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Background The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD; NCT03036150) trial was designed to assess the effect of the sodium–glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on kidney and cardiovascular events in participants with CKD with and without type 2 diabetes (T2D). This analysis reports the baseline characteristics of those recruited, comparing them with those enrolled in other trials. Methods In DAPA-CKD, 4304 participants with a urinary albumin:creatinine ratio (UACR) ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 were randomized to dapagliflozin 10 mg once daily or placebo. Mean eGFR was 43.1 mL/min/1.73 m2 and median UACR was 949 mg/g (108 mg/mmol). Results Overall, 2906 participants (68%) had a diagnosis of T2D and of these, 396 had CKD ascribed to a cause other than diabetes. The most common causes of CKD after diabetes (n  = 2510) were ischaemic/hypertensive nephropathy (n  = 687) and chronic glomerulonephritis (n  = 695), of which immunoglobulin A nephropathy (n  = 270) was the most common. A total of 4174 participants (97%) were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 1882 (43.7%) diuretics, 229 (5.3%) mineralocorticoid receptor antagonists and 122 (2.8%) glucagon-like peptide 1 receptor agonists. In contrast to the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), the DAPA-CKD trial enrolled participants with CKD due to diabetes and to causes other than diabetes. The mean eGFR of participants in the DAPA-CKD trial was 13.1 mL/min/1.73 m2 lower than in CREDENCE, similar to that in the Finerenone in Reducing Kidney Failure and Disease Progression in DKD (FIDELIO-DKD) trial and the Study Of diabetic Nephropathy with AtRasentan (SONAR). Conclusions Participants with a wide range of underlying kidney diseases receiving renin–angiotensin system blocking therapy have been enrolled in the DAPA-CKD trial. The trial will examine the efficacy and safety of dapagliflozin in participants with CKD Stages 2–4 and increased albuminuria, with and without T2D. [ABSTRACT FROM AUTHOR]

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19: a randomized clinical trial. Editorial There has been considerable interest in the potential role of renin-angiotensin system (RAS) inhibitors in patients with COVID-19 given that angiotensin-converting enzyme 2 (ACE2) is the functional receptor for SARS-CoV-2.[1] Because ACE inhibitors and angiotensin receptor blockers (ARBs) may upregulate ACE2, there is a theoretical concern that these agents might increase susceptibility to, or the severity of, SARS-CoV-2 infection. Effect of discontinuing vs continuing angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on days alive and out of the hospital in patients admitted with COVID-19: a randomized clinical trial. [Extracted from the article]

Yet, low doses of drugs for HFrEF yield important benefits to reduce morbidity and mortality, and target doses are often only modestly more effective than low starting doses in reducing the risk of cardiovascular death. 5 Fifth, and importantly, because much of the benefits of foundational treatments are seen within 30 days of initiating treatment, the algorithm should achieve therapy with all 4 classes of drugs within 4 weeks. If physicians prioritize the achievement of target doses of each drug class before initiating treatment with the next, it may take >=6 months to prescribe all recommended treatments. [Extracted from the article]

Aims: Recurrent hospitalizations are a major part of the disease burden in heart failure (HF), but conventional analyses consider only the first event. We compared the effect of sacubitril/valsartan vs. enalapril on recurrent events, incorporating all HF hospitalizations and cardiovascular (CV) deaths in PARADIGM-HF, using a variety of statistical approaches advocated for this type of analysis.Methods and Results: In PARADIGM-HF, a total of 8399 patients were randomized and followed for a median of 27 months. We applied various recurrent event analyses, including a negative binomial model, the Wei, Lin and Weissfeld (WLW), and Lin, Wei, Ying and Yang (LWYY) methods, and a joint frailty model, all adjusted for treatment and region. Among a total of 3181 primary endpoint events (including 1251 CV deaths) during the trial, only 2031 (63.8%) were first events (836 CV deaths). Among a total of 1195 patients with at least one HF hospitalization, 410 (34%) had at least one further HF hospitalization. Sacubitril/valsartan compared with enalapril reduced the risk of recurrent HF hospitalization using the negative binomial model [rate ratio (RR) 0.77, 95% confidence interval (CI) 0.67-0.89], the WLW method [hazard ratio (HR) 0.79, 95% CI 0.71-0.89], the LWYY method (RR 0.78, 95% CI 0.68-0.90), and the joint frailty model (HR 0.75, 95% CI 0.66-0.86) (all P < 0.001). The effect of sacubitril/valsartan vs. enalapril on recurrent HF hospitalizations/CV death was similar.Conclusions: In PARADIGM-HF, approximately one third of patients with a primary endpoint (time-to-first) experienced a further event. Compared with enalapril, sacubitril/valsartan reduced both first and recurrent events. The treatment effect size was similar, regardless of the statistical approach applied. [ABSTRACT FROM AUTHOR]

Aims: Because of concerns about the safety of aliskiren in patients with diabetes, study treatment was stopped prematurely in the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE). We examined outcomes and treatment effect in these patients compared with those without diabetes.Methods and Results: ATMOSPHERE included 7016 patients with heart failure and a reduced ejection fraction (HFrEF) randomly assigned to enalapril plus aliskiren, aliskiren alone, or enalapril. At baseline, 1944 (27.7%) patients had diabetes. Median follow-up was shorter in patients with diabetes compared with those without (24 months vs. 46 months). Among patients with diabetes, the primary endpoint of cardiovascular death or hospitalization for heart failure occurred in 216 patients (33.1%) in the enalapril group (reference), 172 (27.4%) in the aliskiren group [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.67-1.00; P = 0.053], and 196 (29.5%) in the combination group (HR 0.86, 95% CI 0.71-1.04; P = 0.13). The effects of the treatments studied did not differ significantly compared with patients without diabetes. In patients with diabetes, aliskiren monotherapy was associated with a lower risk of symptomatic hypotension compared to enalapril [42 (6.7%) vs. 65 (10.0%); P = 0.04], whereas other adverse events were generally balanced between the three groups.Conclusion: In patients with HFrEF and diabetes, there was no signal of harm and a trend towards benefit when direct renin inhibition monotherapy was compared with an angiotensin-converting enzyme inhibitor, whereas combined aliskiren and enalapril treatment led to more adverse events with no improvement in outcomes. Treatment effects did not differ in patients with diabetes compared with those without. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658. [ABSTRACT FROM AUTHOR]

Objective: Investigation of variations in provider performance and its determinants may help inform strategies for improving patient outcomes.Methods: We used the National Heart Failure Audit comprising 68 772 patients with heart failure with reduced left ventricular ejection fraction (HFREF), admitted to 185 hospitals in England and Wales (2007-2013). We investigated hospital adherence to three recommended key performance measures (KPMs) for inhospital care (ACE inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) on discharge, β-blockers on discharge and referral to specialist follow-up) individually and as a composite performance score. Hierarchical regression models were used to investigate hospital-level variation.Results: Hospital-level variation in adherence to composite KPM ranged from 50% to 97% (median 79%), but after adjustments for patient characteristics and year of admission, only 8% (95% CI 7% to 10%) of this variation was attributable to variations in hospital features. Similarly, hospital prescription rates for ACE-I/ARB and β-blocker showed low adjusted hospital-attributable variations (7% CI 6% to 9% and 6% CI 5% to 8%, for ACE-I/ARB and β-blocker, respectively). Referral to specialist follow-up, however, showed larger variations (median 81%; range; 20%, 100%) with 26% of this being attributable to hospital-level differences (CI 22% to 31%).Conclusion: Only a small proportion of hospital variation in medication prescription after discharge was attributable to hospital-level features. This suggests that differences in hospital practices are not a major determinant of observed variations in prescription of investigated medications and outcomes. Future healthcare delivery efforts should consider evaluation and improvement of more ambitious KPMs. [ABSTRACT FROM AUTHOR]

Background: Among patients with chronic heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction.Methods: After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure.Results: After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009) and an elevated potassium level (17.1% vs. 12.5%, P<0.001).Conclusions: In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapril. (Funded by Novartis; ATMOSPHERE ClinicalTrials.gov number, NCT00853658.). [ABSTRACT FROM AUTHOR]

Background--Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. Methods and Results--We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-B- type natriuretic peptide and troponin) versus enalapril. Conclusions--Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. [ABSTRACT FROM AUTHOR]

Aims Although the focus of therapeutic intervention has been on neurohormonal pathways thought to be harmful in heart failure (HF), such as the renin–angiotensin–aldosterone system (RAAS), potentially beneficial counter-regulatory systems are also active in HF. These promote vasodilatation and natriuresis, inhibit abnormal growth, suppress the RAAS and sympathetic nervous system, and augment parasympathetic activity. The best understood of these mediators are the natriuretic peptides which are metabolized by the enzyme neprilysin. LCZ696 belongs to a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNIs), which both block the RAAS and augment natriuretic peptides. Methods Patients with chronic HF, NYHA class II–IV symptoms, an elevated plasma BNP or NT-proBNP level, and an LVEF of ≤40% were enrolled in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortailty and morbidity in Heart Failure trial (PARADIGM-HF). Patients entered a single-blind enalapril run-in period (titrated to 10 mg b.i.d.), followed by an LCZ696 run-in period (100 mg titrated to 200 mg b.i.d.). A total of 8436 patients tolerating both periods were randomized 1:1 to either enalapril 10 mg b.i.d. or LCZ696 200 mg b.i.d. The primary outcome is the composite of cardiovascular death or HF hospitalization, although the trial is powered to detect a 15% relative risk reduction in cardiovascular death. Perspectives PARADIGM-HF will determine the place of the ARNI LCZ696 as an alternative to enalapril in patients with systolic HF. PARADIGM-HF may change our approach to neurohormonal modulation in HF. Trial registration NCT01035255 [ABSTRACT FROM AUTHOR]

The article provides information on the study "The Angiotensin Receptor Neprilysin Inhibitor LCZ696 in Heart Failure with Preserved Ejection Fraction," by Scott D. Solomon et al. The pharmacologic therapies that have been tested in clinical trials includes beta-blockers, calcium-channel blockers and angiotensin converting enzyme (ACE) inhibitors. The key inclusion and exclusion criteria for the clinical trial are mentioned.

Background Angiotensin-converting-enzyme (ACE) inhibitors improve outcome of patients with chronic heart failure (CHF). A substantial proportion of patients, however, experience no benefit from ACE inhibitors because of previous intolerance. We aimed to find out whether candesartan, an angiotensinreceptor blocker, could improve outcome in such patients not taking an ACE inhibitor. Methods Between March, 1999, and March, 2001, we enrolled 2028 patients with symptomatic heart failure and left-ventricular ejection fraction 40% or less who were not receiving ACE inhibitors because of previous intolerance. Patients were randomly assigned candesartan (target dose 32 mg once daily) or matching placebo. The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF. Analysis was by intention to treat. Findings The most common manifestation of ACE-inhibitor intolerance was cough (72%), followed by symptomatic hypotension (13%) and renal dysfunction (12%). During a median follow-up of 33.7 months, 334 (33%) of 1013 patients in the candesartan group and 406 (40%) of 1015 in the placebo group had cardiovascular death or hospital admission for CHF (unadjusted hazard ratio 0.77 [95% CI 0.67--0.89], p=0.0004; covariate adjusted 0.70 [0.60--0.81], p<0.0001). Each component of the primary outcome was reduced, as was the total number of hospital admissions for CHF. Study-drug discontinuation rates were similar in the candesartan (30%) and placebo (29%) groups. Interpretation Candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic heart failure and intolerance to ACE inhibitors. [ABSTRACT FROM AUTHOR]

Background Angiotensin II type 1 receptor blockers have favourable effects on haemodynamic measurements, neurohumoral activity, and left-ventricular remodelling when added to angiotensin-converting-enzyme (ACE) inhibitors in patients with chronic heart failure (CHF). We aimed to find out whether these drugs improve clinical outcome. Methods Between March, 1999, and November, 1999, we enrolled 2548 patients with New York Heart Association functional class II--IV CHF and left-ventricular ejection fraction 40% or lower, and who were being treated with ACE inhibitors. We randomly assigned patients candesartan (n=1276, target dose 32 mg once daily) or placebo (n=1272). At baseline, 55% of patients were also treated with blockers and 17% with spironolactone. The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF. Analysis was done by intention to treat. Findings The median follow-up was 41 months. 483 (38%) patients in the candesartan group and 538 (42%) in the placebo group experienced the primary outcome (unadjusted hazard ratio 0.85 [95% CI 0.75--0.96], p=0.011; covariate adjusted p=0.010). Candesartan reduced each of the components of the primary outcome significantly, as well as the total number of hospital admissions for CHF. The benefits of candesartan were similar in all predefined subgroups, including patients receiving baseline blocker treatment. Interpretation The addition of candesartan to ACE inhibitor and other treatment leads to a further clinically important reduction in relevant cardiovascular events in patients with CHF and reduced left-ventricular ejection fraction. [ABSTRACT FROM AUTHOR]

Aims We wanted to examine some of the mechanisms by which aspirin might be responsible for counteraction of the effects of ACE inhibitors. Aspirin has been reported to counteract the effects of ACE inhibitors in patients with heart failure. Despite this, there is little evidence on what the mediator of such an effect might be, although there is some evidence to implicate bradykinin and, perhaps, substance P. Methods Twelve patients with congestive heart failure treated with an ACE inhibitor were studied on two occasions, after abstaining from aspirin for 14 days, and after 14 days of aspirin 150 mg once daily. Forearm blood flow was measured by venous occlusion plethysmography during intrabrachial infusions of bradykinin and substance P, before and after intrabrachial aspirin. Results Bradykinin caused profound vasodilation (peak 390%, 95% confidence intervals (CI) 300, 480%; P < 0.01), substance P slightly less (peak 222%, 95% CI 162, 283%; P < 0.01). Intra-brachial aspirin had no effect on its own. The response to bradykinin was unchanged by intrabrachial aspirin (peak 404%, 95% CI 304, 504%) or oral aspirin (peak 320%, 95% CI 209, 431%; P = 0.2). The response to substance P was unchanged by intrabrachial aspirin (peak 226%, 95% CI 171, 281%) or oral aspirin (peak 220%, 95% CI 142, 297%; P = 0.86). Conclusions Aspirin has no effect on the vasodilator response to bradykinin and substance P in patients with heart failure treated with an ACE inhibitor. Neither bradykinin nor substance P is likely to contribute to the reported interaction between aspirin and ACE inhibitors. [ABSTRACT FROM AUTHOR]

The article discusses utilization of implantable cardioverter-defibrillators (ICDs) in management of heart failure. Topics discussed include reduction in premature death by ICDs usage in ventricular systolic dysfunction, involvement of nonischemic cardiomyopathy in patients, usage of angiotensin-converting- enzyme inhibitors along with mineralocorticoid-receptor, description of cardiac-resynchronization therapy for treatment process and implications for reduction in cardiac disease mortality.

Background: Three drug classes (mineralocorticoid receptor antagonists [MRAs], angiotensin receptor-neprilysin inhibitors [ARNIs], and sodium/glucose cotransporter 2 [SGLT2] inhibitors) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF.Methods: In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and β blocker).Findings: The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30-0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 [95% CI 0·37-0·67]), hospital admission for heart failure alone (0·32 [0·24-0·43]), and all-cause mortality (0·53 [0·40-0·70]). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy.Interpretation: Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, β blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard.Funding: None. [ABSTRACT FROM AUTHOR]

In this article the author talks about the study of the renin-angiotensin-aldosterone system (RAAS) which is an elegant cascade of vasoactive peptides that orchestrate key processes in human physiology. Topics discussed Tissue-specific and circulating components of RAAS make up complex intersecting network of regulatory, and switching from a RAAS inhibitor to another antihypertensive therapy in a stable ambulatory patient require careful follow-up to avoid rebound increases in blood pressure.

Background: Many episodes of worsening of heart failure (HF) are treated by increasing oral therapy or temporary intravenous treatment in the community or emergency department (ED), without hospital admission. We studied the frequency and prognostic importance of these episodes of worsening in the Prospective Comparison of ARNI (angiotensin-receptor-neprilysin inhibitor) with ACEI (angiotensin-converting enzyme inhibitor) to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF).Methods and Results: Outpatient intensification of HF therapy was added to an expanded composite outcome with ED visits, HF hospitalizations, and cardiovascular deaths. In an examination of first nonfatal events, 361 of 8399 patients (4.3%) had outpatient intensification of HF therapy without a subsequent event (ie, ED visit/HF hospitalizations) within 30 days; 78 of 8399 (1.0%) had an ED visit without previous outpatient intensification of HF therapy or a subsequent event within 30 days; and 1107 of 8399 (13.2%) had HF hospitalizations without a preceding event. The risk of death (in comparison with no-event patients) was similar after each manifestation of worsening: outpatient intensification of HF therapy (hazard ratio, 4.8; 95% confidence interval, 3.9-5.9); ED visit (hazard ratio, 4.5; 95% confidence interval, 3.0-6.7); HF hospitalizations (hazard ratio, 5.9; 95% confidence interval, 5.2-6.6). The expanded composite added 14% more events and shortened time to accrual of a fixed number of events. The benefit of sacubitril/valsartan over enalapril was similar to the primary outcome for the expanded composite (hazard ratio, 0.79; 95% confidence interval, 0.73-0.86) and was consistent across the components of the latter.Conclusions: Focusing only on HF hospitalizations underestimates the frequency of worsening and the serious implications of all manifestations of worsening. For clinical trials conducted in an era of heightened efforts to avoid HF hospitalizations, inclusion of episodes of outpatient treatment intensification (and ED visits) in a composite outcome adds an important number of events and shortens the time taken to accrue a target number of end points in an event-driven trial.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255. [ABSTRACT FROM AUTHOR]

Background Patients with chronic heart failure (CHF) are at high risk of cardiovascular death and recurrent hospital admissions. We aimed to find out whether the use of an angiotensin- receptor blocker could reduce mortality and morbidity. Methods In parallel, randomised, double-blind, controlled, clinical trials we compared candesartan with placebo in three distinct populations. We studied patients with left-ventricular ejection fraction (LVEF) 40% or less who were not receiving angiotensin-converting-enzyme inhibitors because of previous intolerance or who were currently receiving angiotensinconverting- enzyme inhibitors, and patients with LVEF higher than 40%. Overall, 7601 patients (7599 with data) were randomly assigned candesartan (n=3803, titrated to 32 mg once daily) or matching placebo (n=3796), and followed up for at least 2 years. The primary outcome of the overall programme was all-cause mortality, and for all the component trials was cardiovascular death or hospital admission for CHF. Analysis was by intention to treat. Findings Median follow-up was 37.7 months. 886 (23%) patients in the candesartan and 945 (25%) in the placebo group died (unadjusted hazard ratio 0.91 [95% CI 0.83--1.00], p=0.055; covariate adjusted 0.90 [0.82--0.99], p=0.032), with fewer cardiovascular deaths (691 [18%] vs 769 [20%], unadjusted 0.88 [0.79--0.97], p=0.012; covariate adjusted 0.87 [0.78--0.96], p=0.006) and hospital admissions for CHF (757 [20%] vs 918 [24%], p<0.0001) in the candesartan group. There was no significant heterogeneity for candesartan results across the component trials. More patients discontinued candesartan than placebo because of concerns about renal function, hypotension, and hyperkalaemia. Interpretation Candesartan was generally well tolerated and significantly reduced cardiovascular deaths and hospital admissions for heart failure. Ejection fraction or treatment at baseline did not alter these effects. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Aliskiren, enalapril, or aliskiren and enalapril in heart failure" by John J. V. McMurray, and colleagues in the April 21, 2016 issue.