Clinical Trials Of Antithrombotic Therapy Research Articles

Abstract 14916: Adverse Event Reporting in >48,000 Participants in Four Acute Coronary Syndrome Trials

Background: Adverse event (AE) collection in randomized clinical trials establishes the safety of investigational products. Although costly and regulated, it is rarely a topic of study. Methods and Results: Post-discharge AEs were collected per protocol and classified as serious or non-serious in 48,118 participants from 40 countries enrolled in 4 clinical trials of antithrombotic therapy in acute coronary syndromes (APPRAISE-2, PLATO, TRACER, TRILOGY ACS). Pooled data was used to compare patterns and determinants of AE reporting; study endpoints were excluded. Overall, 46.1% of participants had no AEs, 16.3% had at least 1 serious AE (SAE), and another 37.7% had only non-serious AEs (nsAE). A total of 12,266 SAEs and 72,635 nSAEs were reported. AEs were generally well distributed in most system organ classes, including general disorders (11%), infection (10%), gastrointestinal (10%), respiratory (9%), and other (35%), whereas cardiac events were more common among SAEs (14.0% of SAEs, 8.4% of nSAEs). AE rates, particularly non-serious, were highest after hospital discharge, and decreased rapidly during the following 3 months (Figure 1). Using a Cox proportional hazards model, the independent predictors of having an SAE included older age (HR 1.07, 95% CI 1.05-1.09 for every 5-year increase), female sex (HR 1.11, 95% CI 1.03-1.18), and common comorbidities (HF, COPD, Afib, CKD, DM), while enrollment in Asia (HR 0.84, 95% CI 0.75-0.94) or Eastern Europe (HR 0.63, 95% CI 0.58-0.69) predicted fewer SAEs. Conclusions: Most reported AEs are non-serious, non-cardiac, and reported early in follow-up. The high volume of AEs and the significant variation in SAE reporting across patient characteristics and region of enrollment make efforts to focus the approach to AE collection in large trials warranted.

Trends in clinical trials of non-ST-segment elevation acute coronary syndromes over 15 years

BackgroundData are limited on whether clinical trials have randomized higher-risk patients over time and how trends in risk profiles and evidence-based pharmacotherapies have influenced trial outcomes. We quantified changes in baseline risk, treatment, and outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) randomized in 9 phase 3 clinical trials of antithrombotic therapy over 15years. MethodsWe studied 58,771 patients in GUSTO IIb, PURSUIT, PARAGON-A, PARAGON-B, PRISM, PRISM-PLUS, GUSTO IV-ACS, SYNERGY, and EARLY ACS. Patient-level data were mapped to 3 pre-specified 5-year randomization periods. Temporal trends in GRACE score-predicted mortality were compared with trends in observed mortality. ResultsOver time, in-hospital and discharge use of thienopyridines (p=0.001), statins (p<0.0001), and angiotensin-converting enzyme inhibitors (p<0.0001) increased, and hospital length-of-stay decreased (p=0.024). Blood transfusion use increased (8.3% [1994–98], 10.7% [1999–2003], 13% [2004–08], p=0.0002) despite stable rates of severe bleeding (0.9% [1994–98], 1.4% [1999–2003] and 1.1% [2004–08], p=0.127) and coronary artery bypass grafting (12.4% [1994–98], 13.7% [1999–2003] 13.1% [2004–08], p=0.880). Although predicted 6-month mortality increased (6.9% [1994–98], 9.0% [1999–2003], 7.9% [2004–08], p=0.017), observed 6-month mortality decreased (6.7% [1994–98], 5.8% [1999–2003], 5.1% [2004–08], p=0.025). Thirty-day myocardial infarction rates remained stable (9.2% [1994–98], 9.3% [1999–2003], 10% [2004–08], p=0.539). ConclusionsDespite enrolling higher-risk patients into these NSTE ACS trials, with better treatment, observed mortality declined over the past 15years. The appropriateness of increased blood transfusion despite unchanged bleeding rates deserves further study.

Findings of Feasibility Assessment From Multicenter Clinical Trials of Antithrombotic Therapy in Pediatric Venous Thromboembolism

Abstract 4323BACKGROUND:Two major multicenter pediatric randomized controlled clinical trials (RCTs) in pediatric venous thromboembolism (VTE) have been conducted in the last decade, and each was closed early due to poor accrual. With the recent trend in reduced federal grant support for clinical trials, an emphasis on demonstration of feasibility is critical.OBJECTIVE: In order to inform the design and execution of future RCTs in pediatric VTE, we sought to report findings of feasibility assessment from two ongoing and one proposed clinical trials in the field. METHODS: In the UNBLOCK study (ongoing phase 1 trial of bivalirudin in acute DVT; clinicaltrials.gov registration #NCT00812370), feasibility was assessed informally in 2008/9 during grant development teleconferences and early investigator meetings. In the Kids-DOTT trial (ongoing phase 3 RCT of shortened vs. conventional duration of therapy in acute VTE associated with a transient/reversible clinical risk factor; NCT00687882), feasibility was assessed in 2005 and updated in 2011 using standardized questionnaires, with response data summarized via descriptive statistics. The latter approached was also used in 2011 for the PHLO trial (proposed phase II/III RCT of catheter-directed thrombolysis followed by therapeutic anticoagulation vs. anticoagulation alone in completely veno-occlusive acute DVT of the proximal leg). RESULTS: Response rate (Kids-DOTT and PHLO questionnaires) was 100%. Number of investigative sites/principal investigators assessed and geographical distribution, by trial, were as follows: UNBLOCK: n=6 (all USA); Kids-DOTT: n=26 (25 USA, 1 Canada); PHLO: n=7 (all USA). Of the 26 site PIs in Kids-DOTT, 84% reported past experience with 5 or more trials, with a median experience of 20 per PI. Across all 3 trial feasibility assessments, all but one site used electronic health records in clinical care, and all but one investigative team had trial experience in using electronic data capture systems. With regard to size of the screening population for pediatric VTE trials, Figure 1 shows the reported average annual volume of new pediatric VTE cases managed by each Kids-DOTT investigator/site, using data from the prior 2 years. All sites reported use of inpatient/consult lists in screening efforts. CONCLUSIONS: These findings indicate appropriate site experience and capacity to execute multicenter clinical trials in pediatric VTE. Therefore, feasibility of ongoing and future trials in the field is more likely related to such issues as: suitability of funding and number of sites to targeted enrollment; experience/capabilities of the clinical coordinating and data coordinating centers; and pragmatic protocol design, particularly eligibility criteria, enrollment/randomization windows, and frequency, timing, and invasiveness of follow-up and endpoint determinations. Disclosures:No relevant conflicts of interest to declare. [Display omitted]

Venous thromboembolism in patients with heart failure

This review is focussed on the problem of venous thromboembolism in patients with heart failure (HF). The results of the major clinical trials of antithrombotic therapy in HF patients are presented. The authors discuss comparative effectiveness, safety, and tolerability of unfractionated heparins, low molecular weight heparins, and fondaparinux. The results of the two trials, MAGELLAN and ADOPT, are expected to clarify the clinical potential of such oral anticoagulants as rivaroxaban and apixaban (Factor Xa inhibitors). The problem of low rates e of preventive antithrombotic administration is emphasized.

Atrial fibrillation and mortality: the impact of antithrombotic therapy

This editorial refers to ‘Mortality predictors and effects of antithrombotic therapies in atrial fibrillation: insights from ACTIVE-W’[†][1], by R. De Caterina et al. , on page 2133 All of the current guidelines on antithrombotic therapy for atrial fibrillation (AF) emphasize the prevention of stroke and thromboembolism as the primary goal of such treatment, and existing recommendations for antithrombotic therapy are based on an individual patient's risk of stroke. These guidelines have been formulated from the numerous clinical trials of antithrombotic therapy in patients with AF conducted over the last 20 years, where the primary endpoint has been stroke or a composite endpoint of stroke/thromboembolism, vascular events, and death. More recently, clinical trials of antithrombotic therapy in patients with AF have rightly included bleeding events as part of the composite primary endpoint, as treatment decisions should be based upon net clinical benefit. A meta-analysis1 of the 12 trials comparing dose-adjusted warfarin with antiplatelet therapy alone, including the largest trial to date, the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-W) trial,2 revealed a 37% reduction [95% confidence interval (CI) 23–48%] in all strokes associated with dose-adjusted warfarin1 but did not demonstrate a significant mortality benefit of warfarin over aspirin [relative risk reduction (RRR) 9%; 95% CI –19 to 30%]; … *Corresponding author. Tel: +44 121 507 5080, Fax: +44 121 507 5907, Email: deirdre.lane{at}swbh.nhs.uk [1]: #fn-2

Should we use anticoagulation for patients with chronic heart failure?

There are few available data on the incidence and risk factors of thromboembolism in heart failure, and the decision to recommend anticoagulant therapy for these patients is complex. In this Viewpoint, Drs Freudenberger and Halperin discuss the limited existing data on prophylactic approaches to this problem and appeal to physicians to support well-designed, randomized clinical trials of antithrombotic therapy in patients with heart failure.

Prevention of Stroke in Patients with Atrial Fibrillation

Nonvalvular atrial fibrillation (AF) is an independent risk factor for stroke that becomes increasingly prevalent as populations age. More than half a dozen clinical trials have demonstrated that anticoagulation with the vitamin K antagonist warfarin is the most effective therapy for stroke prophylaxis in AF. The narrow therapeutic index of warfarin requires that the intensity of anticoagulation be maintained within the international normalized ratio (INR) range of 2.0 to 3.0 to optimize efficacy while minimizing bleeding risk. The pharmacokinetics of warfarin are subject to variability due to interactions with multiple drugs and foods, making maintenance of the INR within this range difficult to achieve in clinical practice without close coagulation monitoring and frequent dose adjustments. Current guidelines recommend oral anticoagulation for high-risk individuals with AF but these inherent limitations lead to substantial underprescribing, particularly in elderly patients at greatest risk. This has stimulated the development of new agents with improved benefit-risk profiles, such as ximelagatran, the first of the oral direct thrombin inhibitors, which has a wider therapeutic margin and low potential for drug interactions, allowing fixed dosing without anticoagulation monitoring. Ximelagatran has been evaluated for stroke prevention in AF in the Stroke Prevention using an Oral Direct Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) program, the largest clinical trials of antithrombotic therapy for stroke prevention in AF to date. The phase III trials of ximelagatran in AF, SPORTIF III and V, found a fixed oral dose of ximelagatran (36 mg twice daily) comparable to dose-adjusted warfarin (INR 2.0 to 3.0) in preventing stroke and systemic thromboembolic complications among high-risk patients with AF. Results from the population of over 7000 patients in SPORTIF III and V demonstrate noninferiority of ximelagatran compared with warfarin. Data from SPORTIF III show an absolute reduction in stroke and systemic embolic events with ximelagatran compared with warfarin of 1.6% per year versus 2.3% per year, respectively ( P = 0.10). SPORTIF V further supports noninferiority between the two agents with an absolute risk reduction of 0.45%, well within the predefined noninferiority margin (95% confidence interval -0.13, 1.03; P = 0.13). Although event rates for major bleeding did not differ significantly with ximelagatran versus warfarin in either study, combined rates for major and minor bleeding were significantly reduced with ximelagatran. The overall net clinical benefit, taking into account effects on stroke or systemic embolic events, major bleeding, and death, was also greater with ximelagatran compared with warfarin in both studies. Elevated serum transaminase enzymes were observed in approximately 6% of patients given ximelagatran in these trials. These typically occurred 1 to 6 months after initiating treatment and usually abated without clinical sequelae whether or not treatment was continued. Given the consistency of response, the favorable overall benefit-risk ratio and the convenience of fixed oral dosing, ximelagatran may increase the number of patients with AF eligible for anticoagulation and amplify the potential for prophylaxis against stroke.

Inflammation and coagulation: implications for the septic patient.

Sepsis with acute organ dysfunction (severe sepsis) is common, frequently fatal, and associated with a significant national health/economic burden. In addition to standard care, investigators have focused on interrupting the inflammatory and anti-inflammatory cascade associated with this disease. Unfortunately, despite promising preclinical results, interventions directed at the inflammatory elements have not reduced the morbidity and mortality associated with this disease. Inflammation and coagulation are tightly linked. In fact, sepsis-associated coagulopathy is almost universal in patients with severe sepsis. Preclinical observations indicate that antithrombotic-targeted therapy has the potential to reduce morbidity and mortality in patients with this disease. Treatment with recombinant human activated protein C (drotrecogin alpha [activated]) was the first antithrombotic-targeted therapy to significantly reduce 28-day all-cause mortality in patients with severe sepsis. The pathophysiological and clinical significance of this evidence and the relationship of coagulation to inflammation are discussed, as are positive and negative results of clinical trials of antithrombotic therapy.

Randomized clinical trials of antithrombotic therapy in atrial fibrillation: Update 2003

Atrial fibrillation is a prevalent risk marker for preventable stroke. To date, 20 randomized clinical trials involving 13,843 participants have assessed antithrombotic therapies for prevention of stroke in atrial fibrillation. Here, these trials are considered, along with 8 additional randomized trials involving an additional 20,000 patients that are underway. These trials provide a wealth of solid evidence on which to individualize patient management to prevent stroke. A formerly neglected cause of major stroke, atrial fibrillation is now the focus of intensive clinical research aimed at stroke prevention.

Primary stroke prevention in nonvalvular atrial fibrillation: implementing the clinical trial findings.

To review the clinical trials evaluating warfarin for primary stroke prophylaxis in nonvalvular atrial fibrillation (NVAF), to discuss the relative benefits and risks of warfarin versus aspirin therapy, and to review the clinical practice guidelines and identify potential barriers to their implementation in clinical practice. A MEDLINE literature search was performed to identify clinical trials of antithrombotic therapy for NVAF, clinical practice guidelines, studies evaluating physician practices and attitudes, cost-effectiveness studies, and pertinent review articles. Key search terms included atrial fibrillation, stroke, antithrombotic, warfarin, aspirin, and cost-effectiveness. Prospective, randomized clinical trials were selected for analysis. Clinical practice guidelines from recognized panels of experts were reviewed. Comprehensive review articles were selected. NVAF is a common arrhythmia that is associated with a substantial risk for stroke. Seven prospective, randomized, clinical trials have conclusively demonstrated the efficacy of warfarin for stroke prevention. The greatest benefits are achieved in older patients and those with comorbidities that increase their risk for stroke. The potential benefits of preventing a devastating stroke, however, must be weighed against the potential for bleeding complications. Warfarin has been shown to be cost-effective in high-risk patients, provided the rate of complications is minimized. Nonetheless, many physicians remain hesitant to implement warfarin therapy in older, high-risk patients. The clinical data on aspirin are less consistent than those observed with warfarin. Aspirin appears to be most effective in younger individuals or those considered to be at low risk for stroke. In patients with NVAF, the personal, social, and economic consequences of stroke are often devastating. Clinical trials have provided definitive proof that the risks of stroke can be significantly reduced through the use of appropriate antithrombotic therapy. Despite this evidence and the recommendations of a number of clinical practice guidelines, variations in care exist that continue to place patients at risk. Additional outcomes research is needed to evaluate the impact of the clinical trial findings and practice guidelines on clinical practice and to develop methods for overcoming barriers to implementation.

The statistical analysis of graft patency data in a clinical trial of antiplatelet agents following coronary artery bypass grafting

Because most coronary artery bypass patients receive more than one graft at surgery, it is most important to determine whether statistical analysis of graft patency should be performed on the premise that the multiple grafts within patients are dependent or independent experimental units. Veterans Administration Cooperative Study No. 207 was a multicenter clinical trial comparing four different antiplatelet regimens to placebo in the prevention of graft occlusion following coronary artery bypass grafting. Using the results from the 1-week postoperative angiograms from the Veterans Administration Cooperative Study No. 207, in which there were 3.2 distal anastomoses per patient, we have tested the hypothesis that grafts within patients tend to act dependently with respect to patency or occlusion by comparing the graft patency data to a binomial distribution (i.e., that distribution that would have been manifest if grafts were independent). Because the graft patency results in Study No. 207 significantly deviated from the binomial distribution ( p = 0.0003), a more appropriate analysis for graft patency data was applied using a ratio estimate as applied to cluster sampling. The statistical methods used in 11 previous clinical trials of antithrombotic therapy after coronary artery bypass grafting were examined. Only one of the previous studies used such an analysis, and three additional reports attempted to correct for dependency of grafts within patients in their analyses using other statistical methods. In seven of the studies the investigators did not address the potential problem of a dependent relationship between multiple grafts within patients. We conclude that grafts within patients act as dependent experimental units and that the ratio estimate as applied to cluster sampling may be appropriately applied to these data.