Alexander A. Leung

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

A comparison of early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury: a systematic review and meta-analysis

IntroductionOur aim was to investigate the impact of early versus late initiation of renal replacement therapy (RRT) on clinical outcomes in critically ill patients with acute kidney injury (AKI).MethodsSystematic review and meta-analysis were used in this study. PUBMED, EMBASE, SCOPUS, Web of Science and Cochrane Central Registry of Controlled Clinical Trials, and other sources were searched in July 2010. Eligible studies selected were cohort and randomised trials that assessed timing of initiation of RRT in critically ill adults with AKI.ResultsWe identified 15 unique studies (2 randomised, 4 prospective cohort, 9 retrospective cohort) out of 1,494 citations. The overall methodological quality was low. Early, compared with late therapy, was associated with a significant improvement in 28-day mortality (odds ratio (OR) 0.45; 95% confidence interval (CI), 0.28 to 0.72). There was significant heterogeneity among the 15 pooled studies (I2 = 78%). In subgroup analyses, stratifying by patient population (surgical, n = 8 vs. mixed, n = 7) or study design (prospective, n = 10 vs. retrospective, n = 5), there was no impact on the overall summary estimate for mortality. Meta-regression controlling for illness severity (Acute Physiology And Chronic Health Evaluation II (APACHE II)), baseline creatinine and urea did not impact the overall summary estimate for mortality. Of studies reporting secondary outcomes, five studies (out of seven) reported greater renal recovery, seven (out of eight) studies showed decreased duration of RRT and five (out of six) studies showed decreased ICU length of stay in the early, compared with late, RRT group. Early RRT did not; however, significantly affect the odds of dialysis dependence beyond hospitalization (OR 0.62 0.34 to 1.13, I2 = 69.6%).ConclusionsEarlier institution of RRT in critically ill patients with AKI may have a beneficial impact on survival. However, this conclusion is based on heterogeneous studies of variable quality and only two randomised trials. In the absence of new evidence from suitably-designed randomised trials, a definitive treatment recommendation cannot be made.

Hypertension Canada's 2016 Canadian Hypertension Education Program Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention, and Treatment of Hypertension

Hypertension Canadas Canadian Hypertension Education Program Guidelines Task Force provides annually updated, evidence-based recommendations to guide the diagnosis, assessment, prevention, and treatment of hypertension. This year, we present 4 new recommendations, as well as revisions to 2 previous recommendations. In the diagnosis and assessment of hypertension, automated office blood pressure, taken without patient-health provider interaction, is now recommended as the preferred method of measuring in-office blood pressure. Also, although a serum lipid panel remains part of the routine laboratory testing for patients with hypertension, fasting and nonfasting collections are now considered acceptable. For individuals with secondary hypertension arising from primary hyperaldosteronism, adrenal vein sampling is recommended for those who are candidates for potential adrenalectomy. With respect to the treatment of hypertension, a new recommendation that has been added is for increasing dietary potassium to reduce blood pressure in those who are not at high risk for hyperkalemia. Furthermore, in selected high-risk patients, intensive blood pressure reduction to a target systolic blood pressure ≤xa0120 mm Hg should be considered to decrease the risk of cardiovascular events. Finally, in hypertensive individuals with uncomplicated, stable angina pectoris, either a β-blocker or calcium channel blocker may be considered for initial therapy. The specific evidence and rationale underlying each of these recommendations are discussed. Hypertension Canadas Canadian Hypertension Education Program Guidelines Task Force will continue to provide annual updates.

Outcomes of cardiac resynchronization therapy in patients with versus those without atrial fibrillation: A systematic review and meta-analysis

BACKGROUNDnWhether the benefits observed with cardiac resynchronization therapy (CRT) are similar in patients with versus those without atrial fibrillation (AF) is unclear. Furthermore, whether patients with AF receiving CRT should undergo atrioventricular nodal (AVN) ablation remains uncertain.nnnOBJECTIVEnThe purpose of this study was to compare outcomes in patients with and those without AF receiving CRT and to evaluate the influence of AVN ablation on outcomes in patients with AF.nnnMETHODSnA systematic review and meta-analysis was performed. Outcomes included death, CRT nonresponse, and changes in left ventricular (LV) remodeling, quality of life (QoL), and 6-minute hall walk distance (6MWD).nnnRESULTSnTwenty-three observational studies were included and followed a total of 7,495 CRT recipients, 25.5% with AF, for a mean of 33 months. AF was associated with an increased risk of nonresponse to CRT (34.5% vs 26.7%; pooled relative risk [RR] 1.32; 95% confidence interval [CI] 1.12, 1.55; P = .001)) and all-cause mortality (10.8% vs 7.1% per year, pooled RR 1.50, 95% CI 1.08, 2.09; P = .015). The presence of AF was also associated with less improvement in QoL, 6-minute hall walk distance, and LV end-systolic volume but not LV ejection fraction. Among patients with AF, AVN ablation appeared favorable with a lower risk of clinical nonresponse (RR 0.40; 95% CI 0.28, 0.58; P <.001) and a reduced risk of death.nnnCONCLUSIONnThe benefits of CRT appear to be attenuated in patients with AF. The presence of AF is associated with an increased risk of clinical nonresponse and death than in patients without AF. AVN ablation may improve CRT outcomes in patients with AF.

Hypertension Canada's 2017 Guidelines for Diagnosis, Risk Assessment, Prevention, and Treatment of Hypertension in Adults

Hypertension Canada provides annually updated, evidence-based guidelines for the diagnosis, assessment, prevention, and treatment of hypertension. This year, we introduce 10 new guidelines. Three previous guidelines have been revised and 5 have been removed. Previous age and frailty distinctions have been removed as considerations for when to initiate antihypertensive therapy. In the presence of macrovascular target organ damage, or in those with independent cardiovascular risk factors, antihypertensive therapy should be considered for all individuals with elevated average systolic nonautomated office blood pressure (non-AOBP) readings ≥ 140 mm Hg. For individuals with diastolic hypertension (with or without systolic hypertension), fixed-dose single-pill combinations are now recommended as an initial treatment option. Preference is given to pills containing an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in combination with either a calcium channel blocker or diuretic. Whenever a diuretic is selected as monotherapy, longer-acting agents are preferred. In patients with established ischemic heart disease, caution should be exercised in lowering diastolic non-AOBP to ≤xa060 mm Hg, especially in the presence of left ventricular hypertrophy. After a hemorrhagic stroke, in the first 24 hours, systolic non-AOBP lowering to < 140 mm Hg is not recommended. Finally, guidance is now provided for screening, initial diagnosis, assessment, and treatment of renovascular hypertension arising from fibromuscular dysplasia. The specific evidence and rationale underlying each of these guidelines are discussed.

Aspirin effect on the incidence of major adverse cardiovascular events in patients with diabetes mellitus: a systematic review and meta-analysis

BackgroundAspirin has been recommended for the prevention of major adverse cardiovascular events (MACE, composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) in diabetic patients without previous cardiovascular disease. However, recent meta-analyses have prompted re-evaluation of this practice. The study objective was to evaluate the relative and absolute benefits and harms of aspirin for the prevention of incident MACE in patients with diabetes.MethodsWe performed a systematic review and meta-analysis on seven studies (N = 11,618) reporting on the use of aspirin for the primary prevention of MACE in patients with diabetes. Two reviewers conducted a systematic search of electronic databases (MEDLINE, EMBASE, the Cochrane Library, and BIOSIS) and hand searched bibliographies and clinical trial registries. Reviewers extracted data in duplicate, evaluated the quality of the trials, and calculated pooled estimates.ResultsA total of 11,618 participants were included in the analysis. The overall risk ratio (RR) for MACE was 0.91 (95% confidence intervals, CI, 0.82-1.00) with little heterogeneity among trials (I2 0.0%). Secondary outcomes of interest included myocardial infarction (RR, 0.85; 95% CI, 0.66-1.10), stroke (RR, 0.84; 95% CI, 0.64-1.11), cardiovascular death (RR, 0.95; 95% CI, 0.71-1.27), and all-cause mortality (RR, 0.95; 95% CI, 0.85-1.06). There were higher rates of hemorrhagic and gastrointestinal events. In absolute terms, these relative risks indicate that for every 10,000 diabetic patients treated with aspirin, 109 MACE may be prevented at the expense of 19 major bleeding events (with the caveat that the relative risk for the latter is not statistically significant).ConclusionsThe studies reviewed suggest that aspirin reduces the risk of MACE in patients with diabetes without cardiovascular disease, while also causing a trend toward higher rates of bleeding and gastrointestinal complications. These findings and our absolute benefit and risk calculations suggest that those with diabetes but without cardiovascular disease lie somewhere between primary and secondary prevention patients on the spectrum of benefit and risk. This underscores the importance of considering individual risk in clinical decision making regarding aspirin in those with diabetes.

Risk of Heart Failure in Patients With Recent-Onset Type 2 Diabetes: Population-Based Cohort Study

BACKGROUNDnAlthough thiazolidinediones precipitate fluid retention in clinical trials, current guidelines advocate their use for patients with diabetes who are felt to be at low risk for heart failure (HF).nnnMETHODS AND RESULTSnAn inception cohort study was conducted using Saskatchewan Health databases spanning the years 1991 to 1999 (before use of thiazolidinediones) to compare incidence rates of new HF in patients with recent-onset diabetes vs. the general population. Of 12,272 patients with new-onset type 2 diabetes (mean age 63 years), 718 (6%) developed HF over 5.2 years; median time until development of HF was 2.8 years. The adjusted rate of incident HF for the diabetes cohort was 794 cases per 100,000 person years compared with 275 per 100,000 person-years in the general population. Patients with recent-onset diabetes were more likely to develop HF than the general population (adjusted rate ratio 2.9; 95% CI 2.6 to 3.2) and the relative risk was most pronounced in those younger than 60 years (adjusted rate ratio 12.8; 95% CI 8.2 to 20.0).nnnCONCLUSIONSnThe incidence of HF is relatively high within 5 years of diabetes onset, calling into question the ease with which individuals with diabetes at low risk of HF can be identified.

Hypertension Canada’s 2018 Guidelines for Diagnosis, Risk Assessment, Prevention, and Treatment of Hypertension in Adults and Children

Hypertension Canada provides annually updated, evidence-based guidelines for the diagnosis, assessment, prevention, and treatment of hypertension in adults and children. This year, the adult and pediatric guidelines are combined in one document. The new 2018 pregnancy-specific hypertension guidelines are published separately. For 2018, 5 new guidelines are introduced, and 1 existing guideline on the blood pressure thresholds and targets in the setting of thrombolysis for acute ischemic stroke is revised. The use of validated wrist devices for the estimation of blood pressure in individuals with large arm circumference is now included. Guidance is provided for the follow-up measurements of blood pressure, with the use of standardized methods and electronic (oscillometric) upper arm devices in individuals with hypertension, and either ambulatory blood pressure monitoring or home blood pressure monitoring in individuals with white coat effect. We specify that all individuals with hypertension should have an assessment of global cardiovascular risk to promote health behaviours that lower blood pressure. Finally, an angiotensin receptor-neprilysin inhibitor combination should be used in place of either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in individuals with heart failure (with ejection fraction <xa040%) who are symptomatic despite appropriate doses of guideline-directed heart failure therapies. The specific evidence and rationale underlying each of these guidelines are discussed.

Sex, Socioeconomic Status, Access to Cardiac Catheterization, and Outcomes for Acute Coronary Syndromes in the Context of Universal Healthcare Coverage

Background—Sex and neighborhood socioeconomic status (nSES) may independently affect the care and outcomes of acute coronary syndrome, partly through barriers in timely access to cardiac catheterization. We sought to determine whether sex modifies the association between nSES and the receipt of cardiac catheterization and mortality after an acute coronary syndrome in a universal healthcare system. Methods and Results—We studied 14 012 patients with acute coronary syndrome admitted to cardiology services between April 18, 2004, and December 31, 2011, in Southern Alberta, Canada. We used multivariable logistic regression to compare the odds of cardiac catheterization within 2 and 30 days of admission and the odds of 30-day and 1-year mortality for men and women by quintile of neighborhood median household income. Significant relationships between nSES and the receipt of cardiac catheterization and mortality after acute coronary syndrome were detected for women but not men. When examined by nSES, each incremental decrease in neighborhood income quintile for women was associated with a 6% lower odds of receiving cardiac catheterization within 30 days (P=0.01) and a 14% higher odds of 30-day mortality (P=0.03). For men, each decrease in neighborhood income quintile was associated with a 2% lower odds of receiving catheterization within 30 days (P=0.10) and a 5% higher odds of 30-day mortality (P=0.36). Conclusions—Associations between nSES and receipt of cardiac catheterization and 30-day mortality were noted for women but not men in a universal healthcare system. Care protocols designed to improve equity of access to care and outcomes are required, especially for low-income women.

Announcing "Up to Date in the Science of Sodium"

From the Faculty of Health Sciences, University of Ontario Institute of Technology, Oshawa, ON, Canada; George Institute for Global Health, University of Sydney, Sydney, NSW, Australia; George Institute for Global Health India, Hyderabad, India; The George Institute for Global Health, University of Sydney and the Royal Prince Alfred Hospital, Sydney, NSW, Australia; Departments of Preventive & Social Medicine/Human Nutrition, University of Otago, Dunedin, New Zealand; Arbor Research Collaborative for Health, Ann Arbor, MI; Department of Medicine, University of Calgary, Calgary, AB, Canada; and Department of Medicine, Physiology and Pharmacology and Community Health Sciences, O’Brien Institute for Public Health and Libin Cardiovascular Institute of Alberta, University of Calgary,Calgary, AB, Canada