Randomized Trial of an Oral Platelet Glycoprotein IIb/IIIa Antagonist, Sibrafiban, in Patients After an Acute Coronary Syndrome

Cannon, Christopher P.; McCabe, Carolyn H.; Borzak, Steven; Henry, Timothy D.; Tischler, Marc D.; Mueller, Hiltrud S.; Feldman, Robert L.; Palmeri, Sebastian T.; Ault, Kenneth A.; Hamilton, Scott; Rothman, Joel; Novotny, William; Braunwald, Eugene

doi:10.1161/01.cir.97.4.340

Cited by 159 publications

(95 citation statements)

References 24 publications

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“…The study cohort eligible for these analyses consisted of 41 637 patients with ACS from the following 16 Thrombolysis In Myocardial Infarction (TIMI) trials: IIIB, 15 4,16 9A, 17 9B, 18 10A, 19 10B, 20 11A, 21 11B, 22 12, 23 14,24 16 (OPUS), 25 17 (InTIME II), 26 18 (TACTICS), 27 20 (INTEGRITI), 28 23 (ENTIRE), 29 and 24 (FAST-ER), 30 the details for which have been published. Patients with active cancer, significant liver or renal disease (typically a creatinine Ͼ2.0 mg/dL), active or recent internal bleeding, known bleeding diathesis, and other significant comorbidities were excluded from these trials.…”

Section: Patient Populationsmentioning

confidence: 99%

Association of Hemoglobin Levels With Clinical Outcomes in Acute Coronary Syndromes

et al. 2005

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Background— In the setting of an acute coronary syndrome (ACS), anemia has the potential to worsen myocardial ischemia; however, data relating anemia to clinical outcomes in ACS remain limited. Methods and Results— We examined the association between baseline hemoglobin values and major adverse cardiovascular events through 30 days in 39 922 patients enrolled in clinical trials of ACS. After adjustment for differences in baseline characteristics and index hospitalization treatments, a reverse J-shaped relationship between baseline hemoglobin values and major adverse cardiovascular events was observed. In patients with ST-elevation myocardial infarction, when those with hemoglobin values between 14 and 15 g/dL were used as the reference, cardiovascular mortality increased as hemoglobin levels fell below 14 g/dL, with an adjusted OR of 1.21 (95% CI 1.12 to 1.30, P <0.001) for each 1-g/dL decrement in hemoglobin. At the other end of the range of hemoglobin, patients with hemoglobin values >17 g/dL also had excess mortality (OR 1.79, 95% CI 1.18 to 2.71, P =0.007). In patients with non–ST-elevation ACS, with those with hemoglobin 15 to 16 g/dL used as the reference, the likelihood of cardiovascular death, myocardial infarction, or recurrent ischemia increased as the hemoglobin fell below 11 g/dL, with an adjusted OR of 1.45 (95% CI 1.33 to 1.58, P <0.001) for each 1 g/dL decrement in hemoglobin. Patients with hemoglobin values >16 g/dL also had an increased rate of death or ischemic events (OR 1.31, 95% CI 1.03 to 1.66, P =0.027). Conclusions— Anemia is a powerful and independent predictor of major adverse cardiovascular events in patients across the spectrum of ACS.

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Section: Patient Populationsmentioning

confidence: 99%

Association of Hemoglobin Levels With Clinical Outcomes in Acute Coronary Syndromes

et al. 2005

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“…11 With oral administration, peaks and troughs (corresponding to the drug's half-life) exist in the level of platelet inhibition; these are not present with intravenously administered IIb/IIIa inhibitors. In addition, substantial variability between patients in the level of inhibition has been observed with all oral agents 12,13 ; this is related in part to differences in bioavailability. As such, with a fixed dose, some orbofibantreated patients have as high as 100% inhibition at peak and others as low as 0% to 20% inhibition at trough.…”

Section: Potential Explanations For Lack Of Benefitmentioning

confidence: 99%

Oral Glycoprotein IIb/IIIa Inhibition With Orbofiban in Patients With Unstable Coronary Syndromes (OPUS-TIMI 16) Trial

et al. 2000

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Background —Although intravenous glycoprotein IIb/IIIa inhibitors are beneficial in patients with acute coronary syndromes, prolonged oral IIb/IIIa inhibition might provide an additional reduction in recurrent events. Methods and Results —Investigators at 888 hospitals in 29 countries enrolled 10 288 patients with acute coronary syndromes, which was defined as ischemic pain at rest within 72 hours of randomization, associated with positive cardiac markers, electrocardiographic changes, or prior cardiovascular disease. Patients received aspirin and were randomized to receive, for the duration of the trial, (1) 50 mg of orbofiban twice daily (50/50 group), (2) 50 mg of orbofiban twice daily for 30 days followed by 30 mg of orbofiban twice daily (50/30 group), or (3) a placebo. The primary composite end point was death, myocardial infarction, recurrent ischemia requiring rehospitalization, urgent revascularization, or stroke. The trial was terminated prematurely because of an unexpected increase in 30-day mortality in the 50/30 orbofiban group. Mortality through 10 months was 3.7% for the placebo group versus 5.1% in the 50/30 group ( P =0.008) and 4.5% in the 50/50 group ( P =0.11). There were no differences in the primary end point (22.9%, 23.1%, and 22.8%, for the placebo, 50/30, and 50/50 groups, respectively). Major or severe bleeding (but not intracranial hemorrhage) was higher with orbofiban; it occurred in 2.0%, 3.7% ( P =0.0004), and 4.5% ( P <0.0001) of patients, respectively. Exploratory subgroup analyses found that patients who underwent percutaneous coronary intervention had a lower mortality and a significant reduction in the composite end point ( P =0.001) with orbofiban. Conclusions —Fixed-dose orbofiban failed to reduce major cardiovascular events and was associated with increased mortality in this broad population of patients with acute coronary syndromes; however, a benefit was observed among patients who underwent percutaneous coronary intervention.

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“…29 In the PK/PD cohort of TIMI 12, 106 patients were randomized to receive one of seven dosing regimens of sibrafiban, ranging from 5 mg daily to 10 mg twice daily for 28 days. In the safety cohort, 223 patients were randomized to one of four dose regimens of sibrafiban (ranging from 5 mg twice daily to 15 mg once daily) or aspirin for 28 days.…”

Section: The Thrombolysis In Myocardial Infarction 12 Trialmentioning

confidence: 99%

“…In a multivariate model, minor bleeding was related to total daily dose (p = 0.002), once-versus twice-daily dosing (p < 0.0001), renal function (p < 0.0001), and presentation with unstable angina (p < 0.01). 29 Thus, the oral IIb/IIIa antagonist sibrafiban achieved effective, chronic platelet inhibition with a clear dose-response, but at the expense of a relatively high incidence of minor bleeding. The mucocutaneous bleeds appeared to be related to plasma drug concentrations, the degree of platelet inhibition, and other patient factors (weight, renal function).…”

Section: The Thrombolysis In Myocardial Infarction 12 Trialmentioning

confidence: 99%

Oral platelet glycoprotein IIb/IIIa receptor inhibitors—part I

Cannon

2003

Clinical Cardiology

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Summary:With the central importance of antiplatelet therapy in patients with coronary artery disease and the numerous positive trials with glycoprotein (GP) IIb/IIIa inhibitors given intravenously, it was hoped that one could extend the benefit of IIb/IIIa inhibition to long-term treatment. Although the hypothesis that prolonged oral IIb/IIIa inhibition was appealing, many issues have been identified in the initial Phase II trials that would limit the usefulness of these compounds. Variability of the level of platelet inhibition was one major culprit that distinguished the oral compounds from intravenous ones. The problems that arose were that increased bleeding has been seen when levels of platelet inhibition are high (e.g., > 90%) and that, conversely, efficacy would likely be limited when levels of platelet inhibition were low. If further development of this class of drugs is undertaken, formal dosing studies would have to establish an oral dosing strategy that achieves appropriately high (80-95% inhibition) and steady levels of inhibition.

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Randomized Trial of an Oral Platelet Glycoprotein IIb/IIIa Antagonist, Sibrafiban, in Patients After an Acute Coronary Syndrome

Cited by 159 publications

References 24 publications

Association of Hemoglobin Levels With Clinical Outcomes in Acute Coronary Syndromes

Association of Hemoglobin Levels With Clinical Outcomes in Acute Coronary Syndromes

Oral Glycoprotein IIb/IIIa Inhibition With Orbofiban in Patients With Unstable Coronary Syndromes (OPUS-TIMI 16) Trial

Oral platelet glycoprotein IIb/IIIa receptor inhibitors—part I

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