International differences in clinical characteristics, management, and outcomes in acute heart failure patients: better short-term outcomes in patients enrolled in Eastern Europe and Russia in the PROTECT trial

Abstract

Aims: The implications of geographical variation are unknown following adjustment for hospital length of stay (LOS) in heart failure (HF) trials that included patients whether or not they had systolic dysfunction. We investigated regional differences in an international acute HF trial.

Methods and results: The PROTECT trial investigated 2033 patients with acute HF and renal dysfunction hospitalized at 173 sites in 17 countries with randomization to rolofylline or placebo. We grouped enrolling countries into six regions. Baseline characteristics, in-hospital management, and outcomes were explored by region. The primary study outcome was 60-day mortality or cardiovascular/renal hospitalization. Secondary outcomes included 180-day mortality. Of 2033 patients, 33% were from Eastern Europe, 19% from Western Europe, 16% from Israel, 15% from North America, 14% from Russia, and 3% from Argentina. Marked differences in baseline characteristics, HF phenotype, in-hospital diuretic and vasodilator strategies, and LOS were observed by region. LOS was shortest in North America and Israel (median 5 days) and longest in Russia (median 15 days). Regional event rates varied significantly. Following multivariable adjustment, region was an independent predictor of the risk of mortality/hospitalization at 60 days, with the lowest risk in Russia (hazard ratio 0.39, 95% confidence interval 0.23-0.64 vs. Western Europe) due to lower rehospitalization; mortality differences were attenuated by 180 days.

Conclusions: In an international HF trial, there were differences in baseline characteristics, treatments, LOS, and rehospitalization amongst regions, but little difference in longer term mortality. Rehospitalization differences exist independent of LOS. This analysis may help inform future trial design and should be externally validated.

Keywords: Acute heart failure; Global variation; Length of stay; Outcomes; Regional differences; Trial.

Conflict of interest statement

Conflict of interest: M.M. and B.M.M. have received honoraria and reimbursements from NovaCardia, sponsors of the study, and from Merck, which purchased the rights to rolofylline after completion of the PROTECT pilot study. B.A.D. and G.D. are employees of Momentum Research Inc., which was contracted to perform work on the project by Merck. J.G.F.C. was on the Steering Committee for the study, served on the advisory board for MSD, and received payments for both. J.R.T. has received research funds and consulting fees from Merck and has also received research funds and consulting fees from Abbott, Amgen, Biogen Idec, Corthera, Cytokinetics, Johnson & Johnson/Scios, Novartis, Relypsa, and Solvay for research in related areas. A.A.V. has received speaker and consultancy fees from Merck. D.M.B. is an employee of Merck. M.M.G. has received institutional research support and served on a scientific Advisory Board for Merck. P.P. has received honoraria from Merck, consulting fees from Vifor Pharma and Amgen, Inc., honoraria from Vifor Pharma, and travel/accommodation expenses covered by Vifor Pharma and Amgen, Inc. C.M.O. is a consultant to Merck and Amgen. All other authors have no conflicts of interest to declare.

© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.

Figures

Figure 1

Medication changes from 2 weeks prior to admission to discharge/day 7 based on region for (A) ACE inhibitors/ARBs, (B) beta-blockers, and (C) mineralocorticoid receptor antagonists (MRAs). Continued, continued use at discharge/day 7 in patients taking prior to admission; Started, use at discharge/day 7 in those not taking prior to admission; Discontinued, stopped by discharge/day 7 in those taking prior to admission; Never received, not taking at discharge/day day 7 in patients who were also not taking prior to admission.

Figure 2

Unadjusted time to event for (A) death or cardiovascular/renal rehospitalization and (B) death or all-cause hospitalization up to 60 days and (C) all-cause mortality up to 180 days by region.