Abstract
Background
Right ventricular ejection fraction (RVEF) <20% is an independent predictor of poor outcomes in patients with advanced chronic systolic heart failure (HF). The aim of this study was to examine if the adverse effect of abnormally reduced RVEF varies by the receipt of beta-blockers.
Methods
In the Beta-Blocker Evaluation of Survival Trial (BEST), 2708 patients with chronic advanced HF and left ventricular ejection fraction <35%, receiving standard background therapy with renin-angiotensin inhibition, digoxin, and diuretics, were randomized to receive bucindolol or placebo. Of these 2008 had data on baseline RVEF, and 14% (146/1017) and 13% (125/991) of the patients receiving bucindolol and placebo respectively had RVEF <20%.
Results
Among patients in the placebo group, all-cause mortality occurred in 33% and 43% of patients with RVEF ≥20% and <20% respectively (unadjusted hazard ratios {HR}, 1.33; 95% confidence intervals {CI}, 0.99–1.78; p =0.055 and adjusted HR, 0.99; 95% CI, 0.71–1.37; p =0.934). Among those receiving bucindolol, all-cause mortality occurred in 28% and 49% of patients with RVEF ≥20% and <20% respectively (unadjusted HR, 2.15; 95% CI, 1.65–2.80; p <0.001 and adjusted HR, 1.50; 95% CI, 1.08–2.07; p =0.016). These differences were statistically significant (unadjusted and adjusted p for interaction, 0.016 and 0.053 respectively).
Conclusions
In ambulatory patients with chronic advanced systolic HF receiving renin-angiotensin inhibition, digoxin, and diuretics, RVEF <20% had no intrinsic association with mortality. However, in those receiving additional therapy with bucindolol, RVEF <20% had a significant independent association with increased risk of mortality.
Keywords: Heart failure, Right ventricle, Bucindolol, Mortality, Morbidity
1. Introduction
Right ventricular ejection fraction (RVEF) is a powerful predictor of mortality and morbidity in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF) [1–4]. Beta-blockers are commonly used in patients with systolic HF and low RVEF is also common in these patients. However, the effect of beta-blockers on RV failure is not clearly understood and preliminary data from studies of idiopathic pulmonary hypertension suggest that it may be detrimental [5–7]. Similarly, it is also unknown if the deleterious effect of low RVEF on outcomes in patients with systolic HF would vary between patients receiving and not receiving beta-blockers. Therefore, the purpose of the current study was to determine if the effect of low RVEF on outcome would vary between patients receiving bucindolol versus placebo.
2. Methods
2.1. Study design
The Beta-Blocker Evaluation of Survival Trial (BEST) was a randomized clinical trial of bucindolol in HF and was sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and the Department of Veterans Affairs Cooperative Studies Program. The rationale, design and results of the BEST have been previously reported [8, 9]. Briefly, 2708 patients with advanced chronic HF were recruited from 90 clinical sites in the United States and Canada between May 1995 and December 1998, randomly assigned to receive either bucindolol or placebo, and followed for a mean duration of 24 months. The institutional review board of each site approved the protocol and all patients gave written informed consent. We obtained a public-use copy of the BEST dataset from the NHLBI. All but one participant consented to be included in the public-use copy of the database used for the current analysis.
2.2. Patients
All BEST participants had LVEF ≤35% and had New York Heart Association (NYHA) functional class III (92%) or IV (8%) symptoms. They had HF for a mean of 49 months, and most were receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (>90%), diuretics (>90%) and digoxin (>90%).
2.3. Estimation of LVEF and RVEF
Data on baseline LVEF and RVEF were collected before randomization by gated-equilibrium radionuclide ventriculography using standard techniques at each of the sites. If a patient did not have a LVEF and RVEF by radionuclide ventriculography at a BEST site during the 60 days before randomization, a study was performed at the time of randomization. For quality control purposes, the first two examinations at each site were sent for re-reading at a core laboratory. Thereafter, a random sample of 5% of all the examinations was sent to the core laboratory for quality control. Valid measurements of RVEF were available for 2008 patients. Of these, 991 patients were in the placebo group and 1017 were in the bucindolol group.
2.4. Definition of low RVEF
Based on our initial observation of a significant independent association between RVEF <20% and poor outcomes in HF, we defined markedly abnormal RVEF as RVEF <20% [4]. Although a RVEF of ≥40% is considered normal by gated-equilibrium radionuclide ventriculography [10, 11], because adjusted outcomes in those with RVEF 20–39% were similar to those with RVEF ≥40%, we used RVEF ≥20% as the reference category. Among the 991 patients in the placebo group, 13% and 87% had RVEF <20% and ≥20% respectively, and among the 1017 patients in the bucindolol group, 14% and 86% had RVEF <20% and ≥20% respectively.
2.5. Study outcomes
The primary outcome for the current analysis was all-cause mortality, which was also the primary outcome in BEST. Our secondary outcomes were cardiovascular and HF mortality, sudden cardiac death, and all-cause hospitalization and HF hospitalization.
2.6. Statistical analysis
For descriptive analyses, we used Pearson’s chi-square test and student’s t test as appropriate, to compare baseline characteristics between RVEF ≥20% and RVEF <20% groups, separately for patients in the bucindolol and placebo groups. Kaplan-Meier plots and a stepwise multivariable Cox proportional hazard models were used to estimate associations between RVEF <20% (vs. RVEF ≥20%) and all-cause mortality, separately for bucindolol and placebo patients, formally checking for first-order interactions. Variables were entered into the model in multiple steps in the following order: step 1 (unadjusted: RVEF <20% alone), and step 2 (step 1 plus LVEF), step 3 (step 2 plus demographics), step 4 (step 3 plus medical history), step 5 (step 4 plus medications), step 6 (step 5 plus clinical findings), and step 7 (step 6 plus laboratory findings). Similar models were used for other outcomes. Subgroup analyses were conducted to determine the homogeneity of the association of RVEF <20% (versus ≥40%) with all-cause mortality. All statistical tests were evaluated using two-tailed 95% confidence levels and tests with p-value <0.05 were considered significant. Data analyses were performed using SPSS for Windows, Rel. 15. 2009. Chicago: SPSS Inc.
3. Results
3.1. Baseline characteristics
Overall, patients had a mean age of 60 (±12) years, 21% were women and 21% were African-Americans. Demographics of patients in the placebo and bucindolol groups are displayed in Table 1. In general, compared to patients with RVEF ≥20%, those with RVEF <20% had lower mean systolic blood pressure and LVEF. Although patients with RVEF <20% did not have a higher comorbidity burden, they had a higher burden of symptoms and disease severity (Table 1).
Table 1.
Baseline patient characteristics by right ventricular ejection fraction (RVEF) <20% and ≥20% in patients randomized to receive placebo or bucindolol
| Placebo | Bucindolol | ||||||
|---|---|---|---|---|---|---|---|
| n (%) or mean (±SD) | RVEF ≥20 (n=866) |
RVEF <20 (n=125) |
p value |
RVEF ≥20 (n=871) |
RVEF <20 (n=146) |
p value |
|
| Age, years | 61 (±12) | 58 (±12) | 0.004 | 60 (±12) | 59 (±14) | 0.135 | |
| Female | 194 (22) | 19 (15) | 0.067 | 182 (21) | 19 (13) | 0.027 | |
| African American | 168 (19) | 34 (27) | 0.043 | 172 (20) | 54 (37) | <0.001 | |
| Current smoker | 139 (16) | 12 (10) | 0.061 | 164 (19) | 25 (17) | 0.624 | |
| Smoking, pack-year | 21 (±18) | 20 (±17) | 0.734 | 22 (±18) | 22 (±18) | 0.825 | |
| Body mass index, kilogram/m2 | 37 (±8) | 36 (±8) | 0.677 | 37 (±8) | 35 (±8) | 0.100 | |
| New York Heart Association class III | 789 (91) | 108 (86) | 0.093 | 810 (93) | 121 (83) | <0.001 | |
| Duration of heart failure, months | 51 (±49) | 51 (±55) | 0.848 | 48 (±48) | 50 (±44) | 0.567 | |
| Past medical history | |||||||
| Coronary artery disease | 518 (60) | 78 (62) | 0.581 | 519 (60) | 83 (57) | 0.533 | |
| Angina pectoris | 462 (53) | 58 (46) | 0.146 | 445 (51) | 76 (52) | 0.829 | |
| Hypertension | 496 (57) | 79 (63) | 0.210 | 497 (57) | 86 (59) | 0.677 | |
| Atrial fibrillation | 216 (25) | 27 (22) | 0.417 | 216 (25) | 30 (21) | 0.267 | |
| Ventricular fibrillation | 90 (10) | 9 (7) | 0.266 | 93 (11) | 14 (10) | 0.692 | |
| Pacemaker | 88 (10) | 11 (9) | 0.635 | 70 (8) | 13 (9) | 0.723 | |
| Diabetes mellitus | 287 (33) | 49 (39) | 0.181 | 311 (36) | 54 (37) | 0.765 | |
| Chronic kidney disease | 316 (37) | 50 (40) | 0.447 | 340 (39) | 57 (39) | 0.999 | |
| Hyperlipidemia | 373 (43) | 48 (38) | 0.323 | 387 (44) | 61 (42) | 0.550 | |
| Peripheral arterial disease | 156 (18) | 14 (11) | 0.059 | 145 (17) | 21 (14) | 0.493 | |
| Clinical findings | |||||||
| Heart rate per minute | 81 (±13) | 86 (±13) | <0.001 | 81 (±13) | 88 (±14) | <0.001 | |
| Systolic blood pressure, mm Hg | 118 (±18) | 114 (±17) | 0.023 | 117 (±18) | 111 (±18) | <0.001 | |
| Diastolic blood pressure, mm Hg | 70 (±11) | 73 (±10) | 0.010 | 71 (±11) | 71 (±11) | 0.801 | |
| Jugular venous distension | 403 (47) | 74 (59) | 0.008 | 399 (46) | 82 (56) | 0.020 | |
| Third heart sound | 380 (44) | 70 (76) | 0.011 | 385 (44) | 84 (58) | 0.003 | |
| Pulmonary râles | 132 (15) | 23 (18) | 0.364 | 123 (14) | 28 (19) | 0.112 | |
| Hepatomegaly | 100 (12) | 28 (22) | 0.001 | 99 (11) | 29 (20) | 0.004 | |
| Medications | |||||||
| ACE inhibitors | 835 (96) | 117 (94) | 0.130 | 838 (96) | 141 (97) | 0.830 | |
| Digitalis | 795 (92) | 119 (95) | 0.185 | 811 (93) | 139 (95) | 0.345 | |
| Diuretics | 804 (93) | 120 (96) | 0.188 | 811 (93) | 142 (97) | 0.056 | |
| Vasodilators | 411 (48) | 60 (48) | 0.910 | 384 (44) | 67 (46) | 0.685 | |
| Anti-coagulants | 513 (59) | 73 (58) | 0.859 | 510 (59) | 90 (62) | 0.482 | |
| Anti-arrhythmic drugs | 18 (2) | 5 (4) | 0.182 | 30 (3) | 5 (3) | 0.990 | |
| Aspirin | 398 (46) | 45 (36) | 0.036 | 388 (45) | 58 (40) | 0.277 | |
| Statins | 205 (24) | 25 (20) | 0.363 | 201 (23) | 28 (19) | 0.297 | |
| Laboratory values | |||||||
| Creatinine, mg/dL | 1.2 (±0.4) | 1.3 (±0.4) | 0.021 | 1.2 (±0.4) | 1.3 (±0.4) | 0.015 | |
| Uric acid, mg/dL | 8.0 (±2.3) | 9.3 (±2.5) | <0.001 | 8.1 (±2.4) | 9.2 (±2.8) | <0.001 | |
| Cholesterol, mg/dL | 196 (±47) | 183 (±44) | 0.005 | 195 (±53) | 185 (±47) | 0.033 | |
| Triglyceride, mg/dL | 222 (±202) | 162 (±112) | 0.001 | 221 (±326) | 166 (±150) | 0.043 | |
| Albumin, g/dL | 4.1 (±0.4) | 4.0 (±0.5) | 0.025 | 4.1 (±0.4) | 4.0 (±0.5) | 0.004 | |
| Norepinephrine, pg/mL | 494 (±267) | 577 (±320) | 0.002 | 501 (±247) | 666 (±484) | <0.001 | |
| Hemoglobin, g/dL | 14.0 (±1.6) | 14.2 (±1.6) | 0.201 | 14.0 (±1.7) | 14.0 (±1.8) | 0.764 | |
| Pulmonary edema by chest x-ray | |||||||
| Current | 26 (3) | 6 (5) | 0.035 | 20 (2) | 9 (6) | <0.001 | |
| Past | 60 (7) | 16 (13) | 59 (7) | 34 (23) | |||
| Never | 780 (90) | 103 (82) | 792 (91) | 103 (71) | |||
| Cardiothoracic ratio by chest x-ray | 55 (±7.1) | 58 (±6.8) | <0.001 | 55 (±7.0) | 59 (±6.7) | <0.001 | |
| Multiple-gated nuclear scan | |||||||
| Left ventricular ejection fraction, % | 24 (±7) | 17 (±6) | <0.001 | 23 (±7) | 16 (±6) | <0.001 | |
| Right ventricular ejection fraction, % | 38 (±12) | 14 (±3) | <0.001 | 38 (±12) | 14 (±3) | <0.001 | |
ACE=angiotensin converting enzyme
3.2. Low RVEF and mortality in patients receiving placebo
Among patients in the placebo group, all-cause mortality occurred in 33% and 43% of patients with RVEF ≥20% and <20% respectively (unadjusted hazard ratio {HR}, 1.33; 95% confidence interval {CI}, 0.99–1.78; p=0.055 and adjusted HR, 0.99; 95% CI, 0.71–1.37; p=0.934; Table 2 and Figure 1a). When RVEF was used as a continuous variable, each unit increase in RVEF was associated with a 1% reduction in the risk of total mortality (unadjusted HR, 0.99; 95% CI, 0.98– 0.996; p=0.003), which lost significance after multivariable adjustment (adjusted HR, 1.00; 95% CI, 0.99–1.01; p=0.636; data not shown). Associations of RVEF <20% with cause-specific mortalities among placebo patients are displayed in Table 3.
Table 2.
Associations of right ventricular ejection fraction (RVEF) <20% (versus ≥20%) with all-cause mortality among patients randomized to receive placebo or bucindolol
| Placebo (n=991) | Bucindolol (n=1017) | ||||
|---|---|---|---|---|---|
| RVEF ≥20% (n=866) |
RVEF <20% (n=125) |
RVEF ≥20% (n=871) |
RVEF <20% (n=146) |
Interaction p value |
|
| All-cause mortality (%) | 33% | 43% | 28% | 49% | |
| Step 1:Unadjusted | 1.00 (Reference) |
1.33 (0.99–1.78); p =0.055 |
1.00 (Reference) |
2.15 (1.65–2.80) p <0.001 |
0.016 |
| Step 2: Step 1 + LVEF* | 1.00 (Reference) |
1.06 (0.78–1.43); p =0.722 |
1.00 (Reference) |
1.73 (1.30–2.30) p =0.001 |
|
| Step 3: Step 2 + demographics** | 1.00 (Reference) |
1.13 (0.83–1.53); p =0.436 |
1.00 (Reference) |
1.80 (1.34–2.42) p <0.001 |
|
| Step 4: Step 3 + medical history*** | 1.00 (Reference) |
1.06 (0.77–1.45); p =0.721 |
1.00 (Reference) |
1.90 (1.41–2.57) p <0.001 |
|
| Step 5: Step 4 + medications**** | 1.00 (Reference) |
1.04 (0.76–1.43); p =0.792 |
1.00 (Reference) |
1.89 (1.40–2.56) p <0.001 |
|
| Step 6: Step 5 + clinical findings***** | 1.00 (Reference) |
1.01 (0.74–1.39); p =0.941 |
1.00 (Reference) |
1.74 (1.27–2.38) p =0.001 |
|
| Step 7: Step 6 + laboratory findings****** | 1.00 (Reference) |
0.99 (0.71–1.37); p =0.934 |
1.00 (Reference) |
1.50 (1.08–2.07) p =0.016 |
0.053 |
LVEF=left ventricular ejection fraction
Demographics: age, sex, and race.
Medical history: duration of smoking, duration of heart failure, New York Heart Association class, coronary artery disease, angina pectoris, diabetes mellitus, hypertension, hyperlipidemia, peripheral vascular disease, atrial fibrillation, >70% coronary artery stenosis, positive stress perfusion test, and electrocardiographic evidence of anterior, lateral and inferior-posterior myocardial infarction
Medications: bucindolol, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, digitalis, diuretics, and anticoagulants
Clinical findings: body mass index, heart rate, systolic and diastolic blood pressure, S3 gallop, pulmonary râles, and x-ray findings of cardiothoracic ratio and pulmonary edema
Laboratory findings: creatinine, potassium, sodium, magnesium, blood urea nitrogen, glucose, uric acid, total cholesterol, albumin, hemoglobin, white blood cells, and platelets
Figure 1.
Kaplan-Meier plots for all-cause mortality in patients receiving (a) placebo or (b) bucindolol (CI=confidence interval; HR=hazard ratio)
Table 3.
Associations of right ventricular ejection fraction (RVEF) <20% (versus ≥20%) with other outcomes among patients randomized to receive placebo or bucindolol
| Placebo (n=991) | Bucindolol (n=1017) | Multivariable -adjusted interaction p value |
||||||
|---|---|---|---|---|---|---|---|---|
| Outcomes | Events (%) |
Unadjusted HR (95% CI); p value |
Adjusted HR* (95% CI); p value |
Events (%) |
Unadjusted HR (95% CI); p value |
Adjusted HR* (95% CI); p value |
||
| Cardiovascular mortality | ||||||||
| RVEF ≥20% | 28% | 1.00 (Reference) |
1.00 (Reference) |
23% | 1.00 (Reference) |
1.00 (Reference) |
0.076 | |
| RVEF <20% | 40% | 1.45 (1.07–1.96); p =0.017 |
1.05 (0.74–1.49); p =0.786 |
45% | 2.27 (1.70–3.02); p <0.001 |
1.48 (1.04–2.09); p =0.029 |
||
| Heart failure mortality | ||||||||
| RVEF ≥20% | 10% | 1.00 (Reference) |
1.00 (Reference) |
8% | 1.00 (Reference) |
1.00 (Reference) |
0.441 | |
| RVEF <20% | 18% | 1.81 (1.13–2.88); p =0.013 |
1.38 (0.78–2.43); p =0.274 |
18% | 2.65 (1.69–4.16); p <0.001 |
1.96 (1.10–3.49); p =0.023 |
||
| Sudden cardiac death | ||||||||
| RVEF ≥20% | 15% | 1.00 (Reference) |
1.00 (Reference) |
12% | 1.00 (Reference) |
1.00 (Reference) |
0.155 | |
| RVEF <20% | 18% | 1.27 (0.82–1.99); p =0.285 |
0.95 (0.58–1.55); p =0.824 |
21% | 2.07 (1.38–3.12); p <0.001 |
1.17 (0.72–1.91); p =0.529 |
||
| All-cause hospitalization | ||||||||
| RVEF ≥20% | 64% | 1.00 (Reference) |
1.00 (Reference) |
60% | 1.00 (Reference) |
1.00 (Reference) |
0.162 | |
| RVEF <20% | 74% | 1.38 (1.10–1.72); p =0.005 |
1.03 (0.80–1.33); p =0.802 |
73% | 1.59 (1.29–1.96); p <0.001 |
1.30 (1.02–1.66); p =0.034 |
||
| Heart failure hospitalization | ||||||||
| RVEF ≥20% | 40% | 1.00 (Reference) |
1.00 (Reference) |
33% | 1.00 (Reference) |
1.00 (Reference) |
0.445 | |
| RVEF <20% | 58% | 1.82 (1.42–2.35); <0.001 |
1.28 (0.96–1.71); p =0.094 |
52% | 2.11 (1.64–2.72); p <0.001 |
1.45 (1.07–1.98); p =0.017 |
||
Multivariable model based on model 7 from Table 2
3.3. RVEF and mortality in patients receiving bucindolol
Among patients in the bucindolol group, all-cause mortality occurred in 28% and 49% of patients with RVEF ≥20% and <20% respectively (HR, 2.15; 95% CI, 1.65–2.80; p<0.0001; Table 2 and Figure 1b). This association was attenuated but remained significant after multivariable adjustment (adjusted HR, 1.50; 95% CI, 1.08–2.07; p=0.016 Table 2). When RVEF was used as a continuous variable, each unit increase in RVEF was associated with a 3% reduction in the risk of total mortality (unadjusted HR, 0.97; 95% CI, 0.96–0.98; p<0.0001), which remained significant after multivariable adjustment (adjusted HR, 0.98; 95% CI, 0.97–0.99; p=0.001; data not shown). Associations of RVEF <20% with cause-specific mortalities among bucindolol patients are displayed in Table 3.
3.4. RVEF and hospitalization
RVEF <20% was associated with increased risk of HF hospitalization in both placebo (HR, 1.82; 95% CI, 1.42–2.35; p<0.0001 Table 3 and Fig 2a) and bucindolol (HR, 2.11; 95% CI, 1.64–2.72; p<0.0001 Table 3 and Fig 2b) groups. After multivariable adjustment, RVEF<20% had non-significant association in placebo (HR, 1.28; 95% CI, 0.96–1.71; p=0.094, Table 3) but significant association in the bucindolol groups (HR, 1.45; 95% CI, 1.07–1.98; p=0.017, Table 3). Association of low RVEF with all-cause hospitalization are displayed in Table 3.
Figure 2.
Kaplan-Meier plots for heart failure (HF) hospitalization in patients receiving (a) placebo or (b) bucindolol (CI=confidence interval; HR=hazard ratio)
4. Discussion
4.1. Summary and relevance of the key findings
Findings from the current analysis demonstrate that in advanced chronic systolic HF patients receiving background therapy with inhibitors of renin-angiotensin system, diuretics and digitalis, RVEF <20% had no significant intrinsic association with mortality. However, when these patients were receiving additional therapy with bucindolol, RVEF <20% had a substantial and significant independent association with increased mortality. Findings of the current study suggest that the effect of severely reduced RVEF on mortality in systolic HF may be worse in patients receiving beta-blockers, which constitute the mainstay of evidence-based therapy in these patients. These findings are important as many of systolic HF patients also have RVEF <20% [4, 12].
4.2. Potential explanation and mechanism of the key findings
A reduced LVEF is the most common cause of reduced RVEF, which in turn may further reduce LVEF, and result in disease progression and poor outcomes [7]. However, among patients receiving placebo, RVEF <20% had no significant bivariate association with increased mortality (Table 2). Further, the near-significant bivariate association disappeared after adjustment for LVEF alone suggests a strong confounding by LVEF. On the other hand, among patients receiving bucindolol, RVEF <20% had significant bivariate association with increased mortality, which though somewhat attenuated, remained significant after adjustment for LVEF alone (Table 2) suggesting that LVEF was a much weaker confounder in these patients. These findings suggest that in patients with chronic advanced systolic HF receiving ACE inhibitors, digitalis and diuretics (the placebo group), LVEF may be prognostically more important than RVEF. However, this association reversed among patients receiving additional therapy with bucindolol an RVEF became prognostically more important. This was confirmed in a post hoc analysis that demonstrated an independent association of LVEF with mortality in patients receiving placebo but not in those receiving bucindolol.
The poor outcomes associated with low RVEF in the bucindolol group is unlikely to be explained by further worsening of RVEF during follow-up. BEST participants receiving bucindolol had substantial improvements in both LVEF and RVEF during follow-up [13]. It is possible that low RVEF-associated poor outcomes may have been mediated by vasodilation associated with bucindolol use. To test this hypothesis, we conducted a post hoc analysis to determine if the association between low RVEF and mortality varied between BEST participants receiving and not receiving vasodilators. We observed that RVEF <20% (versus ≥40%) was associated with increased mortality among those receiving vasodilators (n=467; adjusted HR, 1.86; 95% CI, 1.19–2.89; P=0.006) but not among those not receiving vasodilators (n=537; adjusted HR, 1.17; 95% CI, 0.73–1.88; P=0.520). Although these differences were not statistically significant (adjusted p for interaction =0.505), the cumulative evidence from these findings suggests that the association of low RVEF with mortality may be stronger in patients receiving drugs that may reduce systemic vascular resistance. This is also consistent with experience from patients with idiopathic pulmonary hypertension and isolated RV failure who are highly sensitive to vasodilators and beta-blockers [5–7].
4.3. Comparison with findings from relevant published literature
None of the major randomized clinical trials of beta-blockers in HF reported data on baseline RVEF [14–18]. Therefore, BEST provides a unique opportunity to examine the effect of low RVEF on outcomes in systolic HF [4, 8, 9]. To the best of our knowledge, this is the first report of a significant difference in the effect of baseline RVEF on outcomes between systolic HF patients receiving and not receiving a beta-blocker.
4.4. Clinical and public health importance
Although findings of the current study suggest a potentially important interaction between the beta-blocker therapy and RVEF in chronic systolic HF, these findings need to be interpreted with caution as bucindolol is not approved for use in HF. Unlike other beta-blockers approved for use in HF, namely, carvedilol, long-acting metoprolol and bisoprolol, bucindolol has been suggested to have intrinsic sympathomimetic activity [19], which has been shown to increase mortality in HF [20]. However, several studies have failed to demonstrate intrinsic sympathomimetic activity of bucindolol in human myocardium, in particular in failing myocardium [21, 22]. Unlike other beta-blockers, bucindolol also has potent central sympatholytic properties and it is possible that therapy with bucindolol have removed the critical adrenergic support that patients with advanced HF and abnormally low RVEF are dependent on [23, 24].
4.5. Potential limitations
There are several limitations of our study. Gated-equilibrium radionuclide ventriculography was used to estimate RVEF in our study, which may not be as accurate as first- pass radionuclide ventriculography in the presence of right ventricle enlargement [10]. However, it has been validated extensively and has the advantage of being independent of geometric assumptions in contrast to conventional echocardiography. Magnetic resonance imaging may provide more accurate quantification of RV volumes and function in this population [25]. Since the changes in RV volumes precedes the deterioration of highly load dependent RVEF, assessment of RV volume may provide more insights in to the pharmacobiology of beta-blockers in heart failure patients with right ventricular systolic dysfunction. Moreover, changes in the standard therapy for systolic HF since the BEST trial (1995–1998) may also limit the generalizability of our findings to contemporary HF patients.
4.6. Conclusions
In ambulatory patients with chronic advanced systolic HF in the BEST trial, the independent effect of baseline RVEF on mortality significantly varied by the receipt of bucindolol. Baseline RVEF <20% had no effect on mortality in those receiving inhibitors of the renin-angiotensin system, diuretics, and digoxin, but increased mortality in those receiving additional therapy with bucindolol. Findings of the current study needs to replicated in contemporary HF patients receiving beta-blockers approved for use in HF.
Figure 3.
Association of right ventricular ejection fraction (RVEF) <20% (versus ≥40%) with all-cause mortality in subgroups of patients (CI = confidence interval)
Acknowledgement
The Beta–Blocker Evaluation of Survival Trial (BEST) is conducted and supported by the NHLBI in collaboration with the BEST study investigators. This manuscript was prepared using a limited access dataset obtained from the NHLBI and does not necessarily reflect the opinions or views of the BEST or the NHLBI
The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [26].
Funding Sources: Dr. Ahmed is supported by grants (R01-HL085561 and R01-HL097047) from the National Heart, Lung, and Blood Institute (NHLBI), Bethesda, Maryland and a generous gift from Ms. Jean B Morris of Birmingham, Alabama
Footnotes
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Conflict of Interest Disclosures: None
References
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