Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study

Objectives To investigate the cardiovascular safety of non-steroidal anti-inflammatory drugs (NSAIDs) and estimate the risk of hospital admission for heart failure with use of individual NSAIDs.

Design Nested case-control study.

Setting Five population based healthcare databases from four European countries (the Netherlands, Italy, Germany, and the United Kingdom).

Participants Adult individuals (age ≥18 years) who started NSAID treatment in 2000-10. Overall, 92 163 hospital admissions for heart failure were identified and matched with 8 246 403 controls (matched via risk set sampling according to age, sex, year of cohort entry).

Main outcome measure Association between risk of hospital admission for heart failure and use of 27 individual NSAIDs, including 23 traditional NSAIDs and four selective COX 2 inhibitors. Associations were assessed by multivariable conditional logistic regression models. The dose-response relation between NSAID use and heart failure risk was also assessed.

Results Current use of any NSAID (use in preceding 14 days) was found to be associated with a 19% increase of risk of hospital admission for heart failure (adjusted odds ratio 1.19; 95% confidence interval 1.17 to 1.22), compared with past use of any NSAIDs (use >183 days in the past). Risk of admission for heart failure increased for seven traditional NSAIDs (diclofenac, ibuprofen, indomethacin, ketorolac, naproxen, nimesulide, and piroxicam) and two COX 2 inhibitors (etoricoxib and rofecoxib). Odds ratios ranged from 1.16 (95% confidence interval 1.07 to 1.27) for naproxen to 1.83 (1.66 to 2.02) for ketorolac. Risk of heart failure doubled for diclofenac, etoricoxib, indomethacin, piroxicam, and rofecoxib used at very high doses (≥2 defined daily dose equivalents), although some confidence intervals were wide. Even medium doses (0.9-1.2 defined daily dose equivalents) of indomethacin and etoricoxib were associated with increased risk. There was no evidence that celecoxib increased the risk of admission for heart failure at commonly used doses.

Conclusions The risk of hospital admission for heart failure associated with current use of NSAIDs appears to vary between individual NSAIDs, and this effect is dose dependent. This risk is associated with the use of a large number of individual NSAIDs reported by this study, which could help to inform both clinicians and health regulators.

BMJ 2016;354:i4857

Diabetes treatments and risk of heart failure, cardiovascular disease, and all cause mortality: cohort study in primary care

Objective To assess associations between risks of cardiovascular disease, heart failure, and all cause mortality and different diabetes drugs in people with type 2 diabetes, particularly newer agents, including gliptins and thiazolidinediones (glitazones).

Design Open cohort study.

Setting 1243 general practices contributing data to the QResearch database in England.

Participants 469 688 people with type 2 diabetes aged 25-84 years between 1 April 2007 and 31 January 2015.

Exposures Diabetes drugs (glitazones, gliptins, metformin, sulphonylureas, insulin, other) alone and in combination.

Main outcome measure First recorded diagnoses of cardiovascular disease, heart failure, and all cause mortality recorded on the patients’ primary care, mortality, or hospital record. Cox proportional hazards models were used to estimate hazard ratios for diabetes treatments, adjusting for potential confounders.

Results During follow-up, 21 308 patients (4.5%) received prescriptions for glitazones and 32 533 (6.9%) received prescriptions for gliptins. Compared with non-use, gliptins were significantly associated with an 18% decreased risk of all cause mortality, a 14% decreased risk of heart failure, and no significant change in risk of cardiovascular disease; corresponding values for glitazones were significantly decreased risks of 23% for all cause mortality, 26% for heart failure, and 25% for cardiovascular disease. Compared with no current treatment, there were no significant associations between monotherapy with gliptins and risk of any complications. Dual treatment with gliptins and metformin was associated with a decreased risk of all three outcomes (reductions of 38% for heart failure, 33% for cardiovascular disease, and 48% for all cause mortality). Triple treatment with metformin, sulphonylureas, and gliptins was associated with a decreased risk of all three outcomes (reductions of 40% for heart failure, 30% for cardiovascular disease, and 51% for all cause mortality). Compared with no current treatment, monotherapy with glitazone was associated with a 50% decreased risk of heart failure, and dual treatment with glitazones and metformin was associated with a decreased risk of all three outcomes (reductions of 50% for heart failure, 54% for cardiovascular disease, and 45% for all cause mortality); dual treatment with glitazones and sulphonylureas was associated with risk reductions of 35% for heart failure and 25% for cardiovascular disease; triple treatment with metformin, sulphonylureas, and glitazones was associated with decreased risks of all three outcomes (reductions of 46% for heart failure, 41% for cardiovascular disease, and 56% for all cause mortality).

Conclusions There are clinically important differences in risk of cardiovascular disease, heart failure, and all cause mortality between different diabetes drugs alone and in combination. Overall, use of gliptins or glitazones was associated with decreased risks of heart failure, cardiovascular disease, and all cause mortality compared with non-use of these drugs. These results, which do not account for levels of adherence or dosage information and which are subject to confounding by indication, might have implications for prescribing of diabetes drugs.

BMJ 2016;354:i3477

Effect of Escitalopram on All-Cause Mortality and Hospitalization in Patients With Heart Failure and Depression The MOOD-HF Randomized Clinical Trial

Importance  Depression is frequent in patients with heart failure and is associated with adverse clinical outcomes. Long-term efficacy and safety of selective serotonin reuptake inhibitors in these patients are unknown.

Objective  To determine whether 24 months of treatment with escitalopram improves mortality, morbidity, and mood in patients with chronic systolic heart failure and depression.

Design, Setting, and Participants  The Effects of Selective Serotonin Re-Uptake Inhibition on Morbidity, Mortality, and Mood in Depressed Heart Failure Patients (MOOD-HF) study was a double-blind, placebo-controlled randomized clinical trial conducted at 16 tertiary medical centers in Germany. Between March 2009 and February 2014, patients at outpatient clinics with New York Heart Association class II-IV heart failure and reduced left ventricular ejection fraction (<45%) were screened for depression using the 9-item Patient Health Questionnaire. Patients with suspected depression were then invited to undergo a Structured Clinical Interview based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) to establish the diagnosis.

Interventions  Patients were randomized 1:1 to receive escitalopram (10-20 mg) or matching placebo in addition to optimal heart failure therapy. Study duration was 24 months.

Main Outcomes and Measures  The composite primary outcome was time to all-cause death or hospitalization. Prespecified secondary outcomes included safety and depression severity at 12 weeks of treatment (including the titration period), which were determined using the 10-item Montgomery-Åsberg Depression Rating Scale (total possible score, 0 to 60; higher scores indicate more severe depression).

Results  A total of 372 patients (mean age, 62 years; 24% female) were randomized and had taken at least 1 dose of study medication when the data and safety monitoring committee recommended the trial be stopped early. During a median participation time of 18.4 months (n = 185) for the escitalopram group and 18.7 months (n = 187) for the placebo group, the primary outcome of death or hospitalization occurred in 116 (63%) patients and 119 (64%) patients, respectively (hazard ratio, 0.99 [95% CI, 0.76 to 1.27]; P = .92). The mean Montgomery-Åsberg Depression Rating Scale sum score changed from 20.2 at baseline to 11.2 at 12 weeks in the escitalopram group and from 21.4 to 12.5 in the placebo group (between-group difference, −0.9 [95% CI,−2.6 to 0.7]; P = .26). Safety parameters were comparable between groups.

Conclusions and Relevance  In patients with chronic heart failure with reduced ejection fraction and depression, 18 months of treatment with escitalopram compared with placebo did not significantly reduce all-cause mortality or hospitalization, and there was no significant improvement in depression. These findings do not support the use of escitalopram in patients with chronic systolic heart failure and depression.

Trial Registration Identifier: ISRCTN33128015

JAMA. 2016;315(24):2683-2693.

Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure


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.


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.


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).


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 number,NCT00853658.)

Effect of age and sex on efficacy and tolerability of β blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis

Objectives To determine the efficacy and tolerability of β blockers in a broad age range of women and men with heart failure with reduced ejection fraction (HFrEF) by pooling individual patient data from placebo controlled randomised trials.

Design Prospectively designed meta-analysis of individual patient data from patients aged 40-85 in sinus rhythm at baseline, with left ventricular ejection fraction <0.45.

Participants 13 833 patients from 11 trials; median age 64; 24% women.

Main outcome measures The primary outcome was all cause mortality; the major secondary outcome was admission to hospital for heart failure. Analysis was by intention to treat with an adjusted one stage Cox proportional hazards model.

Results Compared with placebo, β blockers were effective in reducing mortality across all ages: hazard ratios were 0.66 (95% confidence interval 0.53 to 0.83) for the first quarter of age distribution (median age 50); 0.71 (0.58 to 0.87) for the second quarter (median age 60); 0.65 (0.53 to 0.78) for the third quarter (median age 68); and 0.77 (0.64 to 0.92) for the fourth quarter (median age 75). There was no significant interaction when age was modelled continuously (P=0.1), and the absolute reduction in mortality was 4.3% over a median follow-up of 1.3 years (number needed to treat 23). Admission to hospital for heart failure was significantly reduced by β blockers, although this effect was attenuated at older ages (interaction P=0.05). There was no evidence of an interaction between treatment effect and sex in any age group. Drug discontinuation was similar regardless of treatment allocation, age, or sex (14.4% in those give β blockers, 15.6% in those receiving placebo).

Conclusion Irrespective of age or sex, patients with HFrEF in sinus rhythm should receive β blockers to reduce the risk of death and admission to hospital.

BMJ 2016;353:i1855

A Multicenter Observational Study of Incretin-based Drugs and Heart Failure


There is concern that antidiabetic incretin-based drugs, including dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues, can increase the risk of heart failure. Ongoing clinical trials may not have large enough samples to effectively address this issue.


We applied a common protocol in the analysis of multiple cohorts of patients with diabetes. We used health care data from four Canadian provinces, the United States, and the United Kingdom. With the use of a nested case–control analysis, we matched each patient who was hospitalized for heart failure with up to 20 controls from the same cohort; matching was based on sex, age, cohort-entry date, duration of treated diabetes, and follow-up time. Cohort-specific hazard ratios for hospitalization due to heart failure among patients receiving incretin-based drugs, as compared with those receiving oral antidiabetic-drug combinations, were estimated by means of conditional logistic regression and pooled across cohorts with the use of random-effects models.


The cohorts included a total of 1,499,650 patients, with 29,741 hospitalized for heart failure (incidence rate, 9.2 events per 1000 persons per year). The rate of hospitalization for heart failure did not increase with the use of incretin-based drugs as compared with oral antidiabetic-drug combinations among patients with a history of heart failure (hazard ratio, 0.86; 95% confidence interval [CI], 0.62 to 1.19) or among those without a history of heart failure (hazard ratio, 0.82; 95% CI, 0.67 to 1.00). The results were similar for DPP-4 inhibitors and GLP-1 analogues.


In this analysis of data from large cohorts of patients with diabetes, incretin-based drugs were not associated with an increased risk of hospitalization for heart failure, as compared with commonly used combinations of oral antidiabetic drugs. (Funded by the Canadian Institutes of Health Research; number,NCT02456428.)

By Kristian B. Filion et al, N Engl J Med 2016; 374:1145-1154March 24, 2016

Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies

Objectives To examine the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of heart failure or hospital admission for heart failure in patients with type 2 diabetes.

Design Systematic review and meta-analysis of randomised and observational studies.

Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, and searched up to 25 June 2015, and communication with experts.

Eligibility criteria Randomised controlled trials, non-randomised controlled trials, cohort studies, and case-control studies that compared DPP-4 inhibitors against placebo, lifestyle modification, or active antidiabetic drugs in adults with type 2 diabetes, and explicitly reported the outcome of heart failure or hospital admission for heart failure.

Data collection and analysis Teams of paired reviewers independently screened for eligible studies, assessed risk of bias, and extracted data using standardised, pilot tested forms. Data from trials and observational studies were pooled separately; quality of evidence was assessed by the GRADE approach.

Results Eligible studies included 43 trials (n=68 775) and 12 observational studies (nine cohort studies, three nested case-control studies; n=1 777 358). Pooling of 38 trials reporting heart failure provided low quality evidence for a possible similar risk of heart failure between DPP-4 inhibitor use versus control (42/15 701 v33/12 591; odds ratio 0.97 (95% confidence interval 0.61 to 1.56); risk difference 2 fewer (19 fewer to 28 more) events per 1000 patients with type 2 diabetes over five years). The observational studies provided effect estimates generally consistent with trial findings, but with very low quality evidence. Pooling of the five trials reporting admission for heart failure provided moderate quality evidence for an increased risk in patients treated with DPP-4 inhibitors versus control (622/18 554 v 552/18 474; 1.13 (1.00 to 1.26); 8 more (0 more to 16 more)). The pooling of adjusted estimates from observational studies similarly suggested (with very low quality evidence) a possible increased risk of admission for heart failure (adjusted odds ratio 1.41, 95% confidence interval 0.95 to 2.09) in patients treated with DPP-4 inhibitors (exclusively sitagliptin) versus no use.

Conclusions The relative effect of DPP-4 inhibitors on the risk of heart failure in patients with type 2 diabetes is uncertain, given the relatively short follow-up and low quality of evidence. Both randomised controlled trials and observational studies, however, suggest that these drugs may increase the risk of hospital admission for heart failure in those patients with existing cardiovascular diseases or multiple risk factors for vascular diseases, compared with no use.

By Ling Li et al, BMJ 2016;352:i610