and thus provides incremental improvement in early risk stratification.     

Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial

Context  Despite many therapeutic advances, mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) remains high. The role of additional antithrombotic agents is unclear, especially among patients not receiving reperfusion therapy. Objective  To evaluate the effect of fondaparinux, a factor Xa inhibitor, when initiated early and given for up to 8 days vs usual care (placebo in those in whom unfractionated heparin [UFH] is not indicated [stratum 1] or unfractionated heparin for up to 48 hours followed by placebo for up to 8 days [stratum 2]) in patients with STEMI. Design, Setting, and Participants  Randomized double-blind comparison of fondaparinux 2.5 mg once daily or control for up to 8 days in 12 092 patients with STEMI from 447 hospitals in 41 countries (September 2003-January 2006). From day 3 through day 9, all patients received either fondaparinux or placebo according to the original randomized assignment. Main Outcome Measures  Composite of death or reinfarction at 30 days (primary) with secondary assessments at 9 days and at final follow-up (3 or 6 months). Results  Death or reinfarction at 30 days was significantly reduced from 677 (11.2%) of 6056 patients in the control group to 585 (9.7%) of 6036 patients in the fondaparinux group (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.77-0.96; P = .008); absolute risk reduction, 1.5%; 95% CI, 0.4%-2.6%). These benefits were observed at 9 days (537 [8.9%] placebo vs 444 [7.4%] fondaparinux; HR, 0.83; 95% CI, 0.73-0.94; P = .003, and at study end (857 [14.8%] placebo vs 756 [13.4%] fondaparinux; HR, 0.88; 95% CI, 0.79-0.97; P = .008). Mortality was significantly reduced throughout the study. There was no heterogeneity of the effects of fondaparinux in the 2 strata by planned heparin use. However, there was no benefit in those undergoing primary percutaneous coronary intervention. In other patients in stratum 2, fondaparinux was superior to unfractionated heparin in preventing death or reinfarction at 30 days (HR, 0.82; 95% CI, 0.66-1.02; P = .08) and at study end (HR, 0.77; 95% CI, 0.64-0.93; P = .008). Significant benefits were observed in those receiving thrombolytic therapy (HR, 0.79; P = .003) and those not receiving any reperfusion therapy (HR, 0.80; P = .03). There was a tendency to fewer severe bleeds (79 for placebo vs 61 for fondaparinux; P = .13), with significantly fewer cardiac tamponade (48 vs 28; P = .02) with fondaparinux at 9 days. Conclusion  In patients with STEMI, particularly those not undergoing primary percutaneous coronary intervention, fondaparinux significantly reduces mortality and reinfarction without increasing bleeding and strokes. Trial Registration  ClinicalTrials.gov Identifier NCT00064428      

Two-year outcomes in patients admitted with non-ST elevation acute coronary syndrome: results of the OASIS registry 1 and 2

BACKGROUND: Acute coronary syndrome continues to have significant long-term morbidity and mortality. This study sought to compare baseline characteristics, practice patterns and clinical outcomes for patients with non-ST elevation acute coronary syndrome from a broad range of low-, middle- and high-income countries. METHODS AND RESULTS: We compared the data from a prospective registry of patients with non-ST elevation acute coronary syndrome involving 4615 patients from 65 centers in 8 low and middle income countries (OASIS registry 2) with those obtained from 7987 patients from 95 centers in 6 middle and high income countries (OASIS registry 1). Patients in the OASIS registry 2 were younger, were more often males and smokers, presented later to the hospital after symptom onset and had a lower prevalence of diabetes at admission [with the exception of India, which had the highest age-adjusted prevalence (39.1%)]. There were marked variations in the angiography and intervention rates during the hospital stay, but the uses of proven pharmacological therapies were comparable. The two-year mortality rates adjusted for baseline covariates ranged from 6.9% to 15%. Patients from China had the lowest two-year mortality rate (6.9%) and patients from India had the highest rate (15%). Combining the two registries, the covariate-adjusted rate of death or myocardial infarction did not differ across countries with in-hospital angiographic rates of > or = 50% (17.1%), 25-49% (16.7%) or < 25% (16.5%). However, the covariate-adjusted rates for subsequent myocardial infarction (7.6%, 9.2% and 10.8% respectively, p < 0.0001), refractory angina (21.3%, 27.7% and 35.4% respectively, p < 0.0001) and the composite of death, myocardial infarction or refractory angina (34.9%, 40.7% and 46.8% respectively, p < 0.0001) differed depending on the angiographic rates. CONCLUSIONS: Among the participating countries there was a marked heterogeneity in patient characteristics, coronary interventions, resulting in differences in the two-year composite rates of death, myocardial infarction and refractory angina among patients admitted with non-ST elevation acute coronary syndrome.     

Decline in rates of death and heart failure in acute coronary syndromes, 1999-2006

Context  Randomized trials provide robust evidence for the impact of pharmacological and interventional treatments in patients with ST-segment elevation and non–ST-segment elevation acute coronary syndromes (NSTE ACS), but whether this translates to changes in clinical practice is unknown. Objective  To determine whether changes in hospital management of patients with ST-segment elevation myocardial infarction (STEMI) and NSTE ACS are associated with improvements in clinical outcome. Design, Setting, and Patients  In the Global Registry of Acute Coronary Events (GRACE), a multinational cohort study, 44 372 patients with an ACS were enrolled and followed up in 113 hospitals in 14 countries between July 1, 1999, and December 31, 2006. Main Outcome Measures  Temporal trends in the use of evidence-based pharmacological and interventional therapies; patient outcomes (death, congestive heart failure, pulmonary edema, cardiogenic shock, stroke, myocardial infarction). Results  Use of pharmacological medications increased over the study period (-blockers, statins, angiotensin-converting enzyme inhibitors, thienopyridines with or without percutaneous coronary intervention [PCI], glycoprotein IIb/IIIa inhibitors, low-molecular-weight heparin; all P<.001). Pharmacological reperfusion declined in patients with STEMI by –22 percentage points (95% confidence interval [CI], –27 to –17), whereas primary PCI increased by 37 percentage points (95% CI, 33-41). In patients with non-STEMI, rates of PCI increased markedly by 18 percentage points (95% CI, 15-20). Rates of congestive heart failure and pulmonary edema declined in both populations: STEMI, –9 percentage points (95% CI, –12 to –6) and NSTE ACS, –6.9 percentage points (95% CI, –8.4 to –4.7). In patients with STEMI, hospital deaths decreased by 18 percentage points (95% CI, –5.3 to –1.9) and cardiogenic shock by –24 percentage points (95% CI, –4.3 to –0.5). Risk-adjusted hospital deaths declined –0.7 percentage points (95% CI, –1.7 to 0.3) in NSTE ACS patients. Six-month follow-up rates declined among STEMI patients: stroke by –0.8 percentage points (95% CI, –1.7 to 0.1) and myocardial infarction by –2.8 percentage points (95% CI, –6.4 to 0.9). In NSTE ACS, 6-month death declined –1.6 percentage points (95% CI, –3.0 to –0.1) and stroke by 0.7 percentage points (95% CI, –1.4 to 0.1). Conclusions  In this multinational observational study, improvements in the management of patients with ACS were associated with significant reductions in the rates of new heart failure and mortality and in rates of stroke and mycoardial infarction at 6 months.