Clinical Investigation Center INSERM-CHU de Nancy Hopital Jeanne d'Arc,. Dommartin-les Toul, Cedex, France; 3Pharmacia Corporation, Skokie, IL;.
The 7th Annual Scientific Meeting
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HFSA
S57
Clinical Trials 202
203
The EPHESUS Trial: Evaluation of Eplerenone in the Subgroup of Patients with Baseline Left Ventricular Ejection Fraction ⱕ30% Bertram Pitt,1 Faiez Zannad,2 Richard Bittman,3 Myrlene Staten,3 Jeffrey Anderson,4
Efficacy and Safety of Sildenafil Citrate in Men with Erectile Dysfunction and Congestive Heart Failure: A Randomized Placebo-Controlled Trial Stuart D. Katz,1 John D. Parker,2 Alan J. Bank,3 Dale B. Glasser,4 Nancy Sherman,4 Michael Sweeney4—1Yale University School of Medicine, New Haven, CT; 2Department of Medicine, Mount Sinai Hospital, Toronto, ON, Canada; 3St. Paul Heart Clinic, University of Minnesota, St. Paul, MN; 4Pfizer Inc, New York, NY
Mihai Gheorghiade,5 Dirk-Jan van Veldhuisen,6 Jay H. Kleiman3—1University of Michigan Medical Center, Ann Arbor, MI; 2Centre d’Investigation Clinique de Nancy, Clinical Investigation Center INSERM-CHU de Nancy Hopital Jeanne d’Arc, Dommartin-les Toul, Cedex, France; 3Pharmacia Corporation, Skokie, IL; 4 Cardiology, LDS Hopsital, Salt Lake City, UT; 5Northwestern University Medical School, Chicago, IL; 6Department of Cardiology/Thorax Center, University Hospital Groningen, Groningen, Netherlands Background: The EPHESUS Study documented that the selective aldosterone blocker eplerenone reduces total mortality and the composite of cardiovascular (CV) mortality/hospitalizations in patients with heart failure (HF) due to systolic left ventricular dysfunction (SLVD) and a left ventricular ejection fraction (EF) ⱕ40%. Since recent studies have emphasized an increased risk of sudden death (SD) and need for electrical/ mechanical devices in post acute myocardial infarction (AMI) patients with EF ⱕ30%, we retrospectively analyzed outcomes in EPHESUS patients with baseline EF ⱕ30%. Results: Patients were randomized to EPL (n ⫽ 3319; 25 mg titrated to 50 mg QD) or placebo (n ⫽ 3313) 3 to 14 days post-AMI. 1048 EPL patients and 1058 placebo patients had an EF ⱕ30%. Baseline demographics and medications in the 2 subgroups were similar clinically, except that patients with EF ⱕ30% had greater use of digoxin, K⫹ supplements, and loop diuretics. In both subgroups, most patients were receiving ACE inhibitors, β-blockers, aspirin, and diuretics at baseline, and ⬎40% of patients were receiving statins and underwent coronary reperfusion. Treatment benefit in the EF ⬎30% and EF ⱕ30% subgroups did not differ significantly from that seen in the overall study population. Only the analysis of hypokalemia (K⫹ ⬍3.5 mEq/L) showed a statistically significant interaction between treatment and baseline EF, likely reflecting the greater diuretic use in those with an EF ⱕ30%. Conclusion: Addition of EPL to current standard of care treatment in Patients With Events/Total Patients (%) Event Total Mortality CV Mortality/CV Hospitalization Sudden Death Nonfatal Hospitalization for HF (patients) Nonfatal Hospitalization for HF (episodes) Hypokalemia (K⫹ ⬍3.5 mEq/L in treated patients) Hyperkalemia (K⫹ ⱖ6.0 mEq/L in treated patients)
Placebo
Eplerenone
Risk Treatment by Group P-value Ratio Interaction P-value
254/1058 433/1058
(24.0) (40.9)
205/1048 359/1048
(19.6) (34.3)
0.011 0.79 0.001 0.79
0.34 0.08
103/1058 209/1058
(9.7) (19.8)
71/1048 170/1048
(6.8) (16.2)
0.01 0.67 0.010 0.77
0.15 0.17
(20.5)
295/1058
(27.9)
215/1048
0.014 0.74
0.57
156/1018
(15.3)
78/1014
(7.7) ⬍0.001 0.50
0.02
37/1018
(3.6)
62/1014
(6.1)
0.31
0.009 1.68
EPHESUS patients with baseline EF ⱕ30% was beneficial in reducing total mortality, CV mortality/ hospitalization, SD, and hospitalization for HF. These findings have important implications for developing strategies for device implantation in patients with EF ⱕ30% and suggest the need to define predictors of increased risk for SD and progressive HF in these patients whose treatment has been optimized, including addition of EPL.
Erectile dysfunction (ED) can occur in up to 75% of patients with congestive heart failure (CHF). Because sexual dysfunction can be a distressing symptom of CHF, therapy to improve ED may have a favorable impact on overall quality of life in patients with CHF. According to practice guidelines, patients at low risk for adverse cardiac events during sexual activity can safely use sildenafil for ED. We evaluated the efficacy and tolerability of sildenafil in men with ED and CHF in a 12-week, double-blind, placebo-controlled trial. Men with documented ED (confirmed by scores on the International Index of Erectile Function, IIEF) and stable CHF (dilated cardiomyopathy and left ventricle ejection fraction ⱕ0.40) were randomized to sildenafil (50 mg, flexible to 25 or 100 mg) or placebo. Primary outcome measures were IIEF questions 3 (Q3; frequency of penetration) and 4 (Q4; frequency of maintained erections after penetration). Secondary outcomes included the 5 IIEF domains, Life Satisfaction Checklist (LSC), Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), and 2 Global Efficacy Questions. By week 12, sildenafil patients (n ⫽ 60) showed significant improvements on Q3/ Q4 and on 4 of the 5 IIEF domains compared with placebo patients (n ⫽ 72; p values ⬍0.01). Larger percentages of sildenafil patients reported improved erections (74%) and an improved ability for intercourse (68%) compared with placebo patients (18% and 16%, respectively). Compared with placebo (47.8 ⫾ 7.5), sildenafil patients (75.1 ⫾ 7.6) had significantly higher mean EDITS scores at the end of treatment (p ⬍ 0.0001), indicating they were highly satisfied with treatment. Sildenafil patients also had a significantly higher mean score on the LSC item related to sexual life compared with placebo patients (p ⬍ 0.0001). Sixty percent of sildenafil and 48% of placebo patients experienced adverse events (AEs), including transient headache, flushing, and asthenia. Only 1 sildenafil patient discontinued because of a treatmentrelated AE (headache). The incidence of events related to cardiovascular effects was low; there were no treatment-related serious AEs. The results of this study indicate that sildenafil is an effective and well-tolerated treatment for ED in men with CHF. Sildenafil was not associated with additional safety risks in this patient population.
204
205
Beta-Blockers in Patients with Left Ventricular Ejection Fraction ⬎40%: Results from a Community-Based Registry Barry M. Massie,1 Joseph A. Franciosa,2 William T. Abraham,3 Jeanenne J. Nelson,4 Mary
Heart Failure and a Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION): Design and Rationale David J. Whellan,1 Kerry L. Lee,2 Stephen Ellis,2 Lawton Cooper,3 Jerome L. Fleg,3 Robin Boineau,3 Steven J. Keteyian,4 William E. Kraus,1 Ileana L. Pina,5 Christopher M. O’Connor1—1Duke University Medical Center, Durham, NC; 2 Duke Clinical Research Institute, Durham, NC; 3National Heart, Lung, and Blood Institute, Bethesda, MD; 4Henry Ford Heart and Vascular Institute, Detroit, MI; 5 University Hospitals of Cleveland, Cleveland, OH; For the HF-ACTION Investigators
Ann Lukas,4 Sandra R. Lottes,4 Edward M. Gilbert,5 Michael Fowler,6 Barry Greenberg,7the COHERE Participant Physicians2—1Cardiology Division, San Francisco VAMC, University of California San Francisco, San Francisco, CA; 2 Cardiovascular Institute, Mt. Sinai School of Medicine, New York, NY; 3Division of Cardiology, Ohio State University School of Medicine, Columbus, OH; 4 Cardiovascular Medical Affairs, GlaxoSmithKline Pharmaceuticals, Philadelphia, PA; 5Cardiology, University of Utah Medical Center, Salt lake City, UT; 6Cardiology Division, Stanford University Medical Center, Palo Alto, CA; 7Cardiology, University of California San Diego, San Diego, CA Background: A substantial proportion of patients with chronic heart failure (HF) have preserved left ventricular ejection fraction (LVEF), yet there is little known about the tolerability and efficacy of treatments, including beta-blockers, commonly employed in this population. Therefore, we utilized the Coreg쑓 Heart Failure Registry (COHERE), in which 4,280 unselected HF patients were initiated and followed on carvedilol, to compare the characteristics, experience with carvedilol initiation and titration, and outcomes of patients with LVEF ⬎40% and ⱕ40%. Results: Findings are shown in the table. Of COHERE patients, 17% had LVEF ⬎40%. They were older, more often women, more often had a history of hypertension and diabetes and less often a history of myocardial infarction. Fewer patients with LVEF ⬎40% were receiving ACE inhibitors, diuretics and digoxin. Initiation and titration of carvedilol was considered easy in ⬎80% of both groups, but, despite higher baseline blood pressure, fewer in the group with LVEF ⬎40% were titrated to ⱖ25 mg bid, and their mean daily dose was lower (29.6 vs 36.2 mg). The mortality rate at 15 mos was slightly, but insignificantly lower in the group with LVEF ⬎40% (6.8% vs. 8.8%). Hospitalization rates following beta-blocker initiation were similar in both groups and fell from the prior yr in both groups regardless of cause. Patient Characteristic/outcome LVEF (%, mean ⫾ SD) Age (yr) Women Prior myocardial infarction History of Hypertension Diabetes NYHA class III or IV Systolic blood pressure (mm Hg, mean ⫾ SD) On ACE inhibitor On diuretic On digoxin Carvedilol titrated to ⱖ25 mg bid NYHA class improved NYHA class worsened Change in hospitalization, all-causes Change in hospitalization, HF Change in hospitalization, CV, other than HF
Patients with LVEF Patients with LVEF ⱕ40 (n ⫽ 3,450) ⬎40 (n ⫽ 700) 27 ⫾ 8 66 ⫾ 13 32% 43% 56% 31% 41% 127 ⫾ 20 78% 78% 62% 48% 31% 10% ⫺43% ⫺60% ⫺43%
52 ⫾ 9 68 ⫾ 13 46% 34% 66% 35% 28% 135 ⫾ 21 66% 70% 39% 33% 22% 8% ⫺35% ⫺42% ⫺52%
p value ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⫽0.035 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⫽0.07 Not Applicable Not Applicable Not Applicable
Conclusion: In community practices patients with LVEF ⬎40% are being started on beta-blockers for HF. Although patients with LVEF ⬎40% differ in their characteristics and treatment from those with LVEF ⱕ40%, patients with the higher LVEF experienced similar mortality rates and reduction in hospitalizations following initiation of carvedilol, suggesting that this agent may be beneficial in a broader spectrum of patients than has been studied in clinical trials.
Background: Despite ongoing advances in pharmacotherapy, heart failure (HF) remains associated with considerable morbidity and mortality as well as a poor quality of life (QOL). As the prevalence of HF continues to rise, it is increasingly important to identify novel treatment strategies to improve outcomes; one such strategy is exercise training. Over the last 10 years, a number of small studies have suggested that exercise may improve physiologic parameters such as resting heart rate, exercise duration, and peak oxygen consumption in HF patients; studies have also suggested concurrent improvement in QOL measures. However, it remains unknown whether the physiologic changes caused by exercise training translate into an improvement in morbidity and mortality in patients with HF. A large-scale, long-term, randomized, controlled clinical trial is needed to evaluate the safety, efficacy, and treatment benefit of exercise training in patients with HF. Methods: The NHLBI recently funded HFACTION (Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training). This study is a multicenter, randomized, controlled trial designed to test the long-term safety and efficacy of exercise training versus usual care in patients with left ventricular dysfunction and New York Heart Association Class II-IV HF. Three thousand patients will be randomly assigned to receive either a program consisting of 36 sessions of facility-based exercise training followed by home-based exercise training or usual care (see Figure 1); mean follow-up will be approximately 2.5 years. Attention will be given to recruiting adequate numbers of female, minority, and elderly patients to ensure that trial results are generalizable. The primary endpoint of HF-ACTION is a composite of all-cause mortality and all-cause hospitalization; the trial has a power ⬎0.90 to detect a clinically important reduction (ⱖ20%) in this endpoint. Secondary endpoints include composites of cardiovascular mortality and cardiovascular hospitalization, cardiovascular mortality and HF hospitalization, and each of these components singly, as well as emergency room visits, urgent care visits, changes in physiologic parameters, changes in QOL scores, resource utilization, and economic costs. Conclusions: The primary goal of the HF-ACTION trial is to provide information regarding the safety and efficacy of exercise training in patients with heart failure. The size, duration, and design of this trial will allow examination of clinically relevant endpoints such as morbidity, mortality, quality of life, and cost.
