[Show abstract][Hide abstract] ABSTRACT: 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.
A total of 1,820 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 1,372 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 with the ICD-only group, the CRT-plus-ICD group had greater improvement in left ventricular end-diastolic volume index (-26.2 versus -7.4 mL/m(2)), left ventricular end-systolic volume index (-28.7 versus -9.1 mL/m(2)), left ventricular ejection fraction (11% versus 3%), left atrial volume index (-11.9 versus -4.7 mL/m(2)), and right ventricular fractional area change (8% versus 5%; P<0.001 for all). Improvement in end-diastolic volume at 1 year was predictive of subsequent death or heart failure, with adjustment for baseline covariates and treatment group; each 10% decrease in end-diastolic volume was associated with a 40% reduction in risk (P<0.001).
CRT resulted in significant improvement in cardiac size and performance compared with an ICD-only strategy in patients with mildly symptomatic heart failure. Improvement in these measures accounted for the outcomes benefit. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
European Journal of Heart Failure 09/2010; 12(9):936-42. DOI:10.1093/eurjhf/hfq094 · 6.53 Impact Factor
[Show abstract][Hide abstract] 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.
To better understand the pathophysiological events that lead to sudden death after MI, we assessed autopsy records in a series of cases classified as sudden death events in patients from the VALsartan In Acute myocardial infarctioN Trial (VALIANT). Autopsy records were available in 398 cases (14% of deaths). We determined that 105 patients had clinical circumstances consistent with sudden death. On the basis of the autopsy findings, we assessed the probable cause of sudden death and evaluated how these causes varied with time after MI. Of 105 deaths considered sudden on clinical grounds, autopsy suggested the following causes: 3 index MIs in the first 7 days (2.9%); 28 recurrent MIs (26.6%); 13 cardiac ruptures (12.4%); 4 pump failures (3.8%); 2 other cardiovascular causes (stroke or pulmonary embolism; 1.9%); and 1 noncardiovascular cause (1%). Fifty-four cases (51.4%) had no acute specific autopsy evidence other than the index MI and were thus presumed arrhythmic. The percentage of sudden death due to recurrent MI or rupture was highest in the first month after the index MI. By contrast, after 3 months, the percentage of presumed arrhythmic death was higher than recurrent MI or rupture (chi(2)=23.3, P<0.0001).
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. These findings may help explain the lack of benefit of early implantable cardioverter-defibrillator therapy.
[Show abstract][Hide abstract] ABSTRACT: Myocardial rupture is a relatively rare and usually fatal complication of myocardial infarction (MI). Early recognition of patients at greatest risk of myocardial rupture provides an opportunity for early intervention.
VALIANT was a double-blind, randomized, controlled trial comparing valsartan, captopril, and their combination in high-risk patients post-MI. Myocardial rupture was identified by autopsy (available in 138/589 patients dying within 30 days of index MI), echocardiography, direct surgical visualization, or presence of hemopericardium. An independent clinical end points committee reviewed medical records for all deaths or suspected nonfatal cardiovascular events.
Rupture was identified in 45 (0.31%) patients enrolled in VALIANT, occurring 9.8 +/- 6.0 days after the qualifying MI. Rupture accounted for 7.6% (45/589) of all deaths occurring in the first 30 days of follow-up and 24% (33/138) of deaths in which autopsies were obtained. Compared with survivors, rupture was associated with increased age, hypertension, increased Killip class, lower estimated glomerular filtration rate, and Q wave MI, and inversely related to beta-blocker and diuretic use. Compared with patients who died of other causes within 30 days, patients with myocardial rupture were more likely to have had an inferior MI, Q wave MI, or hypertension; to have used oral anticoagulants; or to have received thrombolytic therapy.
Although rare, myocardial rupture accounted for nearly one fourth of all deaths within the first 30 days after high-risk MI, suggesting an estimated incidence of approximately 1% within the first 30 days. A number of clinical characteristics may identify post-MI patients at higher risk of myocardial rupture.
American heart journal 07/2010; 160(1):145-51. DOI:10.1016/j.ahj.2010.02.037 · 4.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Trialists have an ethical and financial responsibility to plan and conduct clinical trials in a manner that will maximize the scientific knowledge gained from the trial. However, the amount of scientific information generated by randomized clinical trials in cardiovascular medicine is highly variable. Generation of trial databases and/or biobanks originating in large randomized clinical trials has successfully increased the knowledge obtained from those trials. At the 10th Cardiovascular Trialist Workshop, possibilities and pitfalls in designing and accessing clinical trial databases were discussed by a group of trialists. This review focuses on the arguments for conducting posttrial database studies and presents examples of studies in which posttrial knowledge generation has been substantial. Possible strategies to ensure successful trial database or biobank generation are discussed, in particular with respect to collaboration with the trial sponsor and to analytic pitfalls. The advantages of creating screening databases in conjunction with a given clinical trial are described; and finally, the potential for posttrial database studies to become a platform for training young scientists is outlined.
American heart journal 06/2010; 159(6):937-43. DOI:10.1016/j.ahj.2010.03.002 · 4.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is unknown whether there is an interaction between aspirin and angiotensin receptor blockers on outcomes in patients with heart failure (HF).
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).
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.
European Journal of Heart Failure 04/2010; 12(7):738-45. DOI:10.1093/eurjhf/hfq065 · 6.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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, 8.7 vs. 9.2%, P = 0.46). Beta-blocker utilization was markedly lower in patients receiving bronchodilators compared with those without (overall 31.9 vs. 57.6%, P < 0.0001). Bronchodilator use was associated with increased all-cause mortality [HR 1.26 (1.09-1.45), P = 0.0015], cardiovascular death [HR 1.21 (1.03-1.42), P = 0.0216], HF hospitalization [HR 1.49 (1.29-1.72), P < 0.0001], and major adverse cardiovascular events [HR 1.32 (1.17-1.76), P < 0.0001]. 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.
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.
European Journal of Heart Failure 03/2010; 12(6):557-65. DOI:10.1093/eurjhf/hfq040 · 6.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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+/-9.5 years) from 27 countries completed the Mini-Mental State Examination (MMSE). Of these patients, 171 (6.8%) had an MMSE score <24, suggesting dementia, and 194 (7.7%) 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 (6.7% versus 3.6% per 100 patient-years; P=0.002) and more bleeding (9.6% versus 7% per 100 patient-years; P=0.04). After controlling for TTR, the MMSE no longer conferred increased risk, suggesting that if improved anticoagulation was provided, vascular events and bleeding would be reduced. Other independent factors associated with a TTR <65% were region of the world, recent initiation of vitamin K antagonist, type of anticoagulant, and concurrent use of amiodarone or insulin. After adjustment for these factors, lower MMSE scores still predicted a reduced TTR.
Cognitive dysfunction is common in elderly patients with atrial fibrillation and is related to less effective anticoagulation and more vascular events. The MMSE identifies patients with atrial fibrillation in whom extra efforts are needed to maintain effective anticoagulation and improve outcomes. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00243178.
[Show abstract][Hide abstract] ABSTRACT: 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.
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 failure were assessed. In a multivariate Cox model adjusted for clinical and echocardiographic variables, the SD of time to peak velocity (hazard ratio per 10 ms, 1.10; 95% confidence interval, 1.02 to 1.18; P=0.010) and the SD of time to strain rate (hazard ratio per 10 ms, 1.16; 95% confidence interval, 1.06 to 1.27; P=0.001) were independent predictors of death or heart failure.
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.
[Show abstract][Hide abstract] ABSTRACT: Higher levels of serum alkaline phosphatase (AlkP) are associated with excess mortality in dialysis patients, but whether AlkP is associated with adverse outcomes among people without kidney failure is unknown.
We first analyzed the association between AlkP and cardiovascular outcomes among 4115 participants with a previous myocardial infarction (the Cholesterol And Recurrent Events [CARE] study). Results were validated by analyzing the association between AlkP and mortality in an independent sample of 14,716 adults from the general US population (the Third National Health and Nutrition Examination Survey). A graded, independent association was noted between baseline tertile of AlkP and the adjusted hazard ratio of all-cause mortality in CARE participants (P(trend)=0.02). After adjustment for serum phosphate, hepatic enzymes, and other potential confounders, participants with AlkP in the highest tertile had an adjusted hazard ratio of 1.43 (95% confidence interval 1.08 to 1.89) compared with those in the lowest tertile. Multivariable-adjusted associations between higher AlkP and all-cause and cardiovascular mortality were present in the Third National Health and Nutrition Examination Survey (P(trend) across tertiles of AlkP=0.006 and 0.038, respectively). Findings from both CARE and the Third National Health and Nutrition Examination Survey were similar among individuals with and without evidence of kidney disease, defined by estimated glomerular filtration rate <60 mL min(-1) 1.73 m(-2).
We found an independent relation between higher levels of AlkP and adverse outcomes among survivors of myocardial infarction and in a general population sample. The excess risk of death was present in people without evidence of kidney disease and was particularly high among people with higher levels of both AlkP and serum phosphate.
[Show abstract][Hide abstract] ABSTRACT: Although many patients with heart failure have incomplete adherence to prescribed medications, predisposing factors remain unclear. This analysis investigates factors associated with adherence, with particular emphasis on age and sex.
A multivariable regression analysis of 7599 heart failure patients from the CHARM trial was done to evaluate factors associated with adherence. Adherence was measured as the proportion of time patients took more than 80% of study medication. The mean age was 66 years (SD 11) and 31.5% (n = 2400) were women. Women were slightly less adherent than men (87.3 vs. 89.8%, P = 0.002), even in adjusted, multivariable models (treatment, P = 0.006; placebo P = 0.004; and overall P < 0.001). However, all-cause mortality was lower in women (21.5%) than in men (25.3%) (adjusted hazard ratio, 0.77; 95% CI, 0.69-0.86; P < 0.001), but patients with a low adherence regardless of sex had a higher mortality. Age, severity of heart failure, number of medications, and smoking status were not associated with adherence.
Women, particularly those <75 years of age, were less likely to be adherent in this large sample of patients with symptomatic heart failure. Understanding factors associated with adherence may provide opportunities for intervention.
European Journal of Heart Failure 11/2009; 11(11):1092-8. DOI:10.1093/eurjhf/hfp142 · 6.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In most patients with stable coronary artery disease, plasma cardiac troponin T levels are below the limit of detection for the conventional assay. The distribution and determinants of very low circulating troponin T levels, as well as their association with cardiovascular events, in such patients are unknown.
We used a new, high-sensitivity assay to determine the concentration of cardiac troponin T in plasma samples from 3679 patients with stable coronary artery disease and preserved left ventricular function. Results of the assay were analyzed in relation to the incidence of cardiovascular events during a median follow-up period of 5.2 years.
With the highly sensitive assay, concentrations of cardiac troponin T were at or above the limit of detection (0.001 microg per liter) in 3593 patients (97.7%) and at or above the 99th percentile for apparently healthy subjects (0.0133 microg per liter) in 407 patients (11.1%). After adjustment for other independent prognostic indicators, there was a strong and graded increase in the cumulative incidence of cardiovascular death (adjusted hazard ratio per unit increase in the natural logarithm of the troponin T level, 2.09; 95% confidence interval [CI], 1.60 to 2.74; P<0.001) and of heart failure (adjusted hazard ratio, 2.20; 95% CI, 1.66 to 2.90; P<0.001) in this study group. Increased risk associated with higher levels of troponin T was evident well below the limit of detection of conventional cardiac troponin T assays and below the 99th percentile of values in a healthy population. There was no association between troponin T levels as measured with the highly sensitive assay and the incidence of myocardial infarction (adjusted hazard ratio, 1.16; 95% CI, 0.97 to 1.40; P=0.11).
After adjustment for other independent prognostic indicators, cardiac troponin T concentrations as measured with a highly sensitive assay were significantly associated with the incidence of cardiovascular death and heart failure but not with myocardial infarction in patients with stable coronary artery disease.
New England Journal of Medicine 11/2009; 361(26):2538-47. DOI:10.1056/NEJMoa0805299 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested.
In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease.
Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group.
The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.)
New England Journal of Medicine 10/2009; 361(21):2019-32. DOI:10.1056/NEJMoa0907845 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This trial was designed to determine whether cardiac-resynchronization therapy (CRT) with biventricular pacing would reduce the risk of death or heart-failure events in patients with mild cardiac symptoms, a reduced ejection fraction, and a wide QRS complex.
During a 4.5-year period, we enrolled and followed 1820 patients with ischemic or nonischemic cardiomyopathy, an ejection fraction of 30% or less, a QRS duration of 130 msec or more, and New York Heart Association class I or II symptoms. Patients were randomly assigned in a 3:2 ratio to receive CRT plus an implantable cardioverter-defibrillator (ICD) (1089 patients) or an ICD alone (731 patients). The primary end point was death from any cause or a nonfatal heart-failure event (whichever came first). Heart-failure events were diagnosed by physicians who were aware of the treatment assignments, but they were adjudicated by a committee that was unaware of assignments.
During an average follow-up of 2.4 years, the primary end point occurred in 187 of 1089 patients in the CRT-ICD group (17.2%) and 185 of 731 patients in the ICD-only group (25.3%) (hazard ratio in the CRT-ICD group, 0.66; 95% confidence interval [CI], 0.52 to 0.84; P=0.001). The benefit did not differ significantly between patients with ischemic cardiomyopathy and those with nonischemic cardiomyopathy. The superiority of CRT was driven by a 41% reduction in the risk of heart-failure events, a finding that was evident primarily in a prespecified subgroup of patients with a QRS duration of 150 msec or more. CRT was associated with a significant reduction in left ventricular volumes and improvement in the ejection fraction. There was no significant difference between the two groups in the overall risk of death, with a 3% annual mortality rate in each treatment group. Serious adverse events were infrequent in the two groups.
CRT combined with ICD decreased the risk of heart-failure events in relatively asymptomatic patients with a low ejection fraction and wide QRS complex. (ClinicalTrials.gov number, NCT00180271.)
New England Journal of Medicine 10/2009; 361(14):1329-38. DOI:10.1056/NEJMoa0906431 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic kidney disease is associated with a higher risk of cardiovascular outcomes. The prognostic significance of worsening renal function has also been shown in various cohorts of cardiac disease; however, the predictors of worsening renal function and the contribution of inflammation remains to be established.
Worsening renal function was defined as a 25% or more decrease in estimated GFR (eGFR) over a 1-mo period in patients after a non-ST or ST elevation acute coronary syndromes participating in the Aggrastat-to-Zocor Trial; this occurred in 5% of the 3795 participants.
A baseline C-reactive protein (CRP) in the fourth quartile was a significant predictor of developing worsening renal function (odds ratio, 2.48; 95% confidence interval, 1.49, 4.14). After adjusting for baseline CRP and eGFR, worsening renal function remained a strong multivariate predictor for the combined cardiovascular composite of CV death, recurrent myocardial infarction (MI), heart failure or stroke (hazard ratio, 1.6; 95% confidence interval, 1.1, 2.3).
Patients with an early decline in renal function after an acute coronary syndrome are at a significant increased risk for recurrent cardiovascular events. CRP is an independent predictor for subsequent decline in renal function and reinforces the idea that inflammation may be related to the pathophysiology of progressive renal disease.
Clinical Journal of the American Society of Nephrology 10/2009; 4(11):1811-7. DOI:10.2215/CJN.03510509 · 4.61 Impact Factor