Showing papers by "Eric J. Topol published in 2002"

Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.

Abstract: ContextFollowing percutaneous coronary intervention (PCI), short-term clopidogrel therapy in addition to aspirin leads to greater protection from thrombotic complications than aspirin alone. However, the optimal duration of combination oral antiplatelet therapy is unknown. Also, although current clinical data suggest a benefit for beginning therapy with a clopidogrel loading dose prior to PCI, the practical application of this therapy has not been prospectively studied.ObjectivesTo evaluate the benefit of long-term (12-month) treatment with clopidogrel after PCI and to determine the benefit of initiating clopidogrel with a preprocedure loading dose, both in addition to aspirin therapy.Design, Setting, and ParticipantsThe Clopidogrel for the Reduction of Events During Observation (CREDO) trial, a randomized, double-blind, placebo-controlled trial conducted among 2116 patients who were to undergo elective PCI or were deemed at high likelihood of undergoing PCI, enrolled at 99 centers in North America from June 1999 through April 2001.InterventionsPatients were randomly assigned to receive a 300-mg clopidogrel loading dose (n = 1053) or placebo (n = 1063) 3 to 24 hours before PCI. Thereafter, all patients received clopidogrel, 75 mg/d, through day 28. From day 29 through 12 months, patients in the loading-dose group received clopidogrel, 75 mg/d, and those in the control group received placebo. Both groups received aspirin throughout the study.Main Outcome MeasuresOne-year incidence of the composite of death, myocardial infarction (MI), or stroke in the intent-to-treat population; 28-day incidence of the composite of death, MI, or urgent target vessel revascularization in the per-protocol population.ResultsAt 1 year, long-term clopidogrel therapy was associated with a 26.9% relative reduction in the combined risk of death, MI, or stroke (95% confidence interval [CI], 3.9%-44.4%; P = .02; absolute reduction, 3%). Clopidogrel pretreatment did not significantly reduce the combined risk of death, MI, or urgent target vessel revascularization at 28 days (reduction, 18.5%; 95% CI, −14.2% to 41.8%; P = .23). However, in a prespecified subgroup analysis, patients who received clopidogrel at least 6 hours before PCI experienced a relative risk reduction of 38.6% (95% CI, −1.6% to 62.9%; P = .051) for this end point compared with no reduction with treatment less than 6 hours before PCI. Risk of major bleeding at 1 year increased, but not significantly (8.8% with clopidogrel vs 6.7% with placebo; P = .07).ConclusionsFollowing PCI, long-term (1-year) clopidogrel therapy significantly reduced the risk of adverse ischemic events. A loading dose of clopidogrel given at least 3 hours before the procedure did not reduce events at 28 days, but subgroup analyses suggest that longer intervals between the loading dose and PCI may reduce events.

Risk of cardiovascular events associated with selective COX-2 inhibitors☆

Abstract: Atherosclerosis is a process with inflammatory features and selective cyclooxygenase 2 (COX-2) inhibitors may potentially have antiatherogenic effects by virtue of inhibiting inflammation. However, by decreasing vasodilatory and antiaggregatory prostacyclin production, COX-2 antagonists may lead to increased prothrombotic activity. To define the cardiovascular effects of COX-2 inhibitors when used for arthritis and musculoskeletal pain in patients without coronary artery disease, we performed a MEDLINE search to identify all English-language articles on use of COX-2 inhibitors published between 1998 and February 2001. We also reviewed relevant submissions to the US Food and Drug Administration by pharmaceutical companies.Our search yielded 2 major randomized trials, the Vioxx Gastrointestinal Outcomes Research Study (VIGOR; 8076 patients) and the Celecoxib Long-term Arthritis Safety Study (CLASS; 8059 patients), as well as 2 smaller trials with approximately 1000 patients each. The results from VIGOR showed that the relative risk of developing a confirmed adjudicated thrombotic cardiovascular event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic attacks) with rofecoxib treatment compared with naproxen was 2.38 (95% confidence interval, 1.39-4.00; P = .002). There was no significant difference in cardiovascular event (myocardial infarction, stroke, and death) rates between celecoxib and nonsteroidal anti-inflammatory agents in CLASS. The annualized myocardial infarction rates for COX-2 inhibitors in both VIGOR and CLASS were significantly higher than that in the placebo group of a recent meta-analysis of 23 407 patients in primary prevention trials (0.52%): 0.74% with rofecoxib (P = .04 compared with the placebo group of the meta-analysis) and 0.80% with celecoxib (P = .02 compared with the placebo group of the meta-analysis).The available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors. Further prospective trial evaluation may characterize and determine the magnitude of the risk.

Platelet Glycoprotein IIb/IIIa Inhibitors Reduce Mortality in Diabetic Patients With Non–ST-Segment-Elevation Acute Coronary Syndromes

Abstract: Background Diabetes mellitus is a major risk factor for adverse outcomes after acute coronary syndromes (ACS). Because this disease may be associated with increased platelet aggregation, we investigated whether diabetic patients with ACS derive particular benefit from platelet glycoprotein (GP) IIb/IIIa receptor inhibition. Methods and Results We performed a meta-analysis of the diabetic populations enrolled in the 6 large-scale platelet GP IIb/IIIa inhibitor ACS trials: PRISM, PRISM-PLUS, PARAGON A, PARAGON B, PURSUIT, and GUSTO IV. Among 6458 diabetic patients, platelet GP IIb/IIIa inhibition was associated with a significant mortality reduction at 30 days, from 6.2% to 4.6% (OR 0.74; 95% CI 0.59 to 0.92; P=0.007). Conversely, 23 072 nondiabetic patients had no survival benefit (3.0% versus 3.0%). The interaction between platelet GP IIb/IIIa inhibition and diabetic status was statistically significant (P=0.036). Among 1279 diabetic patients undergoing percutaneous coronary intervention (PCI) during inde...

Troponin T Levels in Patients with Acute Coronary Syndromes, with or without Renal Dysfunction

Abstract: Background Among patients with suspected acute coronary syndromes, cardiac troponin T levels have prognostic value. However, there is concern that renal dysfunction may impair the prognostic value, because cardiac troponin T may be cleared by the kidney. Methods We analyzed the outcomes in 7033 patients enrolled in the Global Use of Strategies to Open Occluded Coronary Arteries IV trial who had complete base-line data on troponin T levels and creatinine clearance rates. The troponin T level was considered abnormal if it was 0.1 ng per milliliter or higher, and creatinine clearance was assessed in quartiles. The primary end point was a composite of death or myocardial infarction within 30 days. Results Death or myocardial infarction occurred in 581 patients. Among patients with a creatinine clearance above the 25th percentile value of 58.4 ml per minute, an abnormally elevated troponin T level was predictive of an increased risk of myocardial infarction or death (7 percent vs. 5 percent; adjusted odds rati...

Early and Sustained Survival Benefit Associated With Statin Therapy at the Time of Percutaneous Coronary Intervention

Abstract: Background— Long-term administration of statin therapy has been shown to reduce major coronary events and cardiac mortality within randomized clinical trials. In addition to lowering lipids, statins favorably affect platelet adhesion, thrombosis, endothelial function, inflammation, and plaque stability, which may potentially improve outcome after percutaneous coronary intervention (PCI). Therefore, we hypothesized that statin therapy has an early beneficial effect among patients undergoing PCI. Methods and Results— Each year from 1993 to 1999, we prospectively collected data among the first 1000 patients undergoing PCI. Patients who presented with acute or recent myocardial infarction or cardiogenic shock were excluded from the analysis. Baseline, procedural, and 6-month data of statin-treated and non–statin-treated patients were compared. Propensity score and multivariate survival analysis were used to adjust for heterogeneity between the two groups. Of 5052 patients who completed follow-up, 26.5% were t...

Death Following Creatine Kinase-MB Elevation After Coronary Intervention Identification of an Early Risk Period: Importance of Creatine Kinase-MB Level, Completeness of Revascularization, Ventricular Function, and Probable Benefit of Statin Therapy

Abstract: Background— Creatine kinase (CK)-MB elevation after percutaneous coronary intervention (PCI) has been associated with subsequent cardiac death. The patients at risk, the timing of risk, and potential treatment implications are uncertain. Methods and Results— Eight thousand, four hundred nine consecutive non– acute myocardial infarction patients with successful PCI and no emergency surgery or Q-wave myocardial infarction were followed for 38±25 months; 1446 (17.2%) had post-PCI CK-MB above normal on routine ascertainment. Patients were prospectively stratified into those with CK-MB 1 to 5× or CK-MB >5× normal. No patient with CK-MB 1 to 5× normal died during the first week after PCI, and excess risk of early death for patients with CK-MB elevation occurred primarily in the first 3 to 4 months. The actuarial 4-month risk of death was 8.9%, 1.9%, and 1.2% for patients with CK-MB >5×, CK-MB 1 to 5×, and CK-MB ≤1× normal (P<0.001). Death within 4 months was independently correlated with the degree of CK-MB ele...

Lack of Benefit From Intravenous Platelet Glycoprotein IIb/IIIa Receptor Inhibition as Adjunctive Treatment for Percutaneous Interventions of Aortocoronary Bypass Grafts A Pooled Analysis of Five Randomized Clinical Trials

Abstract: Background— Despite widespread use of platelet glycoprotein (GP) IIb/IIIa receptor inhibitors for percutaneous coronary interventions (PCI) of bypass grafts, data supporting this strategy are lacking. Methods and Results— A pooled analysis of 5 randomized intravenous GP IIb/IIIa inhibitor trials (EPIC, EPILOG, EPISTENT, IMPACT II, and PURSUIT) was performed, and outcomes of graft interventions were assessed at 30 days and 6 months. Compared with PCI of native circulation (n=13 158), graft interventions (n=627) were associated with worse outcomes and in particular with a doubling of mortality at 30 days (2.1% versus 1.0%, P=0.006) and 6 months (4.7% versus 2.0%, P<0.001). Revascularization of a graft was identified as an independent predictor of death, myocardial infarction, or revascularization at 6 months (hazard ratio, 1.42; 95% CI, 1.24 to 1.63; P<0.001). Among patients undergoing graft PCI, the incidence of the triple end point at 30 days was 16.5% in the platelet GP IIb/IIIa inhibitor group and 12.6%...

Platelet glycoprotein IIb/IIIa inhibition in acute coronary syndromes. Gradient of benefit related to the revascularization strategy.

Abstract: Aims To assess the efficacy of platelet glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes primarily medically managed. Methods and Results We performed a meta-analysis of the randomized clinical trials of platelet glycoprotein IIb/IIIa inhibitor therapy in the medical management of non-ST-elevation acute coronary syndromes. Among 29570 patients, IIb/IIIa integrin blockade was associated with a reduction in death or non-fatal myocardial infarction at 30 days, from 11·5% to 10·7% (odds ratio 0·91, P =0·02). Patients undergoing percutaneous coronary intervention during index hospitalization sustained a greater reduction in ischaemic events (odds ratio 0·82, P =0·01) than patients medically managed (odds ratio 0·95, P =0·27). Among patients undergoing intervention, the benefit was more pronounced if the procedure was performed during glycoprotein IIb/IIIa inhibitor infusion (odds ratio 0·74; P =0·02), than if revascularization was performed after drug discontinuation (odds ratio 0·87, P =0·17). Conclusion This analysis, including the entire large-scale trial experience of intravenous glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes primarily medically managed, demonstrates an overall significant, albeit moderate, reduction in 30-day death or myocardial infarction associated with therapy. Although not based on a prospectively defined hypothesis, the findings suggest a gradient of benefit conferred by these agents depending on the revascularization strategy used. Copyright 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved .

Sustained ventricular arrhythmias among patients with acute coronary syndromes with no ST-segment elevation: incidence, predictors, and outcomes.

Abstract: BACKGROUND: The prognosis of ventricular arrhythmias among patients with non-ST-elevation acute coronary syndromes is unknown. We studied the incidence, predictors, and outcomes of sustained ventricular arrhythmias in 4 large randomized trials of such patients. METHODS AND RESULTS: We pooled the datasets of the Global Use of Streptokinase and tPA for Occluded Arteries (GUSTO)-IIb, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON)-A, and PARAGON-B trials (n=26 416). We identified independent predictors of ventricular fibrillation (VF) and ventricular tachycardia (VT) and compared the 30-day and 6-month mortality rates of patients who did (n=552) and did not (n=25 864) develop these arrhythmias during the index hospitalization. Independent predictors of in-hospital VF included prior hypertension, chronic obstructive pulmonary disease, prior myocardial infarction, and ST-segment changes at presentation. Except for hypertension, these variables also independently predicted in-hospital VT. In Cox proportional-hazards modeling, in-hospital VF and VT were independently associated with 30-day mortality (hazard ratio [HR], 23.2 [95% CI, 18.1 to 29.8] for VF and HR, 7.6 [95% CI, 5.5 to 10.4] for VT) and 6-month mortality (HR, 14.8 [95% CI, 12.1 to 18.3] for VF and HR, 5.0 [95% CI, 3.8 to 6.5] for VT). These differences remained significant after excluding patients with heart failure or cardiogenic shock and those who died <24 hours after enrollment. CONCLUSIONS: Despite the use of effective therapies for non-ST-elevation acute coronary syndromes, ventricular arrhythmias in this setting are associated with increased 30-day and 6-month mortality. More effective therapies are needed to improve the survival of patients with these arrhythmias.

Platelet Glycoprotein IIb/IIIa Inhibitors Recognition of a Two-Edged Sword?

Abstract: Glycoprotein (GP) IIb/IIIa antagonists are potent inhibitors of platelet aggregation that provide marked protection from ischemic events in patients undergoing percutaneous coronary intervention (PCI).1,2⇓ Abciximab, the prototypic GP IIb/IIIa inhibitor, has been studied in >8000 patients undergoing elective or high-risk PCI.2,3,4⇓⇓ In these patients, it produces a consistent 35% to 56% reduction in ischemic end points at 30 days, with a significant 22% reduction in the risk of death, as shown in a combined analysis of long-term (3-year minimum) follow-up of the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC), Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade (EPILOG), and Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trials.5 Similar results, albeit of a smaller magnitude, have been seen with the small-molecule antagonists tirofiban and eptifibatide, with a 16% to 35% reduction in ischemic events in patients undergoing PCI.1,6⇓ Attempts to expand the therapeutic indication of GP IIb/IIIa antagonists to other conditions associated with platelet-mediated thrombosis, however, have been less fruitful than expected. Instead of reducing major ischemic events, long-term oral GP IIb/IIIa inhibitor therapy7 has uniformly increased the fatality rate. Furthermore, the overall efficacy of a number of the intravenous antagonists in non–ST-segment elevation acute coronary syndromes (ACS), or in combination with thrombolysis in ST-segment elevation myocardial infarction (MI), has been less than anticipated.8 Of particular concern is the fact that there has been a paradoxical increase in adverse events in 2 of the trials of intravenous therapy in ACS.9,10⇓ Platelets are known to play an important role in the pathogenesis of ACS, yet the high levels of platelet inhibition attainable with GP IIb/IIIa antagonists have failed to dramatically improve clinical outcomes outside of PCI. In this article, we discuss these …

Need to Test the Arterial Inflammation Hypothesis

Abstract: Despite intensive basic and clinical investigation, coronary artery disease remains the principal cause of death and disability in the United States. In recent years, the appreciation of arterial inflammation as an important risk factor has had considerable implications for changing our approach to managing these patients.1,2⇓ Arterial inflammation has emerged as central to the progression of atherothrombosis.3 Of the markers of inflammation, the high-sensitivity C-reactive protein (CRP) is the most studied, with evidence that it may also play a direct pathogenic role in atherosclerotic lesion formation.4– 11⇓⇓⇓⇓⇓⇓⇓ In the absence of active infection, measurements of CRP are reasonably reproducible, comparable to measurements of total cholesterol.12,13⇓ Additionally, elevated CRP appears to be a more potent risk factor than other mediators of inflammation, such as tumor necrosis factor-α, interleukin-6, or serum amyloid A.4,14⇓ A group of pharmacotherapies that are currently available, such as aspirin, statins, angiotensin converting enzyme inhibitors (ACE-Is), thienopyridines, and peroxisome proliferator-activated receptor (PPAR) agonists have been shown, in addition to their other properties, to reduce CRP and/or arterial inflammation. Although it is clear that elevated CRP denotes increased risk and emerging evidence suggests that there are novel therapies that result in lowering of CRP, the most important unanswered question is whether suppression of inflammation and consequent lowering of CRP will translate into a decrease in clinical events.15 Surprisingly, despite the importance of the question, the “inflammation hypothesis” of intentional CRP suppression as compared with standard care has not yet been tested. Such a prospective study of patients with established cardiovascular disease and elevated baseline CRP in which incremental pharmacotherapy would be guided by reassessments of the CRP marker could allow formulation of a rational therapeutic strategy instead of an approach of “polypharmacy” for …

Mortality at 1 year with combination platelet glycoprotein IIb/IIIa inhibition and reduced-dose fibrinolytic therapy vs conventional fibrinolytic therapy for acute myocardial infarction: GUSTO V randomized trial.

Abstract: ContextAmong patients with acute myocardial infarction, combination reperfusion therapy with a platelet glycoprotein IIb/IIIa receptor inhibitor (abciximab) and a half dose of a plasminogen activator (reteplase) did not significantly reduce mortality at 30 days compared with a full dose of reteplase. Rates of nonfatal ischemic complications were significantly diminished.ObjectiveTo determine if the beneficial effects of abciximab and reteplase (combination therapy) on early nonfatal complications would translate into a reduction in the risk of death by 1 year.Design, Setting, and PatientsOne-year follow-up of a randomized controlled trial (Global Use of Strategies To Open Coronary Arteries [GUSTO] V). Of 16 588 patients who had been treated in 820 community and referral hospitals in 20 countries between July 1999 and February 2001, mortality data were available for 16 453 (99.2%).InterventionPatients were randomly assigned to receive (intravenously) a standard dose of reteplase (two 10-U boluses, 30 minutes apart) or the combination of a standard dose of abciximab (0.25 mg/kg bolus, 0.125 µg/kg per minute infusion [maximum 10 µg/min for 12 hours]) and a half dose of reteplase (two 5-U boluses, 30 minutes apart).Main Outcome MeasureOne-year all-cause mortality rates.ResultsAll-cause mortality at 1 year occurred in 692 (8.38%) of 8260 patients in the reteplase group and 698 (8.38%) of the 8328 patients in the combination therapy group (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.90-1.11; P>.99). Reinfarction within the first 7 days occurred in 3.5% of patients in the reteplase group and 2.3% of patients in the combination therapy group, and was significantly associated with 1-year mortality (22.6% in patients with reinfarction vs 8.0% in patients without reinfarction; HR, 3.08; 95% CI, 2.53-3.75; P<.001). However, treatment assignment did not significantly influence time of mortality regardless of reinfarction status.ConclusionCombination therapy (abciximab and reteplase) did not reduce mortality over 1 year compared with fibrinolytic therapy with reteplase alone.

Long-term mortality benefit with the combination of stents and abciximab for cardiogenic shock complicating acute myocardial infarction.

Abstract: Cardiogenic shock secondary to ischemic heart disease is associated with a high mortality rate, and recent trials have established the benefit of an early invasive approach. However, the role of adjunctive abciximab and stenting for cardiogenic shock has not been established. We prospectively examined collected data from 96 consecutive patients who underwent emergent percutaneous coronary intervention for cardiogenic shock over the past 7 years. Patients were classified as receiving stent plus abciximab, stent alone, percutaneous transluminal coronary angiopplasty (PTCA) plus abciximab, or PTCA alone. Baseline characteristics of the 4 groups were similar. During 2.5 years of follow-up, the mortality rates for stent plus abciximab, stent only, PTCA plus abciximab, and PTCA alone were 33%, 43%, 61%, and 68%, respectively (log-rank p = 0.028). Achievement of postprocedural Thrombolysis In Myocardial Infarction 3 flow was higher with stent plus abciximab than with the other interventions (85% vs 65%, p = 0.048). By multivariate analysis, absence of stent use (hazard ratio 2.58, 95% confidence interval 1.36 to 4.90, p = 0.004) and left ventricular ejection function

Impact of Different Platelet Glycoprotein IIb/IIIa Receptor Inhibitors Among Diabetic Patients Undergoing Percutaneous Coronary Intervention Do Tirofiban and ReoPro Give Similar Efficacy Outcomes Trial (TARGET) 1-Year Follow-Up

Abstract: Background— The platelet glycoprotein IIb/IIIa receptor inhibitor abciximab, a monoclonal antibody, has been shown to improve early and late outcomes among diabetic patients undergoing percutaneous coronary intervention (PCI). It is unknown whether small-molecule agents confer similar benefits. Methods and Results— In 18 countries, 4809 patients undergoing PCI with stent implantation were randomized to tirofiban or abciximab. At the time of enrollment, patients were stratified according to diabetes status. As compared with non-diabetic patients, patients with diabetes (n=1117) showed similar 30-day ischemic outcomes, an increased incidence of any target vessel revascularization (TVR) at 6 months (10.3% versus 7.8%; P= 0.008), and a trend toward higher 1-year mortality (2.5% versus 1.6%; P=0.056). Among diabetic patients randomized to tirofiban (n=560), the incidence of death, myocardial infarction (MI), or urgent TVR at 30 days was 6.2%, and among those randomized to abciximab (n=557) it was 5.4% (hazard ...

Impact of Clinical Syndrome Acuity on the Differential Response to 2 Glycoprotein IIb/IIIa Inhibitors in Patients Undergoing Coronary Stenting The TARGET Trial

Abstract: Background— Although glycoprotein IIb/IIIa inhibitors have been shown to reduce periprocedural and late ischemic events in patients undergoing stent implantation, the relative safety and efficacy of different agents in this class is less established. Also unknown is whether the acuity of the presenting clinical syndrome, which may affect the degree of platelet inhibition required or achieved, influences the response to different antiplatelet agents. Methods and Results— A prospective, multicenter, double-blind, randomized trial was performed in which 4809 patients undergoing planned stenting were randomized to receive abciximab or tirofiban. In patients with acute coronary syndromes (ACS; n=3025), abciximab resulted in lower rates of myocardial infarction at 30 days (5.8% versus 8.5%; P=0.004) and 6 months (7.2% versus 9.8%; P=0.013), although 6-month mortality rates were identical (1.39% in both groups; P=0.99). Conversely, in patients without ACS (n=1784), myocardial infarction rates were not significan...