Abstract Large randomized clinical trials in cardiovascular disease have proliferated over the past 3 decades, with results that have influenced every aspect of cardiology practice. Despite these ...advances, there remains a substantial need for more high-quality evidence to inform cardiovascular clinical practice, given the increasing prevalence of cardiovascular disease around the world. Traditional clinical trials are increasingly challenging due to rising costs, increasing complexity and length, and burdensome institutional and regulatory requirements. This review will examine the current landscape of cardiovascular clinical trials in the United States, highlight recently conducted registry-based clinical trials, and discuss the potential attributes of the recently launched pragmatic clinical trial by the Patient-Centered Outcomes Research Institute’s National Patient-Centered Clinical Research Network, called the ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing the Benefits and Long-term Effectiveness) trial.
Background Suspected coronary artery disease (CAD) is one of the most common, potentially life-threatening diagnostic problems clinicians encounter. However, no large outcome-based randomized trials ...have been performed to guide the selection of diagnostic strategies for these patients. Methods The PROMISE study is a prospective, randomized trial comparing the effectiveness of 2 initial diagnostic strategies in patients with symptoms suspicious for CAD. Patients are randomized to either (1) functional testing (exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram) or (2) anatomical testing with ≥64-slice multidetector coronary computed tomographic angiography. Tests are interpreted locally in real time by subspecialty certified physicians, and all subsequent care decisions are made by the clinical care team. Sites are provided results of central core laboratory quality and completeness assessment. All subjects are followed up for ≥1 year. The primary end point is the time to occurrence of the composite of death, myocardial infarction, major procedural complications (stroke, major bleeding, anaphylaxis, and renal failure), or hospitalization for unstable angina. Results More than 10,000 symptomatic subjects were randomized in 3.2 years at 193 US and Canadian cardiology, radiology, primary care, urgent care, and anesthesiology sites. Conclusion Multispecialty community practice enrollment into a large pragmatic trial of diagnostic testing strategies is both feasible and efficient. The PROMISE trial will compare the clinical effectiveness of an initial strategy of functional testing against an initial strategy of anatomical testing in symptomatic patients with suspected CAD. Quality of life, resource use, cost-effectiveness, and radiation exposure will be assessed.
The Truth and Consequences of the COURAGE Trial Kereiakes, Dean J., MD, FACC; Teirstein, Paul S., MD, FACC; Sarembock, Ian J., MB, ChB, MD ...
Journal of the American College of Cardiology,
10/2007, Volume:
50, Issue:
16
Journal Article
Peer reviewed
Open access
The Truth and Consequences of the COURAGE Trial Dean J. Kereiakes, Paul S. Teirstein, Ian J. Sarembock, David R. Holmes, Jr, Mitchell W. Krucoff, William W. O’Neill, Ron Waksman, David O. Williams, ...Jeffrey J. Popma, Maurice Buchbinder, Roxana Mehran, Ian T. Meredith, Jeffrey W. Moses, Gregg W. Stone Percutaneous coronary intervention (PCI) has played an integral role in the therapeutic management strategies for patients who present with either acute coronary syndromes or stable angina pectoris. The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial enrolled patients with chronic stable angina and at least 1 significant (≥70%) angiographic coronary stenosis who were randomly assigned to an initial treatment of either PCI in conjunction with optimal medical therapy or optimal medical therapy alone. Although the initial management strategy of PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events, improvement in angina-free status and a reduction in the requirement for subsequent revascularization was observed. An in-depth analysis of the COURAGE trial design and execution is provided.
Postinfarction left ventricular (LV) remodeling can result in chronic heart failure and functional impairment. Although pharmacological strategies for established heart failure can be beneficial, ...preventing remodeling remains a challenge. Injectable bioabsorbable alginate or “bioabsorbable cardiac matrix” (BCM), composed of an aqueous mixture of sodium alginate and calcium gluconate, is a sterile colorless liquid that is a polysaccharide polymer produced from brown seaweed. When exposed to excess ionized calcium present in infarcted myocardium, BCM assembles to form a flexible gel, structurally resembling extracellular matrix, which provides temporary structural support to the infarct zone through and beyond the time needed for mature fibrotic tissue to develop. The PRESERVATION I trial is an early phase randomized, double-blind, placebo-controlled trial comparing intracoronary application of 4 mL of BCM with saline control in patients who develop large infarctions after successful reperfusion of large ST-segment elevation myocardial infarction (MI). Subjects will be randomized 2:1 to either BCM or saline control and will have the study device deployed through an intracoronary microcatheter in the infarct-related artery 2 to 5 days after index ST-segment elevation MI treated with successful primary or rescue percutaneous coronary intervention. The primary effectiveness end point is the absolute change in LV diastolic volume index as measured by 3-dimensional echocardiography from baseline to 6 months after BCM deployment. Secondary effectiveness end points include clinical outcomes, patient-reported quality of life, additional echocardiographic measures, and functional status measures. In summary, the PRESERVATION I trial is a randomized double-blind trial evaluating the effectiveness and safety of the novel device BCM in preventing LV remodeling patients who have large MIs despite undergoing successful primary or rescue percutaneous coronary intervention.
Abstract Objectives The purpose of this study was to characterize outcomes for everolimus-eluting stent (EES)–treated subjects according to treatment with continued thienopyridine plus aspirin versus ...aspirin alone 12 to 30 months after stenting. Background In the DAPT (Dual Antiplatelet Therapy) study, continued thienopyridine plus aspirin beyond 1 year after coronary stenting reduced ischemic events. Given low rates of stent thrombosis and myocardial infarction (MI) for current drug-eluting stents, we examined outcomes among EES-treated subjects in the DAPT study. Methods The DAPT study enrolled 25,682 subjects (11,308 EES-treated) after coronary stenting. Following 12 months of treatment with thienopyridine and aspirin, eligible subjects continued treatment with aspirin and 9,961 (4,703 with EES) were randomized to 18 months of continued thienopyridine or placebo. Stent type was not randomized, and the EES subset analysis was post hoc. Results Among EES-treated patients, continued thienopyridine reduced stent thrombosis (0.3% vs. 0.7%, hazard ratio HR: 0.38, 95% confidence interval CI: 0.15 to 0.97; p = 0.04) and MI (2.1% vs. 3.2%, HR: 0.63, 95% CI: 0.44 to 0.91; p = 0.01) versus placebo but did not reduce a composite of death, MI, and stroke (4.3% vs. 4.5%, HR: 0.89, 95% CI: 0.67 to 1.18; p = 0.42), and increased moderate/severe bleeding (2.5% vs. 1.3%, HR: 1.79, 95% CI: 1.15 to 2.80; p = 0.01), and death (2.2% vs. 1.1%, HR: 1.80, 95% CI: 1.11 to 2.92; p = 0.02). Death due to cancer and not related to bleeding was increased (0.64% vs. 0.17%; p = 0.01). Conclusions In EES-treated subjects, significant reductions in stent thrombosis and MI and an increase in bleeding were observed with continued thienopyridine beyond 1 year compared with aspirin alone. (The Dual Antiplatelet Therapy Study DAPT Study); NCT00977938 )
Objectives The aim of this study was to identify predictors of clinical events after XIENCE V (Abbott Vascular, Santa Clara, California) stenting. Background The XIENCE V USA (XIENCE V Everolimus ...Eluting Coronary Stent System EECSS USA Post-Approval) study is a prospective, multicenter, Food and Drug Administration-required post-approval study to examine safety and effectiveness in real-world settings. After an initial 5,062 patients, 2,999 more were included as part of the DAPT (Dual Antiplatelet Therapy) trial (total n = 8,061). Methods One-year clinical events, including stent thrombosis (ST), cardiac death/myocardial infarction (MI), target lesion failure, and target lesion revascularization, were adjudicated according to Academic Research Consortium criteria, with ST and cardiac death/MI as primary and co-primary endpoints. Demographic, clinical, and procedural variables were assessed by multivariable analysis. A time-dependent covariate assessed the association between DAPT usage and ST. Results Roughly 61% were off-label; 85.6% remained on DAPT without interruption through 1 year. Incidences of definite/probable ST, cardiac death/MI, target lesion failure, and target lesion revascularization were 0.80% (95% confidence interval CI: 0.61% to 1.03%), 7.1% (95% CI: 6.51% to 7.68%), 8.9% (95% CI: 8.30% to 9.60%), and 4.3% (95% CI: 3.82% to 4.75%), respectively. Several independent clinical and angiographic predictors were identified for each outcome. Predictors of ST included DAPT interruption ≤30 days (hazard ratio HR: 8.63, 95% CI: 2.69 to 27.73, p = 0.0003), renal insufficiency (HR: 3.72, 95% CI: 1.71 to 8.09, p = 0.0009), and total stent length (HR: 1.30, 95% CI: 1.16 to 1.47, p < 0.0001). A DAPT interruption >30 days was not predictive of ST. Conclusions In this large, real-world population, XIENCE V demonstrated low event rates at 1 year, with several independent predictors. Early DAPT interruption (≤30 days) was the most potent predictor of ST, whereas delayed interruption (>30 days) was not predictive. (XIENCE V Everolimus Eluting Coronary Stent System EECSS USA Post-Approval Study; NCT00676520 )
Abstract Background Dual antiplatelet therapy (DAPT) is necessary to prevent thrombosis yet increases bleeding after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). ...Antiplatelet monotherapy with a potent P2Y12 receptor antagonist may reduce bleeding while maintaining anti thrombotic efficacy compared with conventional DAPT. Methods TWILIGHT is a randomized, double blind placebo-controlled trial evaluating the comparative efficacy and safety of antiplatelet monotherapy versus DAPT in up to 9000 high-risk patients undergoing PCI with DES. Upon enrollment after successful PCI, all patients will be treated with open label low-dose aspirin (81–100 mg daily) plus ticagrelor (90 mg twice daily) for 3 months. Event-free patients will then be randomized in a double-blind fashion to low-dose aspirin versus matching placebo with continuation of open-label ticagrelor for an additional 12 months. The primary hypothesis is that a strategy of ticagrelor monotherapy will be superior with respect to the primary endpoint of bleeding academic research consortium (BARC) type 2, 3 or 5, while maintaining non-inferiority for ischemic events compared with ticagrelor plus ASA. Conclusions TWILIGHT is the largest study to date that is specifically designed and powered to demonstrate reductions in bleeding with ticagrelor monotherapy versus ticagrelor plus ASA beyond 3 months post-procedure in a high-risk PCI population treated with DES. The trial will provide novel insights with respect to the potential role of ticagrelor monotherapy as an alternative for long-term platelet inhibition in a broad population of patients undergoing PCI with DES.
Abstract Background Bioabsorbable cardiac matrix (BCM) is a novel device that attenuates adverse left ventricular (LV) remodeling after large myocardial infarctions in experimental models. Objectives ...This study aimed to analyze whether BCM, compared with saline control, would result in less LV dilation and fewer adverse clinical events between baseline and 6 months. Methods In an international, randomized, double-blind, controlled trial, 303 subjects with large areas of infarction despite successful primary percutaneous coronary intervention (PCI) of ST-segment elevation myocardial infarction (STEMI) were randomized 2:1 to BCM or saline injected into the infarct-related artery 2 to 5 days after primary PCI. The primary outcome was mean change from baseline in LV end-diastolic volume index (LVEDVI) at 6 months. Secondary outcomes included change in Kansas City Cardiomyopathy Questionnaire score, 6-minute walk time, and New York Heart Association functional class at 6 months. The primary safety endpoint was a composite of cardiovascular death, recurrent MI, target-vessel revascularization, stent thrombosis, significant arrhythmia requiring therapy, or myocardial rupture through 6 months. Results In total, 201 subjects were assigned to BCM and 102 to saline control. There was no significant difference in change in LVEDVI from baseline to 6 months between the groups (mean change ± SD: BCM 14.1 ± 28.9 ml/m2 vs. saline 11.7 ± 26.9 ml/m2 ; p = 0.49). There was also no significant difference in the secondary endpoints. The rates of the primary safety outcome were similar between the 2 groups (BCM 11.6% vs. saline 9.1%; p = 0.37). Conclusions Intracoronary deployment of BCM 2 to 5 days after successful reperfusion in subjects with large myocardial infarction did not reduce adverse LV remodeling or cardiac clinical events at 6 months. (IK-5001 for the Prevention of Remodeling of the Ventricle and Congestive Heart Failure After Acute Myocardial Infarction PRESERVATION I; NCT01226563 )
This white paper provides a summary of presentations and discussions that were held at an Anticoagulant-Induced Bleeding and Reversal Agents Think Tank co-sponsored by the Cardiac Safety Research ...Consortium and the US Food and Drug Administration (FDA) at the FDA's White Oak Headquarters on April 22, 2014. Attention focused on a development pathway for reversal agents for the novel oral anticoagulants (NOACs). This is important because anticoagulation is still widely underused for stroke prevention in patients with atrial fibrillation. Undertreatment persists, although NOACs, in general, overcome some of the difficulties associated with anticoagulation provided by vitamin K antagonists. One reason for the lack of a wider uptake is the absence of NOAC reversal agents. As there are neither widely accepted academic and industry standards nor a definitive regulatory policy on the development of such reversal agents, this meeting provided a forum for leaders in the fields of cardiovascular clinical trials and cardiovascular safety to discuss the issues and develop recommendations. Attendees included representatives from pharmaceutical companies; regulatory agencies; end point adjudication specialist groups; contract research organizations; and active, academically based physicians. There was wide and solid consensus that NOACs overall offer improvements in convenience, efficacy, and safety compared with warfarin, even without reversal agents. Still, it was broadly accepted that it would be helpful to have reversal agents available for clinicians to use. Because it is not feasible to do definitive outcomes studies demonstrating a reversal agent's clinical benefits, it was felt that these agents could be approved for use in life-threatening bleeding situations if the molecules were well characterized preclinically, their pharmacodynamic and pharmacokinetic profiles were well understood, and showed no harmful adverse events in early human testing. There was also consensus that after such approval, efforts should be made to augment the available clinical information until such time as there is a body of evidence to demonstrate real-world clinical outcomes with the reversal agents. No recommendations were made for more generalized use of these agents in the setting of non–life-threatening situations. This article reflects the views of the authors and should not be construed to represent FDA's views or policies.
Diabetes mellitus is strongly associated with increased cardiovascular morbidity and mortality in patients with ST-segment elevation myocardial infarction. It is unknown whether myocardial perfusion ...is decreased in diabetic compared with nondiabetic patients after primary percutaneous coronary intervention (PCI), which may contribute to their worse prognosis. We compared myocardial perfusion and infarct sizes between diabetic and nondiabetic patients undergoing PCI for acute ST-segment elevation myocardial infarction in the EMERALD trial. EMERALD was a prospective, randomized, multicenter study evaluating distal embolic protection during primary PCI in ST-segment elevation myocardial infarction. End points included final myocardial blush grade, complete ST-segment resolution (STR) 30 minutes after PCI, and final infarct size as determined by technetium-99m single proton emission computed tomography measured between days 5 and 14. Of 501 patients, 62 (12%) had diabetes mellitus. Diabetic patients had impaired myocardial perfusion after PCI as measured by myocardial blush grade 0/1 (34% vs 16%, p = 0.002) and lower rates of complete 30-minute STR (45% vs 65%, p = 0.005). Infarct size (median 20% vs 11%, p = 0.005), development of new onset severe congestive heart failure (12% vs 4%, p = 0.016), and 30-day mortality (10% vs 1%, p <0.0001) were also greater in diabetic patients. After multivariate adjustment, diabetes remained associated with lack of complete STR and mortality at 6 months. Use of distal protection devices did not improve outcomes in diabetic or nondiabetic patients. In conclusion, in patients with ST-segment elevation myocardial infarction undergoing primary PCI, diabetes is independently associated with decreased myocardial reperfusion, larger infarct, development of congestive heart failure, and decreased survival.
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