Biomedical subjects
Publications and source records attributed to Andrzej Budaj.
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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.
BACKGROUND: The combined use of anticoagulants, antiplatelet agents, and invasive coronary procedures reduces ischemic coronary events but also increases bleeding in patients with acute coronary syndromes. We therefore assessed whether fondaparinux would preserve the anti-ischemic benefits of enoxaparin while reducing bleeding. METHODS: We randomly assigned 20,078 patients with acute coronary syndromes to receive either fondaparinux (2.5 mg daily) or enoxaparin (1 mg per kilogram of body weight twice daily) for a mean of six days and evaluated death, myocardial infarction, or refractory ischemia at nine days (the primary outcome); major bleeding; and their combination. Patients were followed for up to six months. RESULTS: The number of patients with primary-outcome events was similar in the two groups (579 with fondaparinux [5.8 percent] vs. 573 with enoxaparin [5.7 percent]; hazard ratio in the fondaparinux group, 1.01; 95 percent confidence interval, 0.90 to 1.13), satisfying the noninferiority criteria. The number of events meeting this combined outcome showed a nonsignificant trend toward a lower value in the fondaparinux group at 30 days (805 vs. 864, P=0.13) and at the end of the study (1222 vs. 1308, P=0.06). The rate of major bleeding at nine days was markedly lower with fondaparinux than with enoxaparin (217 events [2.2 percent] vs. 412 events [4.1 percent]; hazard ratio, 0.52; P<0.001). The composite of the primary outcome and major bleeding at nine days favored fondaparinux (737 events [7.3 percent] vs. 905 events [9.0 percent]; hazard ratio, 0.81; P<0.001). Fondaparinux was associated with a significantly reduced number of deaths at 30 days (295 vs. 352, P=0.02) and at 180 days (574 vs. 638, P=0.05). CONCLUSIONS: Fondaparinux is similar to enoxaparin in reducing the risk of ischemic events at nine days, but it substantially reduces major bleeding and improves long term mortality and morbidity. (ClinicalTrials.gov number, NCT00139815.).
BACKGROUND: Unfractionated heparin is often used as adjunctive therapy with fibrinolysis in patients with ST-elevation myocardial infarction. We compared a low-molecular-weight heparin, enoxaparin, with unfractionated heparin for this purpose. METHODS: We randomly assigned 20,506 patients with ST-elevation myocardial infarction who were scheduled to undergo fibrinolysis to receive enoxaparin throughout the index hospitalization or weight-based unfractionated heparin for at least 48 hours. The primary efficacy end point was death or nonfatal recurrent myocardial infarction through 30 days. RESULTS: The primary end point occurred in 12.0 percent of patients in the unfractionated heparin group and 9.9 percent of those in the enoxaparin group (17 percent reduction in relative risk, P<0.001). Nonfatal reinfarction occurred in 4.5 percent of the patients receiving unfractionated heparin and 3.0 percent of those receiving enoxaparin (33 percent reduction in relative risk, P<0.001); 7.5 percent of patients given unfractionated heparin died, as did 6.9 percent of those given enoxaparin (P=0.11). The composite of death, nonfatal reinfarction, or urgent revascularization occurred in 14.5 percent of patients given unfractionated heparin and 11.7 percent of those given enoxaparin (P<0.001); major bleeding occurred in 1.4 percent and 2.1 percent, respectively (P<0.001). The composite of death, nonfatal reinfarction, or nonfatal intracranial hemorrhage (a measure of net clinical benefit) occurred in 12.2 percent of patients given unfractionated heparin and 10.1 percent of those given enoxaparin (P<0.001). CONCLUSIONS: In patients receiving fibrinolysis for ST-elevation myocardial infarction, treatment with enoxaparin throughout the index hospitalization is superior to treatment with unfractionated heparin for 48 hours but is associated with an increase in major bleeding episodes. These findings should be interpreted in the context of net clinical benefit. (ClinicalTrials.gov number, NCT00077792.).
BACKGROUND: The impact and prognostic value of the redefinition of myocardial infarction (MI) with more sensitive markers have not been evaluated prospectively in a large, less selected population with acute coronary syndrome (ACS). METHODS: We evaluated the attack and case-fatality rates of MI based on initial and/or peak creatine kinase (CK), creatine kinase-MB (CK-MB), and cardiac troponin (the upper limit of normal [ULN] was defined according to the local hospital's standard) in a prospective observational registry of 26,267 patients with ACS admitted to 106 hospitals in 14 countries. RESULTS: The addition of cardiac troponin-positive status to CK status as a criterion for the diagnosis of MI resulted in as many as 1 in 4 additional patients meeting the redefined criteria. Compared with patients without elevated levels of CK and cardiac troponin, the crude odds for dying during hospitalization were significantly higher for patients with elevated troponin but not CK levels of greater than or equal to the ULN (odds ratio [OR] 2.2, 95% CI 1.6-2.9), those without CK levels >2 times the ULN (OR 2.8, 95% CI 2.2-3.5), and those with nonelevated levels of CK-MB (OR 2.1, 95% CI 1.4-3.2). The addition of cardiac troponin-positive status significantly increased the multivariable-adjusted odds for hospital death in patients with CK < or =2 times the ULN (OR 1.6, 95% CI 1.2-2.1) but not for patients without elevated levels of CK or CK-MB. CONCLUSIONS: The prognostic value of cardiac troponin, beyond that supplied by CK status or important baseline characteristics, assists in the identification of patients with ACS who are at increased risk for death.
BACKGROUND: National guidelines recommend the use of secondary prevention modalities for patients with peripheral artery disease (PAD) and coronary artery disease. The effect of prior PAD on the treatment and outcomes of patients with acute coronary syndromes (ACS), however, is not well characterized. The objectives of this study were to assess treatment practices and hospital outcomes in patients with ACS and prior PAD. METHODS: Data were analyzed from 41,108 patients aged > or =18 years with ACS and enrolled in the large multinational GRACE between 1999 and 2004. RESULTS: Of the 41,108 patients, 4003 (9.7%) had prior PAD. Patients with PAD were older, more likely to be men, to have a variety of prior comorbidities, and to present with non-ST-segment elevation myocardial infarction and a higher Killip class than patients without PAD. Patients with PAD were less likely to be treated with effective cardiac medications than patients without PAD. At the time of hospital presentation, patients with prior PAD had low rates of use of beneficial cardiac medications, including angiotensin-converting enzyme inhibitors, aspirin, beta-blockers, and lipid-lowering agents. Patients with PAD were significantly more likely to experience the composite hospital end point (death, shock, recurrent angina, stroke) than patients without prior PAD (adjusted OR 1.17; 95% CI 1.08-1.26). CONCLUSIONS: Patients with prior PAD received less aggressive treatment with proven cardiac medications during hospitalization for an ACS than patients without PAD. Utilization of beneficial medical therapies in patients with PAD before hospitalization with ACS was also less than optimal. Given the poorer hospital outcomes in patients with PAD, our findings suggest considerable opportunity to improve care for these high-risk patients.
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BACKGROUND: Stroke is a recognized complication after acute myocardial infarction, but few studies have investigated the incidence and outcome of stroke in patients with acute coronary syndrome (ACS). This study examined the incidence and outcomes of hemorrhagic and nonhemorrhagic stroke and risk factors associated with stroke in patients with ACS. METHODS AND RESULTS: Data were obtained from 35,233 patients enrolled in the Global Registry of Acute Coronary Events (GRACE) with an ACS. In-hospital strokes occurred in 310 patients (0.9%), of which 100 (32.6%) were fatal. The incidence of in-hospital stroke was significantly higher in patients with ST-segment-elevation myocardial infarction than in non-ST-segment myocardial infarction or unstable angina (1.3%, 0.9%, 0.5%, respectively; P<0.001). Overall, 35.5% of in-hospital strokes occurred within 6 days of hospitalization. The strongest risk factor for in-hospital nonhemorrhagic stroke was in-hospital CABG, followed by in-hospital atrial fibrillation, previous stroke, initial enzyme elevation, and advanced age. Prior statin use was a protective factor. After controlling for potential confounders, in-hospital mortality was significantly higher among patients who experienced an in-hospital stroke (adjusted odds ratio, 8.3; 95% CI, 6.0 to 11.4). A total of 269 additional strokes (1.1%) occurred within 6 months after discharge from hospital, of which 56 (20.9%) were fatal. The most important risk factor for postdischarge stroke was the occurrence of an in-hospital stroke. CONCLUSIONS: Stroke is an uncommon event in patients with ACS but is associated with high mortality. Despite current therapy, the incidence of postdischarge stroke is not low. New approaches are warranted to reduce the risk of stroke in patients with ACS.
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