Differing prognostic value of pulse pressure in patients with heart failure with reduced or preserved ejection fraction: results from the MAGGIC individual patient meta-analysis.

AIMS: Low pulse pressure is a marker of adverse outcome in patients with heart failure (HF) and reduced ejection fraction (HF-REF) but the prognostic value of pulse pressure in patients with HF and preserved ejection fraction (HF-PEF) is unknown. We examined the prognostic value of pulse pressure in patients with HF-PEF [ejection fraction (EF) ≥ 50%] and HF-REF. METHODS AND RESULTS: Data from 22 HF studies were examined. Preserved left ventricular ejection fraction (LVEF) was defined as LVEF ≥ 50%. All-cause mortality at 3 years was evaluated in 27 046 patients: 22 038 with HF-REF (4980 deaths) and 5008 with HF-PEF (828 deaths). Pulse pressure was analysed in quintiles in a multivariable model adjusted for the previously reported Meta-Analysis Global Group in Chronic Heart Failure prognostic variables. Heart failure and reduced ejection fraction patients in the lowest pulse pressure quintile had the highest crude and adjusted mortality risk (adjusted hazard ratio 1.68, 95% confidence interval 1.53-1.84) compared with all other pulse pressure groups. For patients with HF-PEF, higher pulse pressure was associated with the highest crude mortality, a gradient that was eliminated after adjustment for other prognostic variables. CONCLUSION: Lower pulse pressure (especially <53 mmHg) was an independent predictor of mortality in patients with HF-REF, particularly in those with an LVEF < 30% and systolic blood pressure <140 mmHg. Overall, this relationship between pulse pressure and outcome was not consistently observed among patients with HF-PEF.

Heart failure in younger patients: the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC).

AIM: Our understanding of heart failure in younger patients is limited. The Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) database, which consisted of 24 prospective observational studies and 7 randomized trials, was used to investigate the clinical characteristics, treatment, and outcomes of younger patients. METHODS AND RESULTS: Patients were stratified into six age categories: <40 (n = 876), 40-49 (n = 2638), 50-59 (n = 6894), 60-69 (n = 12 071), 70-79 (n = 13 368), and ≥80 years (n = 6079). Of 41 926 patients, 2.1, 8.4, and 24.8% were younger than 40, 50, and 60 years of age, respectively. Comparing young (<40 years) against elderly (≥80 years), younger patients were more likely to be male (71 vs. 48%) and have idiopathic cardiomyopathy (63 vs. 7%). Younger patients reported better New York Heart Association functional class despite more severe left ventricular dysfunction (median ejection fraction: 31 vs. 42%, all P < 0.0001). Comorbidities such as hypertension, myocardial infarction, and atrial fibrillation were much less common in the young. Younger patients received more disease-modifying pharmacological therapy than their older counterparts. Across the younger age groups (<40, 40-49, and 50-59 years), mortality rates were low: 1 year 6.7, 6.6, and 7.5%, respectively; 2 year 11.7, 11.5, 13.0%; and 3 years 16.5, 16.2, 18.2%. Furthermore, 1-, 2-, and 3-year mortality rates increased sharply beyond 60 years and were greatest in the elderly (≥80 years): 28.2, 44.5, and 57.2%, respectively. CONCLUSION: Younger patients with heart failure have different clinical characteristics including different aetiologies, more severe left ventricular dysfunction, and less severe symptoms. Three-year mortality rates are lower for all age groups under 60 years compared with older patients.

Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies.

AIMS: Using a large international database from multiple cohort studies, the aim is to create a generalizable easily used risk score for mortality in patients with heart failure (HF). METHODS AND RESULTS: The MAGGIC meta-analysis includes individual data on 39 372 patients with HF, both reduced and preserved left-ventricular ejection fraction (EF), from 30 cohort studies, six of which were clinical trials. 40.2% of patients died during a median follow-up of 2.5 years. Using multivariable piecewise Poisson regression methods with stepwise variable selection, a final model included 13 highly significant independent predictors of mortality in the following order of predictive strength: age, lower EF, NYHA class, serum creatinine, diabetes, not prescribed beta-blocker, lower systolic BP, lower body mass, time since diagnosis, current smoker, chronic obstructive pulmonary disease, male gender, and not prescribed ACE-inhibitor or angiotensin-receptor blockers. In preserved EF, age was more predictive and systolic BP was less predictive of mortality than in reduced EF. Conversion into an easy-to-use integer risk score identified a very marked gradient in risk, with 3-year mortality rates of 10 and 70% in the bottom quintile and top decile of risk, respectively. CONCLUSION: In patients with HF of both reduced and preserved EF, the influences of readily available predictors of mortality can be quantified in an integer score accessible by an easy-to-use website www.heartfailurerisk.org. The score has the potential for widespread implementation in a clinical setting.

The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities.

The conventional reporting of composite endpoints in clinical trials has an inherent limitation in that it emphasizes each patient's first event, which is often the outcome of lesser clinical importance. To overcome this problem, we introduce the concept of the win ratio for reporting composite endpoints. Patients in the new treatment and control groups are formed into matched pairs based on their risk profiles. Consider a primary composite endpoint, e.g. cardiovascular (CV) death and heart failure hospitalization (HF hosp) in heart failure trials. For each matched pair, the new treatment patient is labelled a 'winner' or a 'loser' depending on who had a CV death first. If that is not known, only then they are labelled a 'winner' or 'loser' depending on who had a HF hosp first. Otherwise they are considered tied. The win ratio is the total number of winners divided by the total numbers of losers. A 95% confidence interval and P-value for the win ratio are readily obtained. If formation of matched pairs is impractical then an alternative win ratio can be obtained by comparing all possible unmatched pairs. This method is illustrated by re-analyses of the EMPHASIS-HF, PARTNER B, and CHARM trials. The win ratio is a new method for reporting composite endpoints, which is easy to use and gives appropriate priority to the more clinically important event, e.g. mortality. We encourage its use in future trial reports.

Days alive and out of hospital and the patient journey in patients with heart failure: Insights from the candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) program.

BACKGROUND: Conventional composite outcomes in heart failure (HF) trials, for example, time to cardiovascular death or first HF hospitalization, have recognized limitations. We propose an alternative outcome, days alive and out of hospital (DAOH), which incorporates mortality and all hospitalizations into a single measure. A refinement, the patient journey, also uses functional status (New York Heart Association [NYHA] class) measured during follow-up. The CHARM program is used to illustrate the methodology. METHODS: CHARM randomized 7,599 patients with symptomatic HF to placebo or candesartan, with median follow-up of 38 months. We related DAOH and percent DAOH (ie, percentage of time spent alive and out of hospital) to treatment using linear regression adjusting for follow-up time. RESULTS: Mean increase in DAOH for patients on candesartan versus placebo was 24.1 days (95% CI 9.8-38.3 days, P < .001). The corresponding mean increase in percent DAOH was 2.0% (95% CI 0.8%-3.1%, P < .001). These findings were dominated by reduced mortality (23 days) but enhanced by reduced time in hospital (1 day). Percent time spent in hospital because of HF was reduced by 0.10% (95% CI 0.04%-0.14%, P < .001). The patient journey analysis showed that patients in the candesartan group spent more follow-up time in NYHA classes I and II and less in NYHA class IV. CONCLUSIONS: Days alive and out of hospital, especially percent DAOH, provide a valuable tool for summarizing the overall absolute treatment effect on mortality and morbidity. In future HF trials, percent DAOH can provide a useful alternative perspective on the effects of treatment.