In ambulatory patients with heart failure (HF) and reduced ejection fraction (rEF), renin-angiotensin system (RAS) and β-blockers at guideline-recommended target dose reduce all-cause mortality and readmissions. Benefits in HF with preserved ejection fraction (pEF), as well as uptitration after a hospitalization, remain uncertain. This study assesses the impact of RAS- and β-blocker uptitrations in patients with HFrEF versus HFpEF during and immediately after a hospital admission. In consecutive patients (209 HFrEF with left ventricular ejection fraction <40% and 108 HFpEF with left ventricular ejection fraction ≥40%), RAS- and β-blocker dose changes were followed during 6 months after an index HF hospitalization. Patients with a RAS- and β-blocker dose increase of ≥10% of the recommended target dose were compared with patients without uptitration. Patients who received uptitration were significantly younger, with a higher heart rate and better renal function, and received spironolactone more often. Both RAS- and β-blocker uptitrations were associated with significant reductions in the composite end-point of all-cause mortality or HF readmissions in HFrEF (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.22 to 0.60 and HR 0.51, 95% CI 0.32 to 0.81, respectively). After correction for age, heart rate, blood pressure, renal function, and spironolactone use, this association remained significant for RAS blockers (HR 0.54, 95% CI 0.31 to 0.93, p = 0.027) but not for β-blockers (HR 0.65, 95% CI 0.39 to 1.09, p = 0.101). No benefit of RAS- or β-blocker uptitration was observed in HFpEF. In conclusion, uptitration of neurohumoral blockers after an HF hospitalization is more frequently performed in younger patients with low co-morbidity burden. RAS-blocker uptitration independently predicts clinical outcome in patients with HFrEF but not in those with HFpEF.
Multiple randomized clinical trials have demonstrated that renin-angiotensin system (RAS) blockers and β-blockers reduce all-cause mortality and heart failure (HF) admissions in “ambulatory” patients with chronic HF and reduced ejection fraction (rEF). However, despite current HF guidelines recommending both medications with the strongest level of evidence, only about 1/3 of patients with HFrEF receive RAS-blockers at the guideline-recommended target dose in clinical practice, and even less patients reach this target dose for β-blockers. Improving adherence to guideline-recommended dosing might be an important strategy to reduce HF morbidity and mortality as cross-sectional studies show an association between RAS- or β-blocker dose and clinical outcome in patients with HFrEF. In contrast, no single pharmacologic treatment has been proved to reduce either mortality or hospital admissions in HF with preserved ejection fraction (pEF). Despite this observation, most patients with HFpEF receive similar drugs compared with those with HFrEF. Interestingly, in a recent large observational HFpEF study, RAS-blocker use was associated with a significant 15% risk reduction of all-cause mortality in patients who took the guideline-recommended dose for HFrEF, whereas no benefit was observed with a lower dose. Importantly, there is a lack of longitudinal data regarding RAS- and β-blocker uptitration in individual patients with HFrEF and HFpEF, especially during and after a HF hospitalization. Therefore, we followed a contemporary cohort of patients with HF—either HFrEF (left ventricular ejection fraction [LVEF] <40%) or HFpEF (LVEF ≥40%)—over time after an index hospitalization during which HF was a primary or secondary diagnosis. We registered dose changes of RAS- and β-blockers serially during a period of 6 months and compared patients who received uptitration with patients who did not. We searched for determinants of non-uptitration and compared clinical outcomes of these patients with those who did receive uptitration.
Methods
In this cohort study, all consecutive patients who were hospitalized from April 2010 to January 2011 at the cardiology department of Ziekenhuis Oost-Limburg (Genk, Belgium) and received a diagnosis of HF were included. Patients who were discharged during the first 24 hours after admission were excluded. The study was conducted in accordance with the Declaration of Helsinki. The locally appointed ethics committee approved the study protocol and waived the need for informed consent as the study was only observational. All investigators had full access to the data and contributed to the writing of the manuscript. Together, they take responsibility for the integrity of the data and agree to the report as written.
For each patient, demographics, clinical data, and medical therapy at the time of admission were collected. Dosages of RAS- and β-blockers were expressed as percentages of the recommended target dose to account for differences between pharmacologic agents. A conversion table is provided as Supplementary Table . Comprehensive 2-dimensional echocardiographic examinations were available for each patient at the time of the index hospitalization and performed by experienced sonographers using a commercially available system (iE33, Philips Healthcare, Eindhoven, The Netherlands). Images were acquired in left lateral decubitus position, triggered to QRS complex, and digitally stored in cine loops in DICOM format. For study purpose, a single experienced investigator, who was blinded to clinical data, reanalyzed the images off-line. LVEF was obtained by Simpson’s biplane or Teicholz method, as recommended by the American Society of Echocardiography. Mitral valve regurgitation was semiquantitatively assessed by color Doppler flow mapping. Serum creatinine levels at the time of admission were available in all patients, and glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration formula. Baseline plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) was available in 177 patients (56%).
The study population was stratified into 2 groups: patients with LVEF <40% at the moment of their index hospitalization were classified as HFrEF and patients with LVEF ≥40% were considered to have HFpEF. Dosages of RAS- and β-blockers were again collected in all patients at discharge and after 6 months of follow-up. If the patient had died (n = 14) or was lost to follow-up (n = 12), then the last observation available was used. RAS- and β-blocker uptitrations were defined as a dose increase of ≥10% of the recommended target dose after 6 months. Patients who were already treated at the recommended target dose at the moment of inclusion and continued to receive this dose after 6 months were considered to be in the uptitration group. The prespecified primary study end-point was a composite of death or HF admission during follow-up starting at discharge from the hospital. Secondary end-points were the separate components of the primary end-point. A HF admission was defined as a hospitalization for ≥24 hours because of dyspnea, signs of systemic congestion, or low cardiac output during which diuretics, inotropes, and/or intravenous vasodilators were administered.
Continuous variables are expressed as mean ± SD, if normally distributed, or otherwise by median (interquartile range). Normality was assessed by the Shapiro-Wilk statistic. Data were compared using the independent samples Student t -test or Mann-Whitney U test, when appropriate. Categorical data are expressed as percentages and were compared with the Pearson chi-square test. Statistical significance was set at a 2-tailed probability level of <0.05. Cumulative actuarial survival rates were calculated according to the Kaplan-Meier method, and the groups were compared with the log-rank test. The Cox proportional hazards model was used to calculate the hazard ratio with corresponding 95% confidence interval for the primary and secondary end-points. Baseline characteristics with a statistically significant different distribution between groups were entered as covariates. All statistical analyses were performed using IBM SPSS (version 20.0, IBM Corporation, Somers, New York) for Windows.
Results
During the study period, 354 patients received a diagnosis of HF while being admitted at the study tertiary care center (Ziekenhuis Oost-Limburg, Genk, Belgium). Thirty-six patients were excluded because they were not hospitalized for ≥24 hours. One patient was excluded because LVEF could not be reliably assessed. The remainder of patients formed the study population (n = 317) and were admitted for a median (interquartile range) of 5 days (3 to 9) during their index hospitalization. The reason of the index hospitalization was a primary diagnosis of acute decompensated HF in 49% patients. Another 34% of patients were electively admitted for advanced HF therapy (e.g., placement of a cardiac device, performance of a catheterization procedure). Finally, in the remaining patients, HF was a secondary diagnosis with the primary diagnosis being an acute coronary syndrome in 7%, arrhythmia in 4%, or a miscellaneous reason in 6%. Baseline characteristics of the study population are listed in Table 1 . Prescribed dosages of neurohumoral blockers at baseline, hospital discharge, and after 6 months of follow-up are presented in Figure 1 . During the course of the study, 102 patients (32%) received a device for cardiac resynchronization therapy (CRT). The proportion of patients receiving CRT was similar in patients with versus without RAS-blocker uptitration (34% vs 30%, respectively, p = 0.520), but more patients who were uptitrated with β-blockers received CRT (37% vs 24% in patients who were not uptitrated, p = 0.014).
