Justin A. Ezekowitz

Apixaban versus warfarin in patients with atrial fibrillation.

BACKGROUND Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. METHODS In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. RESULTS The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42). CONCLUSIONS In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. (Funded by Bristol-Myers Squibb and Pfizer; ARISTOTLE ClinicalTrials.gov number, NCT00412984.).

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure : The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC

Authors/Task Force Members: Piotr Ponikowski* (Chairperson) (Poland), Adriaan A. Voors* (Co-Chairperson) (The Netherlands), Stefan D. Anker (Germany), Héctor Bueno (Spain), John G. F. Cleland (UK), Andrew J. S. Coats (UK), Volkmar Falk (Germany), José Ramón González-Juanatey (Spain), Veli-Pekka Harjola (Finland), Ewa A. Jankowska (Poland), Mariell Jessup (USA), Cecilia Linde (Sweden), Petros Nihoyannopoulos (UK), John T. Parissis (Greece), Burkert Pieske (Germany), Jillian P. Riley (UK), Giuseppe M. C. Rosano (UK/Italy), Luis M. Ruilope (Spain), Frank Ruschitzka (Switzerland), Frans H. Rutten (The Netherlands), Peter van der Meer (The Netherlands)

Effect of Nesiritide in Patients with Acute Decompensated Heart Failure

BACKGROUND Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Anemia Is Common in Heart Failure and Is Associated With Poor Outcomes Insights From a Cohort of 12 065 Patients With New-Onset Heart Failure

Background—Although previous work has suggested that anemia is associated with an increased mortality in selected patients with congestive heart failure (CHF), little is known about the prevalence and predictors of anemia, or whether anemia is an independent prognostic factor in unselected, community-based patients with CHF. Methods and Results—We analyzed a population-based cohort of patients with new-onset CHF from a database of patients discharged from 138 acute-care hospitals in Alberta, Canada, between April 1993 and March 2001. Logistic regression, Kaplan-Meier survival analyses, and Cox proportional hazards model were used. Among the 12 065 patients with CHF (median age 78 years), 17% had anemia, 58% of whom had anemia of chronic disease. After adjustment for clinical and demographic variables, patients with anemia were more likely to be older (odds ratio [OR] 1.01 per year) and female (OR 1.2 [95% confidence interval 1.1 to 1.3]) and to have a history of chronic renal insufficiency (OR=3.2 [95% confidence interval 2.8 to 3.6]), or hypertension (OR 1.3 [95% confidence interval 1.2 to 1.5]). Hazard ratios for mortality, adjusting for covariates, were 1.34 (1.24 to 1.46) in anemic patients, and 1.36 (1.23 to 1.50) in those patients with anemia of chronic disease. Conclusions—In this large cohort of community-dwelling patients with CHF, anemia is common and an independent prognostic factor for mortality. Further research into the mechanisms of anemia in CHF and randomized controlled trials to test whether correction of anemia improves prognosis in CHF are needed.

Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study.

Background—The prevalence, prognostic import, and impact of renal insufficiency on the benefits of ACE inhibitors and &bgr;-blockers in community-dwelling patients with heart failure are uncertain. Methods and Results—We analyzed data from a prospective cohort of 754 patients with heart failure who had ejection fraction, serum creatinine, and weight measured at baseline. Median age was 69 years, and 43% had an ejection fraction ≥35%. By the Cockcroft-Gault equation, 118 patients (16%) had creatinine clearances ≤30 mL/min and 301 (40%) had creatinine clearances between 30 and 59 mL/min. During follow-up (median 926 days), 385 patients (37%) died. Even after adjustment for all other prognostic factors, survival was significantly associated with renal function (P =0.002) in patients with either systolic or diastolic dysfunction; patients exhibited a 1% increase in mortality for each 1-mL/min decrease in creatinine clearance. The associations with 1-year mortality reductions were similar for ACE inhibitors (OR 0.46 [95% CI 0.26 to 0.82] versus OR 0.28 [95% CI 0.11 to 0.70]) and &bgr;-blockers (OR 0.40 [95% CI 0.23 to 0.70] versus OR 0.41 [95% CI 0.19 to 0.85]) in patients with creatinine clearances <60 mL/min versus ≥60 mL/min, although these drugs were used less frequently in patients with renal insufficiency. Conclusions—Renal insufficiency is more prevalent in patients with heart failure than previously reported and is an independent prognostic factor in diastolic and systolic dysfunction. ACE inhibitors and &bgr;-blockers were associated with similar reductions in mortality in patients with and without renal insufficiency.

Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure.

Over the past decade, several randomized clinical trials have established that -blockers are beneficial in patients with heart failure (1, 2). Although resting heart rate is known to be a prognostic factor in patients with heart failure (3, 4), it remains unclear whether the benefits of -blockade in patients with heart failure are related to the degree of reduction in heart rate or the dosage of -blocker administered. This question is important because the adverse effects of -blockers are dose-related (5). Although heart failure guidelines recommend up-titration of -blockers to the target doses used in -blocker trials, outcome studies reveal that only some patients achieve these doses outside of specialized heart failure clinics (68). Secondary analyses of the CIBIS (Cardiac Insufficiency Bisoprolol Study) (9), COMET (Carvedilol Or Metoprolol European Trial) (10), and CIBIS II (11) data suggested that the magnitude of heart rate reduction with -blockers was an important mediator of -blocker effect. In addition, a small clinical trial of 49 pacemaker-dependent patients with left ventricular systolic dysfunction demonstrated that patients who were paced at a lower rate (60 beats/min) had improvements in left ventricular function and left ventricular dimensions compared with those paced at a higher rate (80 beats/min) (12). However, other studies have not confirmed a relationship between the magnitude of heart rate reduction and the efficacy of -blockers (1315). We designed this meta-analysis to investigate the between-study heterogeneity in heart failure -blocker trials. Specifically, we examined whether -blocker dose or magnitude of heart rate reduction could account for the differences in treatment effects among heart failure -blocker trials. Methods Identifying Relevant Studies We searched for randomized trials in MEDLINE (1966 to 2008), EMBASE (1980 to 2008), CINAHL (1982 to 2008), SIGLE (1980 to 2008), Web of Science, and the Cochrane Central Register of Controlled Trials. We did not apply language restrictions, but we restricted our searches to human studies and clinical trial or randomized, controlled trial publications. We used the keywords and Medical Subject Headings adrenergic -antagonists, heart failure, and congestive (exp). We also hand-searched bibliographies of identified studies, recent meta-analyses of -blockers in heart failure (1, 2), and heart failure guidelines. Study Selection and Data Abstraction Two authors independently reviewed the results of the search strategy and selected all studies that reported the effect of -blockers on all-cause mortality in patients with heart failure. The authors excluded studies if they were published in abstract form only, did not report death, used -blockers for 1 month or less, or enrolled fewer than 50 patients. Two authors extracted all outcome data independently, with subsequent discussion of any discrepancies. Outcomes from each study were extracted in intention-to-treat categories rather than per-protocol categories (that is, all outcomes were analyzed by randomization group to avoid bias from excluding patients who dropped out, were withdrawn, or did not adhere to treatment). We calculated the magnitude of heart rate reduction in each trial by comparing the heart rate at the end of the dose titration phase of each trial with the baseline values and subtracted the change in the placebo group from the change in the -blocker group. Statistical Analysis Because of the expected differences in patient samples and length of follow-up in these studies, we did our primary analyses by using the DerSimonianLaird random-effects model. We did analyses by using Review Manager, version 4.2 (The Cochrane Collaboration, Copenhagen, Denmark), and Stata SE, version 10 (StataCorp, College Station, Texas). Because the outcome of interest was relatively common, we calculated risk ratios (RRs) and 95% CIs. We assessed and quantified statistical heterogeneity for each outcome of interest by using the Cochran Q test and the I 2 statistic, respectively (16). The I 2 statistic quantifies the percentage of statistical heterogeneity due to between-study variability. By convention, values less than 25%, 25% to 50%, and greater than 50% are considered low, moderate, and high amounts of heterogeneity, respectively (17). To explore potential explanations for the between-trial heterogeneity, we did meta-regression analyses by using the weighted least-squares method (16). The logarithm of relative risk for death, weighted by the inverse variance of each study, was regressed against the following variables 1 at a time: sex, age, ischemic cause, left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) class, atrial fibrillation, use of digoxin, heart rate at baseline, magnitude of heart rate reduction achieved with treatment, dose of -blocker reached, systolic blood pressure (SBP) at baseline, magnitude of treatment-related SBP reduction, and specific -blocking agent. We explored continuous variables in these meta-regressions both linearly and categorically by using tertiles. We reported the P values from Wald tests. In a sensitivity analysis, we investigated the stability of our meta-regression result by using a Monte Carlo simulation to explore the effect of sampling variability around the point estimates of heart rate reduction in each trial (18). We sampled 5000 data sets, and the mean heart rate reduction was varied along a normal distribution (by using the mean and SE reported by each trial); trial selection remained fixed in each Monte Carlo iteration. In addition, we ran meta-regressions incorporating various combinations of 2 or 3 of these variables to investigate the robustness of our findings (the number of trials was insufficient to run meta-regressions with more than 3 variables). Role of the Funding Source There was no specific funding for this project. Results Study Selection and Evaluation Of the 548 citations that we identified in our search, 108 were potentially eligible for inclusion, but we excluded 85 after detailed review (Figure 1). Of note, the 34 trials that we excluded because they did not report death but instead evaluated levels of biomarkers or neurohormonal measurements, hemodynamic changes, or echocardiographic measurements, were generally small (mean sample size, 43 patients). The 12 trials that reported death, but were excluded because they included fewer than 50 patients (mean sample size, 28 patients), had a total of only 15 deaths (compared with 2720 deaths in the 23 randomized trials included in our meta-analysis). Disagreement between 2 reviewers about eligibility of the studies occurred on 3 occasions, for a value of 0.92. All disagreements were resolved by consensus. Figure 1. Study flow diagram. Studies Included in the Systematic Review Table 1 shows the baseline data from 23 randomized trials (1942). Three trials [23, 28, 38] reported outcome data in -blocker dosage subgroups (each of these subgroups is reported as a separate row in Table 1) (1942). The Appendix Table outlines -blocker titration schedules, dosing, duration, and effect on SBP and heart rate. Four trials (21, 24, 26, 40) could not be included in the analyses comparing death with physiologic variables because they did not report heart rate data for trial participants. Table 1. Baseline Data for Included Trials Appendix Table. Changes in Clinical Variables During Trials Qualitative Synthesis All but 2 (32, 41) trials were restricted to patients with systolic dysfunction, and only 4% of trial participants had preserved systolic function. Two trials enrolled only patients with nonischemic heart failure; 2 trials were restricted to patients with ischemic cardiomyopathy; and in the other trials, the frequency of ischemic heart disease ranged from 27% to 90%, with a median of 59% (Table 1). In addition to standard antiheart failure therapy except -blockers, the control groups received placebo in all but 2 trials (in which the control group received an angiotensin-converting enzyme inhibitor but no -blocker) (33, 36). Use of angiotensin-converting enzyme inhibitors (median, 93% [interquartile range {IQR}, 87% to 96%]) and digoxin (median, 75% [IQR, 57% to 91%]) was high in these trials (Table 1). Mean LVEF in these trials ranged from 0.17 to 0.36 (median, 0.24), with all but 1 trial reporting mean LVEF less than 0.30 (Table 1). Few trials reported comorbid conditions, but in those that did, 12% to 35% of participants had atrial fibrillation (Table 1) and 12% to 36% had diabetes mellitus. Most patients in these trials had NYHA class III or IV symptoms at baseline (median, 54% [IQR, 50% to 66%]). Most of these trials were of relatively short durationonly 6 trials (19, 3335, 39, 40) followed patients longer than 12 months (Appendix Table). Fifteen trials did not report subgroup analyses, whereas 8 trials did: patients with ischemic versus nonischemic heart failure (22, 31, 34, 35, 39, 41, 43); results by NYHA class (22, 3436, 39), age (22, 31, 36, 41, 43), sex (22, 31, 39, 41, 43), or race (39); and results for patients with comorbid conditions, such as diabetes (22, 36, 41), hypertension (22, 36), smoking (22), or chronic kidney disease (36). Although 6 trials reported that -blocker efficacy did not statistically differ between any of the subgroups examined, most of these subgroup analyses were presented as forest plots or KaplanMeier curves with no explicit reporting of raw numbers, such that we could not pool subgroup data to examine the consistency across trials with formal interaction tests. One trial (BEST [Beta-Blocker Evaluation of Survival Trial]) reported that -blockers demonstrated a survival benefit in nonblack patients but not in black patients (P for interaction= 0.02) (39). Because no other trials reported outcomes separately for black and nonblack patients, we could not evaluate the consistency of this subgroup finding across trials. The BEST trial enrol

Implantable cardioverter defibrillators in primary and secondary prevention: a systematic review of randomized, controlled trials.

Context Implantable cardioverter defibrillators (ICDs) clearly prevent death from cardiac arrhythmias, but in which patients? Contribution This meta-analysis summarizes findings from eight randomized trials that compared ICDs with usual care or antiarrhythmic drugs. Implantable cardioverter defibrillators reduced sudden death and total mortality in many patients, including patients with previous ventricular arrest or symptomatic sustained ventricular arrhythmias; patients with left ventricular dysfunction due to coronary artery disease who had asymptomatic nonsustained ventricular tachycardia and sustained tachycardia that could be induced electrophysiologically; and some patients with severe left ventricular dysfunction (ejection fraction 0.3) after myocardial infarction. The Editors Sudden cardiac death accounts for approximately 50% of all deaths from cardiovascular causes (1, 2). Some patients are at higher risk for sudden cardiac death, particularly those with significant coronary artery disease (CAD) and left ventricular systolic dysfunction. Until recently, prevention of sudden cardiac death has focused on antiarrhythmic drugs, -blockers, and improved management of the underlying disease processes. Several published trials in the past few years have evaluated implantable cardioverter defibrillators (ICDs) in patients with cardiovascular disease. There seems to be little doubt that this intervention should be routinely considered in some patients, such as those with advanced ischemic cardiomyopathy who are resuscitated after ventricular fibrillation arrest. However, debate continues about the potential benefits of ICDs in other patient groups (36). Approximately 85% to 90% of sudden cardiac deaths are due to a first arrhythmic event; the remaining 10% to 15% are due to recurrent events (7). We defined primary prevention as prevention of a first life-threatening arrhythmic event (ventricular fibrillation, sustained ventricular tachycardia, or cardiac arrest) (8). Primary prevention of sudden cardiac death routinely focuses on patients at high risk, including those with CAD and left ventricular systolic dysfunction, up to 60% of whom die of dysrhythmia (9). Secondary prevention refers to the prevention of an additional life-threatening arrhythmic event in survivors of sudden cardiac death or patients with recurrent unstable rhythms. A recent meta-analysis using individual-patient data from three studies of secondary prevention suggested a survival benefit for ICD therapy compared with amiodarone therapy but did not include any data on primary prevention (10). Another recent systematic review involving 1610 patients included trials of primary and secondary prevention published before January 2000 (11); however, two primary prevention trials involving 1336 patients have been published since then (12, 13). These trials, in turn, focused exclusively on total mortality and did not calculate summary effect estimates or explore reasons for heterogeneity in the total mortality data. Given the limitations of the existing analyses, the potential impact of ICDs on patient survival, and the major socioeconomic implications of this issue, we performed a systematic review of trials of primary and secondary prevention with ICDs to examine the effects of this therapy on rates of sudden cardiac death and all-cause mortality. Methods Search Strategy We searched for randomized trials in MEDLINE (198024 September 2002), the Cochrane Controlled Clinical Trial Registry (2002, Volume 3), EMBASE (19802002), Web of Science, National Library of Medicine Gateway, Cardiosource, the Clinical Trials Registry, Clinicaltrials.gov, the CRISP (Computer Retrieval of Information on Scientific Projects) Database, the National Research Register, the GlaxoWellcome Clinical Trials Register, the LILACS (Latin American and Caribbean Health Science Literature) Database, OCLC (Online Computer Library Center) ProceedingsFirst, and the National Health Service Economic Evaluation Database. All databases were last accessed on 24 September 2002. In addition, bibliographies of relevant papers were hand searched and experts, device manufacturers, and primary authors were contacted for information on additional trials. Relevant conference proceedings were also searched. The search was not limited by language. We used the following textwords and Medical Subject Headings: ICD, AICD, implantable defibrillators (exp), heart arrest (exp), sudden cardiac death (exp), sudden death (exp), SCD, cardiac arrest, coronary disease (exp), heart disease (exp), systolic dysfunction, ventricular dysfunction (exp), heart failure (exp), ventric* arrhythmia, ventric* rhythm, ventric* fibrillation, ventric* tachycardia, arrhythmia (exp), anti-arrhythmia agents (exp), anti-arrhythmia drug*, anti-arrhythmia therap*, and antiarrhythmi*. Study Selection Two of the study investigators independently reviewed the titles and abstracts of all citations to identify any randomized trials evaluating the efficacy of ICDs versus placebo or ICDs versus antiarrhythmic therapy. Both reviewers used standardized data forms to review the full text of potentially relevant articles. A funnel plot was used to evaluate publication bias. We included any randomized, controlled trials involving patients at risk for sudden cardiac death or ventricular arrhythmia (sustained ventricular tachycardia or ventricular fibrillation) who had evidence of heart failure or CAD (primary prevention), as well as studies in survivors of sudden cardiac death or unstable ventricular rhythm (secondary prevention). The trial outcomes had to include sudden cardiac death or all-cause mortality. Trials in patients with inherited arrhythmic disorders were excluded. We also excluded trials that did not report any of the outcomes of interest or had crossover rates of greater than 50% between study groups. Validity Assessment and Data Abstraction Intention-to-treat analyses were performed, and the outcome definitions used by the original researchers were accepted. All discrepancies in trial eligibility or data collection were resolved by consensus. Outcome Measures We extracted data on all-cause mortality, sudden cardiac death, total cardiac mortality, and total noncardiac mortality. A priori, we decided to examine the effects of ICD therapy in primary versus secondary prevention. Because we anticipated that the primary prevention trials would encompass a broad spectrum of patients, we subdivided them into those enrolling high-risk patients and those enrolling moderate-risk patients. We defined high-risk patients as those with an expected rate of sudden cardiac death of at least 5% per year (that is, patients with ischemic cardiomyopathy, with or without ventricular arrhythmia) (14). Statistical Analysis We used Metaview 4.1 software (Update Software, Oxford, United Kingdom) to calculate summary relative risks (since the outcomes were relatively common) and used the Cochran Q-test to assess for heterogeneity in each outcome of interest. We combined studies using the DerSimonian and Laird random-effects model as well as the MantelHaenszelPeto fixed-effects model; when the results from both models were identical and there was no statistical heterogeneity, we reported only the fixed effects (15). We also conducted sensitivity analyses to examine the effect of year of publication, study quality, and allocation concealment on the results (16, 17). Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Of the 385 potentially relevant articles identified in our search, 9 were parallel-group randomized trials. We excluded 1 trial because patients in both study groups received ICD therapy (18). We then analyzed the data from the 8 trials that fulfilled our inclusion criteria (12, 13, 1924) (Figure 1). There was no disagreement about any of the articles selected for final inclusion in the meta-analysis. Funnel-plot analyses did not suggest any marked publication bias. Figure 1. Selection of trials included in the meta-analysis. In the 8 trials we examined, 4909 patients were randomly assigned to study groups. Three of the 8 trials were trials of secondary prevention, and the remaining 5 (3 involving high-risk patients and 2 involving moderate-risk patients) were classified as trials of primary prevention (Table 1). All but 1 study (12) enrolled patients with ischemic heart disease. All trials reported all-cause mortality, and all but 1 (21) used all-cause mortality as the primary outcome. The control groups and crossover rates are described in Table 1, and concomitant medication use is described in Table 2. Table 1. Characteristics of Included Studies Table 2. Therapies according to Treatment Assignment in the Trials The included trials were randomized and controlled. Because of the nature of the intervention, none of the trials were blinded. Randomization and allocation concealment were adequate in all trials. All-cause mortality and sudden cardiac death were reported in all trials, but other end points were not consistently reported. For several trials, we needed to review secondary publications or contact the authors to determine causes of death. The summary relative risk (RR) for sudden cardiac death was 0.43 (95% CI, 0.35 to 0.53) for all 8 trials. This confirms that ICDs are highly efficacious in preventing sudden cardiac death, both as primary prevention (RR, 0.37 [CI, 0.27 to 0.50]) and secondary prevention (RR, 0.50 [CI, 0.38 to 0.66]) (Figure 2). No appreciable heterogeneity was seen among trials, although no sudden cardiac deaths occurred in either study group in 1 trial (12) because the investigators had recruited lower-risk patients. There was no appreciable difference between Ts of ICD (transthoracic vs. transvenous) in the summary effect estimates for prevention of sudden cardiac death (19, 20). Figu

Declining In-Hospital Mortality and Increasing Heart Failure Incidence in Elderly Patients With First Myocardial Infarction

OBJECTIVES The purpose of this study was to examine the long-term incidence of heart failure (HF) in elderly patients with myocardial infarction (MI). BACKGROUND In-hospital HF is common after MI and is associated with poor short-term prognosis. Limited data exist concerning the long-term incidence or prognosis of HF after MI, particularly in the era of coronary revascularization. METHODS A population-based cohort of 7,733 patients > or = 65 years of age hospitalized for a first MI (International Classification of Diseases-9th Revision-Clinical Modification code 410.x) and without a prior history of HF was established between 1994 and 2000 in Alberta, Canada, and followed up for 5 years. RESULTS During the index MI hospitalization, 2,831 (37%) MI patients were diagnosed with new HF and 1,024 (13%) died. Among hospital survivors who did not have HF during their index hospitalization (n = 4,291), an additional 3,040 patients (71%) developed HF by 5 years, 64% of which occurred in the first year. In total, 5,871 (76%) elderly patients who survived their first MI developed HF over 5 years. Among those who survived the index hospitalization, the 5-year mortality rate was 39.1% for those with HF during the index MI hospitalization compared with 26.7% among those without HF (p < 0.0001) during the index MI hospitalization. Over the study period, the 5-year mortality rate after MI decreased by 28%, whereas the 5-year rate of HF increased by 25%. CONCLUSIONS In this large cohort of elderly patients without a history of HF, HF developed in three-quarters in the 5 years after their first MI; this proportion increased over time as peri-MI mortality rates declined. New-onset HF significantly increases the mortality risk among these patients.

The 2012 Canadian Cardiovascular Society heart failure management guidelines update: focus on acute and chronic heart failure.

The 2012 Canadian Cardiovascular Society Heart Failure (HF) Guidelines Update provides management recommendations for acute and chronic HF. In 2006, the Canadian Cardiovascular Society HF Guidelines committee first published an overview of HF management. Since then, significant additions to and changes in many of these recommendations have become apparent. With this in mind and in response to stakeholder feedback, the Guidelines Committee in 2012 has updated the overview of both acute and chronic heart failure diagnosis and management. The 2012 Update also includes recommendations, values and preferences, and practical tips to assist the medical practitioner manage their patients with HF.

Systematic Review: Implantable Cardioverter Defibrillators for Adults with Left Ventricular Systolic Dysfunction

Left ventricular (LV) systolic dysfunction carries a high risk for sudden cardiac death (1). Implantable cardioverter defibrillators (ICDs) can potentially mitigate this risk by delivering rapid life-saving therapy and have been substantially refined since their initial development in the late 1970s (2). Randomized, controlled trials (RCTs) have tested the efficacy of ICDs in high-risk individuals. We previously reported a systematic review of 8 RCTs (3 RCTs of secondary prevention in survivors of sudden cardiac death; 5 RCTs of primary prevention in patients without a history of ventricular arrhythmias) demonstrating a 26% reduction in all-cause mortality and a 57% reduction in sudden cardiac death with ICDs (3). Since then, additional RCTs of primary prevention have been published, and questions have arisen about the generalizability of the RCT results for ICDs to clinical practice. In particular, it is uncertain whether the benefits of ICDs seen in the trials extend to nontrial populations and whether the risks associated with ICDs may be higher in clinical practice than reported in trials. Given the public policy implications, we extended our previous systematic review of the efficacy (that is, the risks and benefits of a therapy when tested under ideal circumstances) (4) of ICDs in patients with LV systolic dysfunction by updating it with recently published RCTs that examined efficacy. In addition, we expanded the review to include data from observational studies to determine the effectiveness (that is, the risks and benefits of a therapy when tested under usual clinical practice conditions) and safety of ICDs when used in clinical practice. Methods A study protocol meeting Cochrane criteria, including all of the elements described briefly in the following sections, was developed and followed by the study authors in conjunction with the Agency for Healthcare Research and Quality (AHRQ). Search Strategy We sought studies published between 1980 and 27 April 2007 by searching MEDLINE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database, EMBASE, Science Citation Index Expanded (via Web of Science), International Pharmaceutical Abstracts, PubMed, National Library of Medicine Gateway, OCLC ProceedingsFirst and PapersFirst, Computer Retrieval of Information on Scientific Projects, various trial registries (including the National Research Register [United Kingdom], Australian Clinical Trials Registry, ClinicalTrials.gov, and Current Controlled Trials), and U.S. Food and Drug Administration reports. In addition, we hand-searched abstracts from the annual Heart Rhythm Society meetings and the reference lists of review articles and included studies; we also contacted authors of included studies for additional citations and information. Unpublished studies and individual-patient data were sought from device manufacturers, including Medtronic (Minneapolis, Minnesota), Guidant Corp. (Indianapolis, Indiana), and St. Jude Medical (St. Paul, Minnesota). The search was not limited by language or publication status. The search terms included Medtronic InSync, ELA medical, Guidant, St. Jude, implantable defibrillators, implantable cardioverter defibrillators, AICD, ICD, single chamber ICD, dual chamber ICD, congestive heart failure, CHF, chronic heart failure, and heart diseases. A full list of search strategies (adapted for each database) and search results are available at www.ahrq.gov/clinic/tp/defibtp.htm (5). Study Selection We selected original research studies that had at least 25 participants and reported mortality or peri- or postimplantation complications with ICDs in adult patients with LV systolic dysfunction (left ventricular ejection fraction [LVEF]0.35, regardless of whether the patients had heart failure symptoms). To address efficacy questions, we restricted the analyses to RCTs. To address effectiveness questions, we expanded our inclusion criteria to include observational studies with contemporaneous comparison groups (such as cohort studies) and RCTs that did not report efficacy outcomes. To address safety questions, we included evidence from both RCTs and observational studies (including those without contemporaneous control groups, such as case series and registry data). Data Extraction and Analysis Study selection, quality assessment, and data extraction were completed by several investigators in duplicate and independently, using the methods recommended by the Quality of Reporting of Meta-analyses (QUOROM) group (6). We assessed quality by using the methods of Schulz and colleagues (7), the 5-item Jadad scale (8), and the 27-point Downs and Black scale (9). Publication bias was assessed visually by using funnel plots and quantitatively by using the rank correlation test (10), the graphical test (11), and the trim-and-fill method (12). Random-effects models were used to calculate pooled relative risks (RRs) in Review Manager 4.2.5 (Cochrane Collaboration, Copenhagen, Denmark). The length of study follow-up versus all-cause mortality was plotted for each study, and inverse varianceweighted least-squares regression was used to create a best-fit line. Postimplantation complications were expressed per 100 patient-years (calculated by multiplying the frequency of events in each study by the duration of follow-up, and standardizing to a denominator of 100) and are unadjusted rates. All results were reported with 95% CIs and, where appropriate, SDs or SEs. Statistical heterogeneity was quantified by using the I 2 statistic (13). In addition to examining for differences in point estimates across study designs and study quality, we explored device efficacy in different patient subgroups by using meta-regression. Covariates tested included presence of cardiac resynchronization therapy, length of follow-up, ischemic etiology, New York Heart Association (NYHA) class, age, QRS interval, LVEF, and primary versus secondary prevention. Role of the Funding Source The funding source (AHRQ, U.S. Department of Health and Human Services) had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Literature Search From 4439 citations (Figure 1), we identified 12 RCTs (8516 patients) for the ICD efficacy review (1426), 53 studies (26840 patients from 5 nonefficacy RCTs and 48 observational studies [25 retrospective and 23 prospective]) for the ICD effectiveness review (2778), and 64 studies (86809 patients from 11 efficacy RCTs, 10 RCTs without efficacy outcomes, and 43 observational studies [24 retrospective and 19 prospective]) for the ICD safety review (1417, 1927, 29, 30, 34, 3740, 4245, 47, 48, 52, 54, 60, 61, 6366, 69, 70, 7275, 78101). A full list of search strategies, search results, detailed quality assessments for each included study, and tests for publication bias are available at www.ahrq.gov/clinic/tp/defibtp.htm (5). No publication bias was seen on the funnel plots. Figure 1. Flow diagram of study identification and selection. RCTs with Efficacy Data The 12 efficacy RCTs varied in quality (ranging from 1 to 3 on the Jadad scale) and duration (ranging from 15 to 66 months). All but 2 trials (16, 19) evaluated single-chamber ICDs (although no trials reported protocol adherence to single-chamber vs. dual-chamber ICDs). All patients in the RCTs had LV systolic dysfunction: Mean LVEF ranged from 0.21 to 0.28 in the primary prevention trials and from 0.32 to 0.46 in the secondary prevention trials. Most patients also had symptoms of heart failure: 50% had NYHA class II symptoms at baseline; 36%, class III symptoms; and 3%, class IV symptoms. Eleven percent of trial participants were in NYHA class I at baseline (Appendix Table 1). The mean age of RCT participants was 61 years (SD, 4), 74% were male, and 59% had ischemic heart disease. Appendix Table 1. Description of Randomized Trials Included in the Review Use of ICDs reduced all-cause mortality in patients with LV systolic dysfunction by 20% (95% CI, 10% to 29%; I 2= 44.4%) (Figure 2), largely because of a 54% relative reduction (CI, 37% to 63%; I 2= 0%) in sudden cardiac deaths. In patients with LV systolic dysfunction, ICDs were equally beneficial in reducing all-cause mortality in both primary prevention trials (RR, 0.81 [CI, 0.69 to 0.95]; I 2= 53.1% across 9 RCTs) and secondary prevention trials (RR, 0.77 [CI, 0.65 to 0.91]; I 2= 13.2% across 3 RCTs) (P for this indirect comparison= 0.56). Figure 2. Effect of implantable cardioverter defibrillator ( ICDs ) on all-cause mortality in randomized trials. A single trial included cardiac resynchronization therapy in both study groups for its comparison of ICDs versus control (19). All-cause mortality (RR, 0.83 [CI, 0.66 to 1.05]) was similar to that reported from the remainder of the studies, which did not contain cardiac resynchronization therapy in either study group (RR, 0.79 [CI, 0.69 to 0.91]) (P for indirect comparison= 0.92). Only 1 trial reported a statistically significant difference in the effect of ICDs across NYHA classes: The mortality benefits were greater in patients with NYHA class II symptoms than in those with NYHA class III symptoms in the Sudden Cardiac Death in Heart Failure Trial (P< 0.001 for interaction term of NYHA class and mortality) (22). In a series of univariate meta-regression sensitivity analyses, none of the covariates we examined (duration of follow-up, primary vs. secondary prevention, ischemic cause, presence of cardiac resynchronization therapy, NYHA class, mean age, mean LVEF, or mean QRS duration) contributed to the moderate statistical heterogeneity observed in our meta-analysis of all-cause mortality. In addition, our estimate of treatment effect was not associated with study quality. Implantable cardioverter defibrillators