- Email: [email protected]
Recent heart failure trials of neurohormonal modulation (OVERTURE and ENABLE): Approaching the asymptote of efficacy?
Journal of Cardiac Failure Vol. 8 No. 3 2002
Recent Heart Failure Trials Of Neurohormonal Modulation (OVERTURE and ENABLE): Approaching the Asymptote of Efficacy? JOHN R. TEERLINK, MD San Francisco, California
failure, extending the hypothesis developed in the ACE inhibitor trials. The mechanism of action of ACE inhibitors was initially posited to be due to decreased production of angiotensin II via inhibition of the effector enzyme, but continued research revealed a number of other possible mechanisms of action, including decreased degradation of vasodilating compounds, such as bradykinins. Recognizing the important interaction of the vasoconstricting and vasodilating neurohormones, many investigators refocused their efforts on discovering means to augment the endogenous vasodilating systems. Omapatrilat is the result of such a search and it has proven to be a very potent and effective vasodilator whose mechanism of action is to not only inhibit the activity of ACE but to also inhibit the activity of neutral endopeptidase (NEP), which degrades natriuretic peptides, adrenomedullin, and bradykinins. These vasodilating compounds have been demonstrated to have beneficial effects on the pathophysiology of heart failure in experimental models. Early clinical trials with omapatrilat provided additional support for the potential incremental efficacy of vasopeptidase inhibition, although concerns about drug-related adverse effects (including angioedema) also emerged.2 The question that remained was whether this new class of agents could provide any additional benefit compared to ACE inhibitors. The OVERTURE trial was designed to address this question by randomizing patients to either enalapril or omapatrilat and comparing their efficacy with regard to the primary endpoint of all-cause mortality and heart failure hospitalization. This primary endpoint was designed to address two hypotheses, simultaneously, the first being the non-inferiority of omapatrilat compared to enalapril (if upper bound of 97.5% one-sided confidence interval <1.09), which would confirm the efficacy of this agent, and the second investigating the superiority of omapatrilat compared to enalapril (if upper bound of 97.5% onesided confidence interval <1.00). The OVERTURE trial enrolled 5,770 patients with New York Heart Association (NYHA) class II-IV symptoms of at least 2 months dura-
The revolution in heart failure treatment brought about by the success of angiotensin converting enzyme (ACE) inhibitors firmly established the neurohormonal hypothesis of heart failure. Many trials have demonstrated the importance of inhibition of the renin-angiotensinaldosterone system (RAAS), and have encouraged investigators to ask whether further inhibition of other neurohormonal systems might be beneficial. The tremendous morbidity and survival advantage afforded by betaadrenergic receptor blockers has supported this hypothesis for many clinicians (although others might argue that much of the mechanism of beta-blockers is due to RAAS suppression). The recently reported results from ValHeFT (Valsartan Heart Failure Trial) provide an interesting perspective on this issue, where there was no apparent significant additional benefit to the administration of an angiotensin receptor antagonist in the patients already receiving an ACE inhibitor and beta-adrenergic receptor blockade.1 Two very important and informative trials that tested new approaches to neurohormonal modulation in the treatment of heart failure were presented at the recent 2002 American College of Cardiology Scientific Sessions in Atlanta: OVERTURE (Omapatrilat versus Enalapril Randomized Trial of Utility in Reducing Events) and ENABLE (Endothelin Antagonism with Bosentan and Lowering of Events).
OVERTURE The OVERTURE trial investigated the effects of the vasopeptidase inhibitor omapatrilat in patients with heart From the School of Medicine, University of California, and the Section of Cardiology, Veterans Affairs Medical Center, San Francisco, CA. Reprint requests: John R. Teerlink, MD, Cardiology 111C, San Francisco VA Medical Center, 4150 Clement Street, San Francisco, CA 94121-1545. This is a US government work. There are no restrictions on its use. 1071-9164/02/0802-0003$35.00/0 doi:10.1054/jcaf.2002.126486
124
OVERTURE and ENABLE
tion and a left ventricular ejection fraction (LVEF) <30%, who had been hospitalized for heart failure within 12 months and were already receiving diuretics (⫾digoxin, ACE inhibitor, beta-blockers, spironolactone). Patients had their baseline ACE inhibitors discontinued and were randomized to an up-titration schedule of either enalapril (target dose 20 mg) or omapatrilat (target dose 40 mg) and followed until there were at least 850 deaths and at least 8 months follow-up in all patients. The patients in OVERTURE had characteristics of advanced heart failure patients with a mean age of 63 years, 79% male, 55% ischemic etiology, a mean LVEF of 23%, NYHA class II (48%), III (48%), or IV (4%), and about 31% with diabetes mellitus. These patients were well treated with standard therapies at baseline, including 60% on digoxin, 52% on beta-blockers and 42% on spironolactone. The primary endpoint of death or heart failure hospitalization was not significant for the superiority of omapatrilat compared to enalapril, but did demonstrate the non-inferiority to enalapril, confirming that it was an effective therapy by this implicit comparison to placebo. There were 973 events out of 2,884 patients in the enalapril group compared to 914 out of 2,886 patients in the omapatrilat group (hazard ratio: 0.94; confidence intervals: 0.86-1.03; log rank P value: 0.187). There was no significant difference in the secondary endpoint of all-cause mortality (enalapril: 509/2,884, omapatrilat: 477/2,886; hazard ratio: 0.94; confidence intervals: 0.83-1.07; log rank P value: 0.339) and no differences emerged in any of the subgroup analyses for these endpoints. In addition, there were no differences between the two therapies for the secondary endpoints of ischemic events (combined endpoint of cardiovascular death myocardial infarction, stroke or myocardial revascularization), NYHA class, or patient global assessment, but there was a significant benefit of omapatrilat in the combined secondary endpoint of cardiovascular death or hospitalization (enalapril: 1,275/2,884, omapatrilat: 1,178/2,886; hazard ratio: 0.91; confidence intervals: 0.84-0.99; log rank P value: 0.024). There was a slightly lower incidence of worsening renal function in omapatrilat-treated patients, but more pronounced increases in the adverse events of hypotension (enalapril: 332 [11.5%], omapatrilat: 564 [19.5%]) and dizziness (enalapril: 401 [13.9%], omapatrilat: 561 [19.4%]). The incidence of angioedema was slightly higher in the omapatrilat group (enalapril: 14 [0.5%], omapatrilat: 24 [0.8%]), but not as much so as in the hypertension trials. Some might suggest that this discrepancy supports a different pathophysiology in heart failure than in hypertension, with increased resistance to bradykinins and other endogenous vasodilators in these heart failure patients. However, this difference is more likely due to the preselection of patients, most of whom had already been able to tolerate ACE inhibitors prior to
O Teerlink 125
enrolling in OVERTURE. Thus, the OVERTURE trial demonstrated that omapatrilat produced a benefit in reducing morbidity and mortality in patients with severe heart failure which was equivalent to, but not significantly greater than, ACE inhibition alone. Although not a negative trial, the absence of an additional benefit of omapatrilat compared to enalapril was disappointing. Potential explanations for these results were discussed by Dr. Milton Packer during the presentation, including suboptimal dose or dosing regimen, the ineffectiveness of additional neurohormonal modulation in the setting of other therapies, the resistance to natriuretic peptides and other endogenous vasodilators in severe advanced heart failure, and the excessive lowering of blood pressure in patients with low pretreatment blood pressures offsetting the potential benefits. Preliminary analysis was presented to address this last issue and a post-hoc analysis of death and heart failure hospitalizations stratified by pretreatment blood pressure did demonstrate a slight trend favoring omapatrilat with higher systolic blood pressures. However, this marginal benefit was only apparent in the group with initial systolic blood pressure ⱖ140 mmHg, and the sizes of these subgroups was not presented. In addition, the question of whether there were interactions between background therapies (such as beta-blockers, spironolactone, and the combination) and omapatrilat is of great interest, given the suggestion of such interactions in Val-HeFT. The absence of benefit in this large and well-designed trial will most certainly be carefully analyzed and may cause increased caution in pursuing this strategy in the treatment of heart failure patients.
ENABLE The ENABLE trial investigated the inhibition of a newly discovered neurohormonal system with the dual endothelin receptor antagonist, bosentan. Endothelin is a 21–amino acid peptide that is synthesized predominantly by the vasculature in response to cardiovascular stress and is the most potent known vasoconstrictor. Serum endothelin concentrations have been shown to be elevated in experimental models and in patients with chronic heart failure and endothelin has many adverse biological effects that play a central role in the pathophysiology of heart failure. Endothelin antagonism has produced conflicting results in the experimental literature, with many studies demonstrating improved hemodynamics, ventricular remodeling and survival. Clinical studies had also revealed conflicting results with some studies suggesting clinical benefit 3 while others showed adverse effects (i.e. enrasentan in ENCOR [Enrasentan COoperative Randomized evaluation]). Thus, the clinical efficacy of this novel class of agents had not been established.
126
Journal of Cardiac Failure Vol. 8 No. 3 June 2002
ENABLE was designed to incorporate the results from two identical parallel trials, one in Europe (ENABLE-1) and the other in North America (ENABLE-2). The primary endpoint for the two individual trials was the patient’s composite clinical status after 9 months of therapy (each at ␣ ⫽ 0.04), while the results from both trials were combined to evaluate the primary endpoint of all-cause mortality and CHF hospitalizations (␣ ⫽ 0.01) and the secondary endpoint of all-cause mortality. The ENABLE trial enrolled 1,613 patients from 150 sites in Europe and North America who had chronic heart failure due to either ischemic or nonischemic etiology, with a LVEF <35% and NYHA class IIIB or IV symptoms for at least 2 months on standard therapy (diuretics, ACE inhibitor, ⫾digitalis, ⫾beta-blocker, ⫾spironolactone). These patients were randomized into two treatment groups, the first receiving placebo bid and the second receiving a final dose of bosentan 125 mg bid. The trial was event-driven with a goal of 600 events, which occurred with a mean follow-up of 1.5 years. The patients in ENABLE were representative of the advanced heart failure population with a mean age of 67 years old, 75% male, approximately 70% with an ischemic etiology, predominantly NYHA class IIIB and a mean LVEF of 25%. In addition to the required therapies, almost 60% of the patients were on digitalis and over 50% were on beta-blockers. The combined primary endpoint of all-cause mortality and CHF hospitalizations was not met, with 321 of 808 placebo-treated patients compared to 312 of 805 bosentan-treated patients having an event (Hazard ratio: 1.01, 95% C.I. 0.86, 1.18; log rank P ⫽ 0.90). In addition, the main secondary endpoint of all-cause mortality also demonstrated no difference, with 173 deaths in the placebo group compared to 160 deaths in the bosentan group (Hazard ratio: 0.94, 95% C.I. 0.75, 1.16; log rank P ⫽ 0.54). There were no differences in the effect in any of the subgroups presented and there were few adverse effects. Serum increases in liver transaminases to at least three times over the upper limit of normal occurred in 2.7% of the placebo group and 9.5 % in the bosentan-treated patients, but there were no instances of acute or chronic liver failure. These disappointing results of ENABLE have encouraged investigators to assess the reasons for no beneficial effect. During the presentation, Dr. Milton Packer showed that there was evidence of early, sustained fluid retention in the bosentan-treated patients, as indicated by increased weight, decreased hemoglobin in the face of normal hematologic indices, and increased frequency of edema, all of which appeared at 2 weeks and were sustained during the trial. As a purely exploratory analysis, the relationship between this increase in edema and events was investigated and demonstrated to be quite significant. In fact, patients who did not increase their weight by ⱖ2 kg had improved event-free survival (P ⫽
0.011). The interpretation of this post-hoc analysis is difficult; it may suggest that there is a group of patients who cannot tolerate bosentan and that efforts should be directed to clarifying the factors that make them more susceptible to adverse effects. However, it may also suggest that, as was the case with the clinical use of beta-blockers in heart failure, more careful titration and attention to volume status could reveal a beneficial effect. Undoubtedly, other analyses will be performed to clarify the absence of a beneficial effect in this trial, but it should also be recalled that neither enrasentan (ENCOR)4 nor darusentan 5 have appeared promising in their major trials, although the results of the EARTH trial (EndothelinA Receptor Antagonist Trial in Heart Failure)6 are still awaited. For now, the promise suggested by the preclinical trials of endothelin receptor antagonism has not been fulfilled in any of the heart failure clinical trials, including ENABLE.
Conclusions The unexpected neutral results of OVERTURE and ENABLE have raised some important questions. Is the neurohormonal hypothesis still a useful guiding principle for new therapeutics in chronic heart failure? These trials are the first to investigate new neurohormonal modulation strategies in the context of contemporary therapy, and in both trials, almost all patients received ACE inhibition, spironolactone use was substantial, and over 50% of the patients were already being treated with beta-blockers. Perhaps there truly is no further benefit to be gained by additional neurohormonal therapy in the context of ACE inhibitors, beta-blockers and spironolactone. Or, perhaps there is a real benefit, but its magnitude is relatively small or it is restricted to subgroups of patients that have yet to be delineated. While there remains evidence supporting the importance of further neurohormonal inhibition, one must consider that if in fact current approaches have reached an asymptote of efficacy, how will the persistent 7% to 13% mortality and continued significant morbidity in contemporary heart failure trials be addressed? The current challenge of these results for basic scientists and clinical researchers alike is to develop new and innovative solutions that are truly an advance beyond our current therapies. In the clinical realm, these approaches may necessitate different types of trials, using factorial designs to assess combinations of therapies. Additionally, clinicians and clinical investigators must confront the challenging economic, as well as medical, issues associated with adoption of the burgeoning device therapies. In the basic science arena, there remains a pressing need to develop new therapeutic mechanisms, such as cell transplantation and sarcomeredirected therapies, to name two. Furthermore, should we
OVERTURE and ENABLE
reevaluate the preclinical models for our assessment of new therapeutics? In addition to discovering new mechanisms of action, should we be performing preclinical studies that more carefully examine the additive effects of therapies and their potential interactions, or have we also reached limits in the predictive powers of these experimental models? Both OVERTURE and ENABLE address important hypotheses in heart failure and the full publication of these trials and further discussion of the interpretations and implications of their results are eagerly awaited.
References 1. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators: A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667–1675 2. Rouleau JL, Pfeffer MA, Stewart DJ, Isaac D, Sestier F, Kerut EK, Porter CB, Prolux G, Qian C, Block AJ: Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance
O Teerlink 127
and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet 2000;356:615–620 3. Mylona P, Cleland JG, on behalf of the Cardio.net Editorial Team: Update of REACH-1 and MERIT-HF clinical trials in heart failure. Eur J Heart Fail 1999;1: 197–200 4. Abraham WT: Late-breaking clinical trials III: Effects of enrasentan, a non-selective endothelin receptor antagonist in class II-III heart failure: Results of the ENCOR trial. American College of Cardiology 50th Annual Scientific Session, Orlando, FL, 2001. 5. Thackray SD, Witte KK, Khand A, Dunn A, Clark AL, Cleland JG: Clinical trials update: Highlights of the scientific sessions of the American Heart Association year 2000: Val HeFT, COPERNICUS, MERIT, CIBIS-II, BEST, AMIOVIRT, V-MAC, BREATHE, HEAT, MIRACL, FLORIDA, VIVA and the first human cardiac skeletal muscle myoblast transfer for heart failure. Eur J Heart Fail 2001;3:117–124 6. Lüscher TF, Ruschitzka F, Anand I, Konstam MA, McMurray J, Notter T, Cohn JN, on behalf of the EARTH Investigators: EARTH: EndothelinA Receptor Antagonist Trial in Heart Failure. Rationale and design. HeartDrug 2001;1:294–298.
Recent Heart Failure Trials Of Neurohormonal Modulation (OVERTURE and ENABLE): Approaching the Asymptote of Efficacy? JOHN R. TEERLINK, MD San Francisco, California
failure, extending the hypothesis developed in the ACE inhibitor trials. The mechanism of action of ACE inhibitors was initially posited to be due to decreased production of angiotensin II via inhibition of the effector enzyme, but continued research revealed a number of other possible mechanisms of action, including decreased degradation of vasodilating compounds, such as bradykinins. Recognizing the important interaction of the vasoconstricting and vasodilating neurohormones, many investigators refocused their efforts on discovering means to augment the endogenous vasodilating systems. Omapatrilat is the result of such a search and it has proven to be a very potent and effective vasodilator whose mechanism of action is to not only inhibit the activity of ACE but to also inhibit the activity of neutral endopeptidase (NEP), which degrades natriuretic peptides, adrenomedullin, and bradykinins. These vasodilating compounds have been demonstrated to have beneficial effects on the pathophysiology of heart failure in experimental models. Early clinical trials with omapatrilat provided additional support for the potential incremental efficacy of vasopeptidase inhibition, although concerns about drug-related adverse effects (including angioedema) also emerged.2 The question that remained was whether this new class of agents could provide any additional benefit compared to ACE inhibitors. The OVERTURE trial was designed to address this question by randomizing patients to either enalapril or omapatrilat and comparing their efficacy with regard to the primary endpoint of all-cause mortality and heart failure hospitalization. This primary endpoint was designed to address two hypotheses, simultaneously, the first being the non-inferiority of omapatrilat compared to enalapril (if upper bound of 97.5% one-sided confidence interval <1.09), which would confirm the efficacy of this agent, and the second investigating the superiority of omapatrilat compared to enalapril (if upper bound of 97.5% onesided confidence interval <1.00). The OVERTURE trial enrolled 5,770 patients with New York Heart Association (NYHA) class II-IV symptoms of at least 2 months dura-
The revolution in heart failure treatment brought about by the success of angiotensin converting enzyme (ACE) inhibitors firmly established the neurohormonal hypothesis of heart failure. Many trials have demonstrated the importance of inhibition of the renin-angiotensinaldosterone system (RAAS), and have encouraged investigators to ask whether further inhibition of other neurohormonal systems might be beneficial. The tremendous morbidity and survival advantage afforded by betaadrenergic receptor blockers has supported this hypothesis for many clinicians (although others might argue that much of the mechanism of beta-blockers is due to RAAS suppression). The recently reported results from ValHeFT (Valsartan Heart Failure Trial) provide an interesting perspective on this issue, where there was no apparent significant additional benefit to the administration of an angiotensin receptor antagonist in the patients already receiving an ACE inhibitor and beta-adrenergic receptor blockade.1 Two very important and informative trials that tested new approaches to neurohormonal modulation in the treatment of heart failure were presented at the recent 2002 American College of Cardiology Scientific Sessions in Atlanta: OVERTURE (Omapatrilat versus Enalapril Randomized Trial of Utility in Reducing Events) and ENABLE (Endothelin Antagonism with Bosentan and Lowering of Events).
OVERTURE The OVERTURE trial investigated the effects of the vasopeptidase inhibitor omapatrilat in patients with heart From the School of Medicine, University of California, and the Section of Cardiology, Veterans Affairs Medical Center, San Francisco, CA. Reprint requests: John R. Teerlink, MD, Cardiology 111C, San Francisco VA Medical Center, 4150 Clement Street, San Francisco, CA 94121-1545. This is a US government work. There are no restrictions on its use. 1071-9164/02/0802-0003$35.00/0 doi:10.1054/jcaf.2002.126486
124
OVERTURE and ENABLE
tion and a left ventricular ejection fraction (LVEF) <30%, who had been hospitalized for heart failure within 12 months and were already receiving diuretics (⫾digoxin, ACE inhibitor, beta-blockers, spironolactone). Patients had their baseline ACE inhibitors discontinued and were randomized to an up-titration schedule of either enalapril (target dose 20 mg) or omapatrilat (target dose 40 mg) and followed until there were at least 850 deaths and at least 8 months follow-up in all patients. The patients in OVERTURE had characteristics of advanced heart failure patients with a mean age of 63 years, 79% male, 55% ischemic etiology, a mean LVEF of 23%, NYHA class II (48%), III (48%), or IV (4%), and about 31% with diabetes mellitus. These patients were well treated with standard therapies at baseline, including 60% on digoxin, 52% on beta-blockers and 42% on spironolactone. The primary endpoint of death or heart failure hospitalization was not significant for the superiority of omapatrilat compared to enalapril, but did demonstrate the non-inferiority to enalapril, confirming that it was an effective therapy by this implicit comparison to placebo. There were 973 events out of 2,884 patients in the enalapril group compared to 914 out of 2,886 patients in the omapatrilat group (hazard ratio: 0.94; confidence intervals: 0.86-1.03; log rank P value: 0.187). There was no significant difference in the secondary endpoint of all-cause mortality (enalapril: 509/2,884, omapatrilat: 477/2,886; hazard ratio: 0.94; confidence intervals: 0.83-1.07; log rank P value: 0.339) and no differences emerged in any of the subgroup analyses for these endpoints. In addition, there were no differences between the two therapies for the secondary endpoints of ischemic events (combined endpoint of cardiovascular death myocardial infarction, stroke or myocardial revascularization), NYHA class, or patient global assessment, but there was a significant benefit of omapatrilat in the combined secondary endpoint of cardiovascular death or hospitalization (enalapril: 1,275/2,884, omapatrilat: 1,178/2,886; hazard ratio: 0.91; confidence intervals: 0.84-0.99; log rank P value: 0.024). There was a slightly lower incidence of worsening renal function in omapatrilat-treated patients, but more pronounced increases in the adverse events of hypotension (enalapril: 332 [11.5%], omapatrilat: 564 [19.5%]) and dizziness (enalapril: 401 [13.9%], omapatrilat: 561 [19.4%]). The incidence of angioedema was slightly higher in the omapatrilat group (enalapril: 14 [0.5%], omapatrilat: 24 [0.8%]), but not as much so as in the hypertension trials. Some might suggest that this discrepancy supports a different pathophysiology in heart failure than in hypertension, with increased resistance to bradykinins and other endogenous vasodilators in these heart failure patients. However, this difference is more likely due to the preselection of patients, most of whom had already been able to tolerate ACE inhibitors prior to
O Teerlink 125
enrolling in OVERTURE. Thus, the OVERTURE trial demonstrated that omapatrilat produced a benefit in reducing morbidity and mortality in patients with severe heart failure which was equivalent to, but not significantly greater than, ACE inhibition alone. Although not a negative trial, the absence of an additional benefit of omapatrilat compared to enalapril was disappointing. Potential explanations for these results were discussed by Dr. Milton Packer during the presentation, including suboptimal dose or dosing regimen, the ineffectiveness of additional neurohormonal modulation in the setting of other therapies, the resistance to natriuretic peptides and other endogenous vasodilators in severe advanced heart failure, and the excessive lowering of blood pressure in patients with low pretreatment blood pressures offsetting the potential benefits. Preliminary analysis was presented to address this last issue and a post-hoc analysis of death and heart failure hospitalizations stratified by pretreatment blood pressure did demonstrate a slight trend favoring omapatrilat with higher systolic blood pressures. However, this marginal benefit was only apparent in the group with initial systolic blood pressure ⱖ140 mmHg, and the sizes of these subgroups was not presented. In addition, the question of whether there were interactions between background therapies (such as beta-blockers, spironolactone, and the combination) and omapatrilat is of great interest, given the suggestion of such interactions in Val-HeFT. The absence of benefit in this large and well-designed trial will most certainly be carefully analyzed and may cause increased caution in pursuing this strategy in the treatment of heart failure patients.
ENABLE The ENABLE trial investigated the inhibition of a newly discovered neurohormonal system with the dual endothelin receptor antagonist, bosentan. Endothelin is a 21–amino acid peptide that is synthesized predominantly by the vasculature in response to cardiovascular stress and is the most potent known vasoconstrictor. Serum endothelin concentrations have been shown to be elevated in experimental models and in patients with chronic heart failure and endothelin has many adverse biological effects that play a central role in the pathophysiology of heart failure. Endothelin antagonism has produced conflicting results in the experimental literature, with many studies demonstrating improved hemodynamics, ventricular remodeling and survival. Clinical studies had also revealed conflicting results with some studies suggesting clinical benefit 3 while others showed adverse effects (i.e. enrasentan in ENCOR [Enrasentan COoperative Randomized evaluation]). Thus, the clinical efficacy of this novel class of agents had not been established.
126
Journal of Cardiac Failure Vol. 8 No. 3 June 2002
ENABLE was designed to incorporate the results from two identical parallel trials, one in Europe (ENABLE-1) and the other in North America (ENABLE-2). The primary endpoint for the two individual trials was the patient’s composite clinical status after 9 months of therapy (each at ␣ ⫽ 0.04), while the results from both trials were combined to evaluate the primary endpoint of all-cause mortality and CHF hospitalizations (␣ ⫽ 0.01) and the secondary endpoint of all-cause mortality. The ENABLE trial enrolled 1,613 patients from 150 sites in Europe and North America who had chronic heart failure due to either ischemic or nonischemic etiology, with a LVEF <35% and NYHA class IIIB or IV symptoms for at least 2 months on standard therapy (diuretics, ACE inhibitor, ⫾digitalis, ⫾beta-blocker, ⫾spironolactone). These patients were randomized into two treatment groups, the first receiving placebo bid and the second receiving a final dose of bosentan 125 mg bid. The trial was event-driven with a goal of 600 events, which occurred with a mean follow-up of 1.5 years. The patients in ENABLE were representative of the advanced heart failure population with a mean age of 67 years old, 75% male, approximately 70% with an ischemic etiology, predominantly NYHA class IIIB and a mean LVEF of 25%. In addition to the required therapies, almost 60% of the patients were on digitalis and over 50% were on beta-blockers. The combined primary endpoint of all-cause mortality and CHF hospitalizations was not met, with 321 of 808 placebo-treated patients compared to 312 of 805 bosentan-treated patients having an event (Hazard ratio: 1.01, 95% C.I. 0.86, 1.18; log rank P ⫽ 0.90). In addition, the main secondary endpoint of all-cause mortality also demonstrated no difference, with 173 deaths in the placebo group compared to 160 deaths in the bosentan group (Hazard ratio: 0.94, 95% C.I. 0.75, 1.16; log rank P ⫽ 0.54). There were no differences in the effect in any of the subgroups presented and there were few adverse effects. Serum increases in liver transaminases to at least three times over the upper limit of normal occurred in 2.7% of the placebo group and 9.5 % in the bosentan-treated patients, but there were no instances of acute or chronic liver failure. These disappointing results of ENABLE have encouraged investigators to assess the reasons for no beneficial effect. During the presentation, Dr. Milton Packer showed that there was evidence of early, sustained fluid retention in the bosentan-treated patients, as indicated by increased weight, decreased hemoglobin in the face of normal hematologic indices, and increased frequency of edema, all of which appeared at 2 weeks and were sustained during the trial. As a purely exploratory analysis, the relationship between this increase in edema and events was investigated and demonstrated to be quite significant. In fact, patients who did not increase their weight by ⱖ2 kg had improved event-free survival (P ⫽
0.011). The interpretation of this post-hoc analysis is difficult; it may suggest that there is a group of patients who cannot tolerate bosentan and that efforts should be directed to clarifying the factors that make them more susceptible to adverse effects. However, it may also suggest that, as was the case with the clinical use of beta-blockers in heart failure, more careful titration and attention to volume status could reveal a beneficial effect. Undoubtedly, other analyses will be performed to clarify the absence of a beneficial effect in this trial, but it should also be recalled that neither enrasentan (ENCOR)4 nor darusentan 5 have appeared promising in their major trials, although the results of the EARTH trial (EndothelinA Receptor Antagonist Trial in Heart Failure)6 are still awaited. For now, the promise suggested by the preclinical trials of endothelin receptor antagonism has not been fulfilled in any of the heart failure clinical trials, including ENABLE.
Conclusions The unexpected neutral results of OVERTURE and ENABLE have raised some important questions. Is the neurohormonal hypothesis still a useful guiding principle for new therapeutics in chronic heart failure? These trials are the first to investigate new neurohormonal modulation strategies in the context of contemporary therapy, and in both trials, almost all patients received ACE inhibition, spironolactone use was substantial, and over 50% of the patients were already being treated with beta-blockers. Perhaps there truly is no further benefit to be gained by additional neurohormonal therapy in the context of ACE inhibitors, beta-blockers and spironolactone. Or, perhaps there is a real benefit, but its magnitude is relatively small or it is restricted to subgroups of patients that have yet to be delineated. While there remains evidence supporting the importance of further neurohormonal inhibition, one must consider that if in fact current approaches have reached an asymptote of efficacy, how will the persistent 7% to 13% mortality and continued significant morbidity in contemporary heart failure trials be addressed? The current challenge of these results for basic scientists and clinical researchers alike is to develop new and innovative solutions that are truly an advance beyond our current therapies. In the clinical realm, these approaches may necessitate different types of trials, using factorial designs to assess combinations of therapies. Additionally, clinicians and clinical investigators must confront the challenging economic, as well as medical, issues associated with adoption of the burgeoning device therapies. In the basic science arena, there remains a pressing need to develop new therapeutic mechanisms, such as cell transplantation and sarcomeredirected therapies, to name two. Furthermore, should we
OVERTURE and ENABLE
reevaluate the preclinical models for our assessment of new therapeutics? In addition to discovering new mechanisms of action, should we be performing preclinical studies that more carefully examine the additive effects of therapies and their potential interactions, or have we also reached limits in the predictive powers of these experimental models? Both OVERTURE and ENABLE address important hypotheses in heart failure and the full publication of these trials and further discussion of the interpretations and implications of their results are eagerly awaited.
References 1. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators: A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667–1675 2. Rouleau JL, Pfeffer MA, Stewart DJ, Isaac D, Sestier F, Kerut EK, Porter CB, Prolux G, Qian C, Block AJ: Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance
O Teerlink 127
and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet 2000;356:615–620 3. Mylona P, Cleland JG, on behalf of the Cardio.net Editorial Team: Update of REACH-1 and MERIT-HF clinical trials in heart failure. Eur J Heart Fail 1999;1: 197–200 4. Abraham WT: Late-breaking clinical trials III: Effects of enrasentan, a non-selective endothelin receptor antagonist in class II-III heart failure: Results of the ENCOR trial. American College of Cardiology 50th Annual Scientific Session, Orlando, FL, 2001. 5. Thackray SD, Witte KK, Khand A, Dunn A, Clark AL, Cleland JG: Clinical trials update: Highlights of the scientific sessions of the American Heart Association year 2000: Val HeFT, COPERNICUS, MERIT, CIBIS-II, BEST, AMIOVIRT, V-MAC, BREATHE, HEAT, MIRACL, FLORIDA, VIVA and the first human cardiac skeletal muscle myoblast transfer for heart failure. Eur J Heart Fail 2001;3:117–124 6. Lüscher TF, Ruschitzka F, Anand I, Konstam MA, McMurray J, Notter T, Cohn JN, on behalf of the EARTH Investigators: EARTH: EndothelinA Receptor Antagonist Trial in Heart Failure. Rationale and design. HeartDrug 2001;1:294–298.