Showing papers by "Marc A. Pfeffer published in 2010"
TL;DR: A poor initial hematopoietic response to darbepoetin alfa was associated with an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target hemoglobin levels.
Abstract: Patients who had a poor initial response to darbepoetin alfa had a lower average hemoglobin level at 12 weeks and during follow-up than did patients with a better hemoglobin response (a change in hemoglobin level ranging from 2 to 15% or more) (P<0.001 for both comparisons), despite receiving higher doses of darbepoetin alfa (median dose, 232 μg vs. 167 μg; P<0.001). Patients with a poor response, as compared with those with a better response, had higher rates of the composite cardiovascular end point (adjusted hazard ratio, 1.31; 95% confidence interval [CI], 1.09 to 1.59) or death (adjusted hazard ratio, 1.41; 95% CI, 1.12 to 1.78). Conclusions A poor initial hematopoietic response to darbepoetin alfa was associated with an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target hemoglobin levels. Although the mechanism of this differential effect is not known, these findings raise concern about current target-based strategies for treating anemia in patients with chronic kidney disease. (Funded by Amgen; ClinicalTrials.gov number, NCT00093015.)
424 citations
TL;DR: CRT resulted in significant improvement in cardiac size and performance compared with an ICD-only strategy in patients with mildly symptomatic heart failure, and improvement in these measures accounted for the outcomes benefit.
Abstract: Background— Cardiac resynchronization therapy (CRT) plus implantation of an implantable cardioverter defibrillator (ICD) reduced the risk of death or heart failure event in patients with mildly symptomatic heart failure, left ventricular dysfunction, and wide QRS complex compared with an ICD only. We assessed echocardiographic changes in patients enrolled in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation Trial: Cardiac Resynchronization Therapy) to evaluate whether the improvement in outcomes with CRT plus an ICD was associated with favorable alterations in cardiac size and function. Methods and Results— A total of 1820 patients were randomly assigned to CRT plus an ICD or to an ICD only in a 3:2 ratio. Echocardiographic studies were obtained at baseline and 12 months later in 1372 patients. We compared changes in cardiac size and performance between treatment groups and assessed the relationship between these changes over the first year, as well as subsequent outcomes. Compared wit...
315 citations
TL;DR: Both longitudinal and circumferential SRs were independent predictors of outcomes after MI, whereas only circumferent SRs was predictive of remodeling, suggesting that preserved circumferences might serve to restrain ventricular enlargement after MI.
258 citations
TL;DR: Recurrent MI or cardiac rupture accounts for a high proportion of sudden death in the early period after acute MI, whereas arrhythmic death may be more likely subsequently, helping explain the lack of benefit of early implantable cardioverter-defibrillator therapy.
Abstract: The frequency of sudden unexpected death is highest in the early post-myocardial infarction (MI) period; nevertheless, 2 recent trials showed no improvement in mortality with early placement of an implantable cardioverter-defibrillator after MI.
211 citations
TL;DR: Cognitive dysfunction is common in elderly patients with atrial fibrillation and is related to less effective anticoagulation and more vascular events, suggesting that if improved anticogeulation was provided, vascular events and bleeding would be reduced.
Abstract: Background— Patients with atrial fibrillation usually are elderly and may have cognitive dysfunction These patients may receive less effective oral anticoagulation, resulting in more vascular events and bleeding Methods and Results— In an analysis of cognitive function associated with the time in therapeutic range (TTR) in the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events, 2510 patients (mean age, 71±95 years) from 27 countries completed the Mini-Mental State Examination (MMSE) Of these patients, 171 (68%) had an MMSE score <24, suggesting dementia, and 194 (77%) had intermediate scores of 24 to 25 Low MMSE scores were correlated with a low TTR Even mild cognitive impairment was associated with a TTR below the median (<65%) Patients with an MMSE score <26 had more vascular events (67% versus 36% per 100 patient-years; P=0002) and more bleeding (96% versus 7% per 100 patient-years; P=004) After controlling for TTR, the MMSE no longer conferred increa
113 citations
TL;DR: Left ventricular dyssynchrony is independently associated with increased risk of death or heart failure after myocardial infarction, suggesting that contractile pattern may play a role in post–myocardial Infarction prognosis.
Abstract: Background— Mechanical dyssynchrony is considered an independent predictor for adverse cardiovascular outcomes in patients with heart failure. However, its importance as a risk factor after myocardial infarction is not well defined. Methods and Results— We examined the influence of mechanical dyssynchrony on outcome in patients with left ventricular dysfunction, heart failure, or both after myocardial infarction who were enrolled in the Valsartan in Acute Myocardial Infarction (VALIANT) echocardiography study. B-mode speckle tracking with velocity vector imaging was used to assess ventricular synchrony in 381 patients who had image quality sufficient for analysis. Time to regional peak velocity and time to strain rate were measured among 12 left ventricular segments from the apical 4- and 2- chamber views, and the SDs between all 12 segments were used as a measure of dyssynchrony. The relationships between the SD of time to regional peak velocity and strain rate and clinical outcome of death or heart fail...
100 citations
TL;DR: It is indicated that smoking cessation is beneficial after high-risk MI and the importance of smoking cessation as a therapeutic target in patients with LV dysfunction after MI is highlighted.
Abstract: Patients with left ventricular (LV) systolic dysfunction after myocardial infarction (MI) are at particularly high risk for recurrent adverse outcomes. The magnitude of the decrease in risk associated with smoking cessation after MI has not been well described in patients with LV dysfunction after MI. We aimed to quantify the risk decrease associated with smoking cessation in subjects with LV dysfunction after MI. The Survival and Ventricular Enlargement (SAVE) trial randomized 2,231 subjects with LV dysfunction 3 to 16 days after MI. Smoking status was assessed at randomization and at regular intervals during a median follow-up of 42 months. Propensity score-adjusted Cox proportional hazard models were used to quantify the decrease in risk of all-cause mortality, death or recurrent MI, and death or heart failure (HF) hospitalization associated with smoking cessation. In baseline smokers who survived to 6 months without interval events, smoking cessation at 6-month follow-up was associated with a significantly lower adjusted risk of all-cause mortality (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.31 to 0.91), death or recurrent MI (HR 0.68, 95% CI 0.47 to 0.99), and death or HF hospitalization (HR 0.65, 95% CI 0.46 to 0.92). In conclusion, in patients with LV dysfunction after MI, smoking cessation is associated with a 40% lower hazard of all-cause mortality and a 30% lower hazard of death or recurrent MI or death or HF hospitalization. These findings indicate that smoking cessation is beneficial after high-risk MI and highlight the importance of smoking cessation as a therapeutic target in patients with LV dysfunction after MI.
84 citations
TL;DR: Heart failure (HF) and chronic obstructive pulmonary disease are common partners and bronchodilators are associated with adverse cardiovascular outcomes in patients with pulmonary disease.
Abstract: Aims
Heart failure (HF) and chronic obstructive pulmonary disease are common partners Bronchodilators are associated with adverse cardiovascular outcomes in patients with pulmonary disease The outcome of patients with HF prescribed bronchodilators is poorly defined
Methods and results
The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme randomized 7599 patients with symptomatic HF to receive candesartan or placebo The relative risk conveyed by bronchodilator therapy was examined using a multivariable Cox proportional hazards model The prevalence of bronchodilator therapy was similar in patients with reduced and preserved systolic function (respectively, 87 vs 92%, P = 046) Beta-blocker utilization was markedly lower in patients receiving bronchodilators compared with those without (overall 319 vs 576%, P < 00001) Bronchodilator use was associated with increased all-cause mortality [HR 126 (109–145), P = 00015], cardiovascular death [HR 121 (103–142), P = 00216], HF hospitalization [HR 149 (129–172), P < 00001], and major adverse cardiovascular events [HR 132 (117–176), P < 00001] The adverse outcomes were consistent in patients with reduced and preserved systolic function No significant interaction was observed between bronchodilators and beta-blockade with respect to outcomes
Conclusion
Bronchodilator use is a powerful independent predictor of worsening HF and increased mortality in a broad spectrum of patients with HF Whether this relates to a toxic effect of bronchodilators, underlying pulmonary disease, or both is unclear and warrants further investigation
65 citations
TL;DR: Predictors of SCD change with time after myocardial infarction, and future studies of risk stratification for SCD should account for changes in these factors withTime after MI.
Abstract: Aims To determine whether predictors of sudden cardiac death (SCD) vary with time after myocardial infarction (MI).
Methods and results We analysed 11 256 patients enrolled in VALIANT. Landmark analysis and Cox proportional hazards modelling were used to predict SCD during hospitalization, from discharge to 30 days, 30 days to 6 months, and 6 months to 3 years. The cumulative incidence of SCD was 8.6% ( n = 965). Initially, higher baseline heart rate [HR 1.20 per 10 b.p.m. (95% CI 1.06–1.37)] and impaired baseline creatinine clearance [HR 0.82 per 10 mL/min (95% CI 0.74–0.91)] were stronger predictors of SCD. With long-term follow-up, prior MI [HR 1.71 (95% CI 1.39–2.10)], initial left ventricular ejection fraction <40% [HR 0.67 per 10% (95% CI 0.58–0.78)], and recurrent cardiovascular events [HR 1.47 for rehospitalization (95% CI 1.17–1.86)] were more robust risk stratifiers for SCD. Atrial fibrillation post-MI was associated with an increased risk of SCD over the entire follow-up period. As time passed, the associations between baseline clinical characteristics and SCD decreased and time-updated assessments became more important.
Conclusion Predictors of SCD change with time after MI. Future studies of risk stratification for SCD should account for changes in these factors with time after MI.
58 citations
TL;DR: Diabetes is a potent risk factor for death and heart failure hospitalization following myocardial infarction and whether diabetes modifies the relationship between left ventricular ejection fraction and outcomes in the post‐MI population is unknown.
Abstract: Aims
Diabetes is a potent risk factor for death and heart failure (HF) hospitalization following myocardial infarction (MI). Whether diabetes modifies the relationship between left ventricular ejection fraction (LVEF) and outcomes in the post-MI population is unknown.
Methods and results
The Valsartan in Acute Myocardial Infarction trial (VALIANT) enrolled 14 703 patients with acute MI complicated by HF, systolic dysfunction, or both. We compared the risk of death, HF hospitalization, and/or recurrent MI among patients with and without diabetes using Cox proportional hazards models. To assess the relationship between diabetes, LVEF and outcomes, we assessed the relative influence of baseline LVEF on outcomes in diabetic and non-diabetic patients. Totally, 11 325 subjects (3095 diabetics) with site-reported LVEF and known diabetes status were included. At any given LVEF, diabetes was associated with a higher risk of all-cause mortality [adjusted hazard ratio (HR) 1.37, 95% CI 1.25–1.51], death or HF hospitalization (adjusted HR 1.42, 95% CI 1.31–1.51), and death or recurrent MI (adjusted HR 1.36, 95% CI 1.24–1.48). Diabetes modified the relationship between LVEF and death or HF hospitalization (P for interaction = 0.0109), such that the association between diabetes and increased risk was greater in magnitude at higher LVEF. No interaction was noted between diabetes and LVEF on risk of all-cause mortality or death or recurrent MI.
Conclusion
Diabetes is associated with a higher risk of death or HF hospitalization across the spectrum of LVEF in high-risk post-MI patients. The magnitude of reduction in risk of death or HF hospitalization associated with increasing LVEF is significantly attenuated among patients with diabetes when compared to patients without diabetes.
49 citations
TL;DR: In MADIT-CRT, patients with an elevated ratio of BUN to SCr experienced a significantly greater reduction in the risk of HF or death with CRT-D therapy as compared with patients with a low ratio.
TL;DR: ValIANT was a double-blind, randomized, controlled trial comparing valsartan, captopril, and their combination in high-risk patients post-MI, suggesting an estimated incidence of approximately 1% within the first 30 days of follow-up.
TL;DR: The effect of treating anaemia with an ESA in patients with heart failure is examined in a meta‐analysis of randomized clinical trials, including the recently reported TREAT study.
Abstract: Aims
Randomized clinical trials have suggested that treatment of anaemia with erythropoiesis-stimulating agents (ESAs) in patients with cancer or chronic kidney disease may increase cardiovascular risk. We therefore examined the effect of treating anaemia with an ESA in patients with heart failure in a meta-analysis of randomized clinical trials, including the recently reported TREAT study.
Methods and results
We performed a systematic review and meta-analysis of all prospective, randomized, controlled studies of ESAs enrolling patients with heart failure and reporting data on mortality or non-fatal heart failure events. Of 10 trials initially identified by our search strategy, we pooled data from 9 placebo-controlled studies enrolling a total of 2039 patients, of whom 1023 (50.2%) were allocated to ESA treatment. The pooled risk ratio for ESA treatment relative to placebo was 1.03 [95% confidence interval (CI): 0.89–1.21, P = 0.68] for overall mortality and 0.95 (95% CI: 0.82–1.10, P = 0.46) for worsening heart failure.
Conclusions
The use of ESAs to manage anaemia in patients with heart failure was associated with a neutral effect on both mortality and non-fatal heart failure events. Definitive assessment of the balance of risk and benefit in this population awaits the completion of a randomized clinical trial adequately powered to assess clinical outcomes.
TL;DR: The composite score provides a more informative measure of disease burden and may avoid overestimating the evidence supporting a treatment effect when that evidence is largely from less severe early events.
TL;DR: It is unknown whether there is an interaction between aspirin and angiotensin receptor blockers on outcomes in patients with heart failure (HF), and if so, what effects these drugs have on patients' lives.
Abstract: Aims
It is unknown whether there is an interaction between aspirin and angiotensin receptor blockers on outcomes in patients with heart failure (HF).
Methods and results
The efficacy and safety of candesartan vs. placebo was assessed in 7599 patients with symptomatic HF and reduced or preserved left ventricular ejection fraction enrolled in the CHARM programme according to baseline aspirin use. Patients were randomized to candesartan or matching placebo and were followed for a median of 38 months. Aspirin was used in 4246 (55.9%) of patients at baseline. When compared with placebo, candesartan use was associated with lower event rates for cardiovascular (CV) death or HF hospitalization (primary outcome) in both the aspirin group (28 vs. 31.9%, HR 0.81, 95% CI 0.72–0.90) and non-aspirin group (33 vs. 38%, HR 0.81, 95% CI 0.72–0.91). Baseline aspirin use did not modify the effectiveness of candesartan in reducing the risk of CV death or HF hospitalization in CHARM overall (P = 0.64) or in the CHARM individual trials. In addition, there was no significant interaction between aspirin therapy and candesartan in terms of discontinuation of study drug due to adverse reactions (P = 0.72).
Conclusion
There appears to be no significant modification of the benefit of candesartan on CV mortality and morbidity outcomes or safety by concomitant use of aspirin in patients with chronic HF.
TL;DR: This review focuses on the arguments for conducting posttrial database studies and presents examples of studies in which posttrial knowledge generation has been substantial, and the potential for post trial database studies to become a platform for training young scientists is outlined.
TL;DR: Research performance improved during the VALsartan In Acute myocardial iNfarcTion consistent with a “learning curve”, and learning curves in clinical research may have important safety, ethical, research quality and economic implications for trial conduct.
Abstract: Objective Recognition of learning curves in medical skill acquisition has enhanced patient safety through improved training techniques. Clinical trials research has not been similarly scrutinised. The VALsartan In Acute myocardial iNfarcTion, a large multinational, pragmatic, randomised, double-blind, multicentre trial, was retrospectively evaluated for evidence of research conduct consistent with a performance “learning curve”. Design Records provided protocol departure (deviations/violations) and documentation query data. For each site, analysis included patient order (eg, first, second), recruitment rate and first enrolment relative to study start date. Setting Computerised data from a trial coordinated by an academic research organisation collaborating with 10 academic and 2 commercial research organisations and an industry sponsor. Interventions 931 sites enrolled 14 703 patients. Departures were restricted to the first year. Exclusions included patient9s death or loss to follow-up within 12 months and subjects enrolled 80th or higher at a site. Departures were assessed for variance with higher patient rank, more frequent recruitment and later start date. Methods and results 12 367 patients at 931 sites were analysed. Departures were more common for patients enrolled earlier at a site (p Conclusions Research performance improved during the VALsartan In Acute myocardial iNfarcTion consistent with a “learning curve”. Although effects were not related to a change in outcome (mortality), learning curves in clinical research may have important safety, ethical, research quality and economic implications for trial conduct.
Journal Article•
TL;DR: The need for more definitive clinical outcomes trials to better guide clinical practice is emphasized, as the clinical effects produced by a therapy were not adequately predicted by changes in an allegedly reliable and important surrogate.
Abstract: Clinical outcomes-focused randomized clinical trials are the current gold standard for evidence-based medicine. However, it is impractical and not feasible to attempt to answer all questions with large clinical outcomes trials. Surrogate markers are often utilized as alternative measures in smaller and shorter-duration trials. However, they are not always a reliable barometer of intervention-induced alterations in prognosis. This manuscript highlights several prominent instances where the clinical effects produced by a therapy were not adequately predicted by changes in an allegedly reliable and important surrogate. In addition, trials targeting only surrogate markers do not have sufficient exposure to unmask potential safety issues of the intervention. In highlighting the limitations of surrogate-marker-based trials, we emphasize the need for more definitive clinical outcomes trials to better guide clinical practice.
TL;DR: Construction of composite outcomes combining nonfatal clinically important events with deaths into a single end point offers an effective statistical compromise whereby the potential benefits and risks of an intervention can be assessed with relatively smaller sample sizes than in mortality RCTs.
Abstract: “ Medicine is a science of uncertainty and an art of probability .”1
—William Osler (1849 to 1919)
The practice of medicine will always remain an art in which important individual patient decisions are at best guided by incomplete evidence. Randomized controlled clinical trials (RCTs), although imperfect, are the premier tools to generate reliable data to assist in decision making.2 In cardiovascular medicine, we have been fortunate to have a rich legacy of definitive RCTs demonstrating survival benefits of therapies that have deservedly become cornerstone components of clinical practice. However, RCTs with mortality as the primary objective are practical only for evaluating populations with exceedingly high anticipated mortality rates or would require prohibitively long follow-up to obtain a reliable answer. Construction of composite outcomes combining nonfatal clinically important events with deaths into a single end point offers an effective statistical compromise whereby the potential benefits and risks of an intervention can be assessed with relatively smaller sample sizes than in mortality RCTs.3,4 Using composite outcomes that have clinically indisputable and important components extends the application of clinical outcome trials to more prevalent populations with less severely impaired prognosis. However, the compromise is that use of composite end points introduces uncertainty into the interpretation from possible inconsistencies among the components on effect size and at times even direction.5
An even greater end-point compromise is more frequently made in RCTs by targeting a primary objective of determining whether a readily quantifiable laboratory measure considered a surrogate marker of disease progression can be favorably altered by the proposed intervention. Because all patients can generally provide a measure of the surrogate or biomarker, these mechanistically targeted trials require considerably fewer patients and shorter durations.6 A strong link between the surrogates with observational associations of …
TL;DR: The launch of a new section in Circulation provides a perspective on contemporary clinical trials in cardiovascular medicine to allow a multidisciplinary discussion of the trial across at least three of the following domains: clinical practice (medical/interventional), trial design and interpretation, regulatory implications, and clinical practice.
Abstract: We are pleased to announce to our readers the launch of a new section in Circulation . The purpose is to provide a perspective on contemporary clinical trials in cardiovascular medicine. These trials need not be published in Circulation but must fulfill a minimum set of criteria so as to allow a multidisciplinary discussion of the trial across at least three of the following domains: clinical practice (medical/interventional), trial design and interpretation, regulatory implications, …