Effect of the Calcium Antagonist Felodipine as Supplementary Vasodilator Therapy in Patients With Chronic Heart Failure Treated With Enalapril
Background Despite therapy with diuretics, ACE inhibitors and digoxin morbidity and mortality in heart failure remain high and might respond favorably to an additional vasodilator.
Methods and Results Male patients (n=450) with chronic heart failure (cardiac dysfunction and impaired exercise performance) on optimal current therapy (97% enalapril, 89% diuretics) were randomly assigned to double-blind treatment with felodipine extended release (5 mg BID) or placebo for 3 to 39 months (average, 18 months). Felodipine significantly reduced blood pressure and, at 3 months, increased ejection fraction (2.1% versus −0.1% units in the placebo group, P=.001) and reduced plasma atrial natriuretic peptide levels (−2.9 versus 26.9 pg/mL in the placebo group, P=.01) but did not improve exercise tolerance, quality of life, or the need for hospitalization. During long-term follow-up, the favorable effects on ejection fraction and atrial peptide did not persist, but felodipine prevented worsening exercise tolerance and quality of life. In the felodipine and placebo groups, mortality (13.8% versus 12.8%, respectively) and hospitalization (43% versus 42%) rates were similar, and a higher incidence of peripheral edema was the only apparent side effect of felodipine therapy.
Conclusions Felodipine exerts a well-tolerated additional sustained vasodilator effect in patients with heart failure treated with enalapril, but the only possible long-term benefit was a trend for better exercise tolerance and less depression of quality of life in the second year of treatment. The drug appears to be safe but not clearly efficacious in patients with heart failure.
Vasodilator drugs exert a favorable hemodynamic effect in patients with congestive heart failure,1 but their clinical effects have been more difficult to document. In the V-HeFT I, the vasodilator drug combination of isosorbide dinitrate and hydralazine improved exercise tolerance2 and reduced cumulative mortality compared with placebo in male veterans receiving diuretic and digoxin.3 The ACE inhibitor enalapril reduced mortality in patients with chronic heart failure in Cooperative North Scandinavian Enalapril Survival Study4 and Studies of Left Ventricular Dysfunction.5 In V-HeFT II, enalapril therapy was associated with a greater mortality reduction than the isosorbide dinitrate–hydralazine combination6 ; however, the vasodilator combination exerted a greater benefit than enalapril on exercise tolerance and LV function as assessed by serial measurements of EF.6
These observations of a different profile of effect of these drugs, buttressed by the evidence that the isosorbide dinitrate–hydralazine combination may be a more potent vasodilator than the ACE inhibitor,7 raised the possibility that adding another vasodilator to an ACE inhibitor might exert an effect greater than the ACE inhibitor alone on exercise tolerance, LV function, and long-term outcome. The vascular selective calcium antagonist felodipine ER was chosen as the test vasodilator because it would be easier to administer (two versus four times a day) and might have fewer side effects, especially headaches,3 6 than the vasodilator combination previously used. Calcium antagonists have been believed to be contraindicated in heart failure8 because of adverse clinical effects attributed to their negative inotropic properties.9 10 11 Felodipine, however, appears to be devoid of negative inotropism in clinically used doses12 13 and therefore functions almost exclusively as a vascular smooth muscle relaxant.
Most previous heart failure trials have focused either on short-term relief of symptoms and improvement in exercise tolerance or on long-term mortality. The V-HeFT studies have collected long-term physiological data in an effort to provide insight into the effects of therapy on progression of the disease and its consequent morbidity and mortality. The evidence from V-HeFT II and previous trials with flosequinan14 15 have made it clear that short-term exercise effects may not predict a long-term mortality effect. Therefore, the goal of V-HeFT III was twofold: (1) to determine whether addition of felodipine ER to enalapril could favorably affect short-term symptoms and exercise capacity over a 3-month period and (2) to determine whether the addition of felodipine ER could slow the progression of the heart failure syndrome and reduce long-term morbidity and mortality. The study was carried out in the same Veterans Affairs centers involved in V-HeFT I and V-HeFT II augmented by additional Veterans Affairs centers recruited to increase patient enrollment. Entrance criteria were similar to those in the previous trials in an effort to test the hypothesis of a beneficial effect of the ACE inhibitor–vasodilator combination in a comparable population. The study was powered to identify effects on exercise tolerance, LV function, quality of life, and plasma neurohormones with enough mortality and morbidity experience to provide some evidence for the safety of the drug and its effect on progression of the syndrome.
The primary objectives of V-HeFT III were to evaluate (1) the effect of felodipine ER compared with placebo on exercise tolerance, symptoms, and clinical signs of heart failure after 12 weeks of therapy in patients treated with enalapril and a diuretic and (2) the safety, efficacy, and tolerability of long-term treatment (up to 42 months) with felodipine ER. Other objectives were to assess the effect of felodipine ER versus placebo on NYHA functional class, Minnesota Living With Heart Failure questionnaire scores, LVEF, and PNE and ANP levels. Data on efficacy and safety were collected on all randomized patients for the duration of the study, but V-HeFT III was not powered to evaluate the effect of felodipine ER on mortality.
The study was carried out in 24 Veterans Affairs hospitals. Male patients >18 years of age with histories and physical findings of heart failure, including limited exercise tolerance caused by dyspnea or fatigue plus documentation of ventricular enlargement or dysfunction, were included if they exhibited a reduction in peak exercise performance (<14 minutes on a treadmill, modified Naughton protocol) and satisfied one of three imaging criteria. These criteria were identical to those used in V-HeFT I and V-HeFT II3 6 and included radiographic cardiothoracic ratio of ≥0.55, echocardiographic LV internal dimension at end diastole >2.7 cm/m2, or resting LVEF of ≤0.45 by radionuclide scan or contrast ventriculogram. NYHA classification was based on subjective assessment of symptoms: class IIa, slight limitation of physical activity; class IIb, moderate limitation of physical activity; class III, more marked limitation of physical activity with maximal walking distance of 200 m before resting.
Exclusion criteria, as described elsewhere,16 included the following: clinically important renal, hepatic, or hematologic disorders (serum creatinine, 3.0 mg/dL; serum potassium <3.5 or >5.5 mEq/L; or abnormal liver enzymes that were twice the upper limit of normal); severe chronic obstructive bronchopulmonary disease; inability to perform an exercise test owing to causes other than heart failure; symptomatic hypotension; aortic or mitral stenosis; hypertrophic cardiomyopathy; severe aortic or mitral valvular regurgitation; severe hypertension; hemodynamically significant pericardial disease; severe angina pectoris; acute myocardial infarction, coronary artery bypass graft surgery or angioplasty within 3 months of screening; cerebrovascular accident within 6 months of screening; symptomatic or life-threatening arrhythmias that were not controlled medically or with a defibrillator; allergy or intolerance to calcium antagonists; use of β-blockers, long-acting nitrates, or other vasodilators (except ACE inhibitors); treatment with an investigational drug within 4 weeks of screening; and other significant comorbidity that made survival or compliance with the protocol unlikely.
The target sample size of 400 patients (200 per group) would have been sufficient to provide 98% power to detect a 60-second difference in treadmill exercise duration between the two groups or 85% power to detect a 45-second difference with α=0.05 in two-tailed testing. More than 400 were enrolled to enhance the database for evaluating other end points.
Ethics and Informed Consent
The protocol and amendments were approved by each medical center’s institutional review board. At the first clinic visit, the trial objectives, study design, risks, and benefits were explained carefully to each patient, and informed written consent was obtained.
During this 2- to 12-week period, clinical stability on background treatment was documented. Enalapril was titrated to 10 mg BID in all patients unless there was a history of intolerance. Those patients who did not tolerate the minimal dose of 2.5 mg enalapril BID were allowed to participate only if enalapril was discontinued. Therefore, the ACE inhibitor–treated group was confined to patients receiving enalapril in a dose thought to be clinically effective.
In the initial protocol design, a substudy was included that provided for a digoxin/placebo randomization at a minimum of 1 month before the felodipine ER randomization. This digoxin randomization was discontinued after 144 patients had been included because of publications suggesting an adverse effect of discontinuing digoxin.17 18 An attempt was made to maintain blinded randomization in this subgroup, but in subsequent patients, maintenance of digoxin was at the discretion of the attending physician.
The modified Naughton treadmill exercise protocol has been described elsewhere.16 Two consecutive valid exercise tests were performed during the baseline period before felodipine ER or matching placebo randomization. Tests were performed at least 3 hours after a meal. Patients exercised on a motor-driven treadmill to a symptom-limited maximal effort. Heart rhythm was continuously monitored, and blood pressure was recorded in the last 30 seconds of each work stage up to peak exercise and for 5 minutes after exercise. Patients who exercised <2 or >14 minutes or whose exercise was terminated for reasons other than dyspnea or fatigue were excluded. Two successive baseline exercise treadmill tests performed at a 1- to 2-week interval could not vary by more than 10% or 60 seconds, whichever was less.
Additional tests included radionuclide EF, echocardiography, Holter monitoring, quality of life assessment with the Minnesota Living With Heart Failure questionnaire, and PNE (radioenzymatic) and ANP (radioimmunoassay) measurements. Details of these tests are provided elsewhere.16
Felodipine ER Randomization and Follow-up
Eligibility for the felodipine ER randomization required clinical stability, with no dosing change in enalapril for 6 weeks, digoxin or digoxin-placebo for 4 weeks, and loop diuretic for 2 weeks. Participants were randomized to receive oral felodipine ER or matching placebo 2.5 mg BID for 2 weeks; if well-tolerated, the dose was increased to 5 mg BID at the 2-week follow-up visit. Investigators were encouraged to maintain study patients at the 5 mg BID dose. All follow-up was double blind; only the statistical coordinating center had access to the randomization codes. Each center possessed a sealed envelope with the treatment identities for each study participant in the event of an emergency.
Follow-up visits were held at 2-week intervals for 12 weeks and then at 3-month intervals until trial completion.
Vasodilators other than enalapril and more than four tablets per week of sublingual nitroglycerin were proscribed by the study protocol. During the initial 12-week study period during which exercise tolerance was closely monitored, changes in heart failure medication within 2 weeks of a scheduled exercise test excluded, by protocol, that test from inclusion in the data set. Thereafter, if symptoms of heart failure worsened, the investigators were encouraged to use additional oral loop diuretics or, if necessary, to alter other therapy. All follow-up studies were performed regardless of change in medication on an intent-to-treat basis.
All deaths were recorded; each report included a narrative summary of the patient’s clinical status at the last study visit and the relevant details of the patient’s preterminal condition. The local investigator’s classification of the cause of death was recorded. The death reports with local classification were reviewed by the study chairman, who was not aware of the randomization code. Final adjudication of the mechanism of death was made by the study chairman for consistency.
The distributions of baseline and demographic characteristics were compared by use of the χ2 test for categorical variables and the t test for continuous variables. For each efficacy measure, change from baseline was compared at each posttreatment visit by use of the simple t test. Missing data were censored; carry-forward was not used. Survival and hospital-free survival were summarized with Kaplan-Meier curves and compared by use of the Cox proportional hazards model. In these analyses, the time of randomization was defined as time zero, and observation was censored at the close of study on March 31, 1995.
During recruitment, which began in December 1991 and ended in December 1994, 5890 patients were screened for eligibility; 5440 were excluded for various reasons, including angina requiring treatment with nitrates, calcium antagonists, or β-blockers (34.0%); inability to walk on a treadmill (15.8%); severe chronic pulmonary disease (18.1%); other serious illnesses (4.3%); residence too distant for required clinic visits (8.8%); and refusal to give consent (2.7%). The remaining 450 subjects were randomly assigned to felodipine ER (n=224) or placebo (n=226). Follow-up was terminated by trial design on March 31, 1995, and averaged 18 months. The protocol has been described in more detail elsewhere.16
Baseline variables in the two treatment groups were similar (Table 1⇓). Of the 450 patients, 55% were identified as having coronary artery disease as the cause of their heart failure, and the remaining 45% were classified as having a nonischemic cause. The average LVEF was 30%; however, 9.7% of the patients had EFs >45% because patients with a normal EF were eligible if cardiac enlargement was documented by radiography or LV dilation by echocardiography. Exercise time was similarly impaired in both treatment groups (Table 1⇓).
During follow-up, which by protocol design ranged from 3 to 39 months, 22 (10.0%) of the patients randomized to receive felodipine and 17 (7.8%) of those randomized to receive placebo permanently discontinued the study drug. Discontinuation in the first 3 months occurred in only 9 felodipine and 5 placebo patients. The average daily dose of felodipine ER taken during the maintenance phase was 8.3 mg; of placebo, the equivalent of 8.6 mg. On the basis of the intent-to-treat principle, all randomized patients were followed until they died or until the prospectively determined termination of the trial on March 31, 1995. One patient underwent heart transplantation.
Blood pressure fell significantly in the felodipine ER group and remained significantly lower than in the placebo group throughout most of the follow-up period (Fig 1⇓). Supine heart rate was reduced in the felodipine group by a mean of 0.4 to 3.3 bpm at follow-up visits, whereas it tended to increase slightly in the placebo group. The difference was significant (P<.05) for most visits in the first year of follow-up (Fig 2⇓).
Exercise duration was terminated by dyspnea or fatigue in 95% of the tests. The duration was not altered by felodipine ER during the first 12 weeks, which was a primary end point for the trial (Fig 3⇓). Thereafter, there was a trend for exercise tolerance to fall in the placebo arm but not in the felodipine ER arm. The difference between the exercise times reached significance at 27 months after randomization (n=86, P=.01).
Radionuclide EF was measured at baseline and at 3 and 12 months after randomization. EF was significantly increased in the felodipine ER group at 3 months (n=204; 2.1±7.0% [mean±SD]) compared with the placebo group (n=200; −0.1±6.0%; P=.001). This difference did not persist at 12 months. (Table 2⇓).
Quality of Life Assessment
The Minnesota Living With Heart Failure questionnaire was administered twice at baseline and at 3-month intervals throughout the study. At baseline, the mean scores of 33.6 in the felodipine group and 30.9 in the placebo group indicated moderate impairment in quality of life. No significant difference was observed between the two treatment arms during early follow-up, but a trend for less worsening in the felodipine group became significant (n=112; P=.038) at 27 months, the same time period in which this group displayed significantly better exercise tolerance than in the placebo group. (Fig 4⇓). NYHA classification did not differ significantly between the groups during follow-up.
PNE and plasma ANP levels were measured at baseline and at 3 months and 1, 2, and 3 years after randomization. The change in ANP between baseline and 3 months was significantly (P=.01) different in the felodipine ER group (n=185; −2.9±101.5 pg/mL) than in the placebo group (n=186; 26.9±120.6 pg/mL; Fig 5⇓). The difference at 12 months was not significant (P=.18) by analysis of raw data but was significant (P=.03) if the ANP values were log transformed. This statistical difference did not persist on subsequent measurements. PNE did not differ between the treatment arms. Both ANP and PNE rose progressively during prolonged follow-up.
During the entire follow-up period, 96 patients randomized to felodipine ER (43%) and 96 randomized to placebo (42%) had at least one hospitalization. Hospitalization for a cardiovascular cause occurred in 71 in the felodipine ER group and 68 in the placebo group. This difference was not significant. The time to first hospitalization also was not significantly different between the groups. A similar percentage of patients in class II heart failure required hospitalization in the felodipine and placebo groups, whereas in class III heart failure, fewer patients in the felodipine treatment group than in the placebo group required hospitalization (Table 3⇓).
During the first 3 months after randomization, there were slightly more hospitalizations in the felodipine group (n=33, 14.7%) than in the placebo group (n=24, 10.6%; P=.67). This modest difference disappeared during longer-term follow-up.
The only adverse event significantly more common in the felodipine group was edema, which was reported at least once during follow-up in 47 (21%) of patients in the felodipine group and 29 (12.8%) of patients in the placebo group (P=.02). Other adverse events were similar in the two treatment arms (Table 4⇓).
During the first 3 months after randomization, there were a few more adverse events in the felodipine group (n=167) than in the placebo group (n=156) that were related to more patients with peripheral edema assigned to felodipine (n=28) than to placebo (n=11). The diagnosis of worsening heart failure based on pulmonary congestion was made during the first 3 months in 32 felodipine and 23 placebo patients. This trend for early events in the felodipine group did not persist after 3 months.
An increase in diuretic dose was prescribed during the first 30 days in 16.6% of the felodipine group and 12.3% of the placebo group (P=.21). During the first year after randomization, diuretic dose was increased in 25.0% of the felodipine group and 20.5% of the placebo group (P=.38).
During the follow-up period, 60 patients died: 31 (13.8%) in the felodipine arm and 29 (12.8%) in the placebo arm (Fig 6⇓). Mortality was therefore similar in the two treatment groups, but the study was not powered to test for a difference. The risk ratio for felodipine versus placebo mortality was 1.084, with a 95% confidence interval of 0.653 to 1.799. Mortality also was similar in the two treatment arms in different NYHA classification groups (Table 5⇓).
Assessment of the combined end point of hospitalization and mortality also revealed no difference between the treatment groups. Time to first event was similar in NYHA classes IIa (P=.67) and IIb (P=.38) but tended to be improved by felodipine in class III (P=.02), largely because of the fewer patients requiring hospitalization in this treatment group.
There were slightly fewer deaths in the felodipine arm of the subgroup with heart failure caused by coronary artery disease and slightly fewer deaths in the placebo arm of the subgroup with a diagnosis of nonischemic cardiomyopathy (Table 6⇓). The adjudicated mechanism of death in the two treatment arms is also shown in Table 6⇓.
Growing evidence supports the concept that short-term symptom relief and long-term benefit on morbidity and mortality in heart failure may be influenced independently.19 Exercise tolerance and quality of life assessment often are used as quantitative surrogates for symptom relief. Because sympathetic stimulation and progressive functional depression or structural remodeling of the left ventricle appear to be markers for shortened life expectancy,20 21 these measurements may serve as a guide to effects on long-term morbidity and mortality. The goal in V-HeFT III was to assess all these end points with a focus on early changes in exercise tolerance and long-term effects on morbidity, mortality, LV structure and function, and PNE and ANP concentration.
Exercise tolerance is best studied in short-term trials of <6 months when this physiological measurement will not be seriously confounded by deaths and dropouts. Long-term morbidity and mortality are measures of the progression of the disease, which should be marked by a reduction in EF and an increase in neurohormones. As a potent vasodilator, it was hoped that felodipine ER added to enalapril would augment exercise tolerance and improve LV function or structure, much as isosorbide dinitrate and hydralazine did in the absence of an ACE inhibitor in V-HeFT I and V-HeFT II.5
Not all vasodilators, however, exert a favorable effect on symptoms or mortality despite a desirable hemodynamic effect. In V-HeFT I, prazosin, the α-adrenoceptor antagonist, failed to increase exercise tolerance or reduce mortality despite a persistent lowering of blood pressure.3 The calcium antagonist nifedipine has exerted an unfavorable short-term effect on symptoms in heart failure,10 11 and flosequinan, a potent vasodilator, exhibited a favorable short-term effect on exercise tolerance14 but an adverse effect on longer-term mortality.15 This differential effect of various vasodilators is probably related to actions other than vascular smooth muscle relaxation.
The most attractive possibility is that the differential effect of vasodilators resides in their direct action on the structure of the LV myocardium. α-Adrenergic receptor blockade in an animal model of LV remodeling appears not to affect LV mass or volume,22 which are reduced by nitrates23 and ACE inhibitors.22 24 25 Progressive LV remodeling is characterized by an enlargement in end-diastolic volume, and its regression should be associated with a decrease in this volume. Because the EF is a ratio with end-diastolic volume as the denominator and because the numerator (stroke volume) should stay the same or decrease as remodeling progresses, a decreasing EF should be a useful surrogate for remodeling. A long-term increase in EF, therefore, should imply a regression of remodeling. Acute changes in loading conditions may induce short-term alterations in EF, but structural changes should predominate during long-term follow-up. A clinical antiremodeling effect is suggested by the long-term increase in LVEF observed in V-HeFT I and II in response to the nitrate-hydralazine combination and an ACE inhibitor but not to prazosin.21 The favorable effect on remodeling may be related to a myocardial growth-inhibiting effect of some vasodilators.26 Other actions, including cardiac stimulation, cardiac depression, reflex tachycardia, and sodium retention, also may vary among the vasodilator drugs.
Dihydropyridine calcium antagonists are potent arterial vasodilators that are widely used for the treatment of hypertension and ischemic heart disease. In some reported series of patients with heart failure, >30% of the population were receiving a calcium antagonist,5 presumably for an indication other than heart failure. Because felodipine is devoid of negative inotropic properties12 13 and is effective in reversing LV hypertrophy in hypertensive subjects,27 it is important to know not only whether the drug is effective in the treatment of heart failure but also whether it is safe in such patients if used for another clinical condition. ACE inhibitors had been established as standard therapy for heart failure at the time this study was initiated28 29 ; therefore, enalapril, if tolerated, served as background therapy in the study population.
Felodipine ER appeared to exert a desirable hemodynamic effect in the V-HeFT III study population. A lowering of blood pressure confirmed its potency as a vasodilator. The absence of reflex tachycardia—indeed a significant cardiac slowing—may not only reflect its extended release but also relate to the depressed baroreceptor function in heart failure or to a possible improvement in LV function. A reduced ANP level at 3 months, perhaps persisting for a year, compared with the placebo group suggests an early decrease in atrial pressures in response to felodipine.30 An increase in LVEF at 3 months suggests improved LV emptying and/or a regression or slowing of the structural remodeling process in the left ventricle. This latter effect, however, did not appear to persist.
Despite these modestly favorable hemodynamic and hormonal effects, however, felodipine ER therapy was not associated with clear-cut short-term or long-term clinical benefit. During the first 3 months after randomization, there was a nonsignificant trend toward more adverse events in the felodipine ER group, related primarily to an increased incidence of edema. A similar trend was observed by Littler et al31 in a 12-week study of felodipine versus placebo in 252 patients with heart failure, only 61% of whom were receiving an ACE inhibitor. No long-term benefit on morbidity or mortality could be demonstrated in the present study, although exercise tolerance and quality of life may have been maintained better and there was a trend for fewer NYHA class III patients to require hospitalization in the felodipine ER group than the placebo group. The cause of heart failure did not strikingly influence the long-term response to felodipine ER. This observation, although underpowered, stands in sharp contrast to the results in a trial with another calcium antagonist, amlodipine, which appeared to exert a favorable mortality effect in the nonischemic population but not in the group with coronary artery disease.32 The possible surrogates for long-term response, EF and PNE, were not uniformly affected. EF exhibited a modest increase at 3 months, but PNE was not affected by felodipine because it rose progressively in both groups, as it has in other trials.33
This study, therefore, does not support the concept that a dihydropyridine calcium antagonist can strikingly augment the favorable clinical response to ACE inhibitors in heart failure. Nonetheless, the data suggest that felodipine ER can be used safely in patients with heart failure if used for another indication. Furthermore, this study provided no evidence for an excess of cardiovascular events in response to dihydropyridine therapy, as suggested by other recent analyses.34
Selected Abbreviations and Acronyms
|ANP||=||atrial natriuretic peptide|
|NYHA||=||New York Heart Association|
|V-HeFT||=||Vasodilator Heart Failure Trial|
The following individuals and institutions participated in V-HeFT III.
Study Chairman’s Office (Minneapolis, Minn): Jay N. Cohn, MD (study chairman); Susan Ziesche, RN (study coordinator); and JoAnn Underhill (secretary).
Department of Veterans Affairs Medical Centers in the following cities (principal investigators and study coordinators): Albuquerque, NM: Milton Icenogle, MD, and Jean-Pierre Letellier; Atlanta, Ga: Robert Taylor, MD, and Alberta Lane, RN; Birmingham, Ala: Gilbert Perry, MD, Edmund Brown, RN, and Barbara Saunders, RN; Boston, Mass: William E. Boden, MD, Chester H. Conrad, MD, PhD, and Deborah Syat, RN; Bronx, NY: Lawrence Baruch, MD, Proserfino Patacsil, RN, and Selvakumar Chockalingam, MD; Cincinnati, Ohio: Geetha Bhat, MD, Julie Moore, RN, Lynn Smith, RN, and Susan Burwig, RN; Durham, NC: Frederick Cobb, MD, Gwen Dodson, RN, Jean Wilson, RN, and Johnny Etheridge, RN; Fresno, Calif: Prakash Deedwania, MD, and Rebecca Kanefield, RN; Hines, Ill: Henry Loeb, MD, and Ann Henrick, PhD, RN; Little Rock, Ark: James Doherty, MD, and Barbara Cotter, LPN; Loma Linda, Calif: Thomas Heywood, MD, and Amanda Somma, RN; Milwaukee, Wis: C. Vincent Hughes, MD, Grace Daniels, LPN, and Jean Bochert, RN; Minneapolis, Minn: Inder Anand, MD, Shelley Berg, RN, and Anne McCauley-Steckler, RN; Nashville, Tenn: Raphael Smith, MD, Barbara Smith, RN, and Kathy Watkins, RN; Palo Alto, Calif: Edwin Atwood, MD, and Susan Quaglietti, RN; Philadelphia, Pa: W. Bruce Dunkman, MD, Peter Rochin, RN, Liisa Norman, RN, Barbara Murphy, RN, and Donita Gleaves, RN; Pittsburgh, Pa: Morteza Amidi, MD, JoAnn Klein, RN, Julie Puhlman, RN, and Marilyn Bell, RN; Portland, Ore: Henry De Mots, MD, and Lori Gray, RN; San Antonio, Tex: Avanindra Jain, MD, and Deborah Berg, RN; San Diego, Calif: Ralph Shabetai, MD, and Rosemary Cremo, RN; Tampa, Fla: Guillermo Cintron, MD, James Parks III, RN, Joyce Eason, RN, and Connee Parks; Tucson, Ariz: Steven Goldman, MD, Julia Brandt, RN, and Janet Acuna, LPN; Washington, DC: Peter E. Carson, MD, and Joseph Orndorff, RN; West Haven, Conn: Ira Cohen, MD, Luisa Canestri, RN.
Core Laboratories: Central Norepinephrine Laboratory, Minneapolis, Minn: Jay N. Cohn, MD; technical director: Dianne Judd, MS. Central ECG Holter Tape Laboratory, Veterans Affairs Medical Center, Washington, DC: director: Ross Fletcher, MD; technician: Mason Platt. Central Echocardiographic Laboratory, Veterans Affairs Medical Center, West Los Angeles, Calif: director: Maylene Wong, MD; technician: Becky Lopez, RN.
Biostatistical Support: Wayne, Pa: George Anderson, PhD, and Terry Flanagan, MPH; Charlotteville, Va: Teresa Germanson, PhD.
Data Safety Monitoring Board: Richard Gorlin, MD (chairman), Mt Sinai School of Medicine, New York, NY; William Parmley, MD, University of California Medical Center, San Francisco; Genell Knatterud, PhD, Maryland Medical Research Institute, Baltimore; John A. Oates, MD, Vanderbilt University School of Medicine, Nashville, Tenn.
This work was supported by Medical Research Service, Department of Veterans Affairs, and by grants from Astra Merck, Inc, Astra Hässle, and Merck Research Laboratories.
↵1 A complete list of the participants in this research study appears in the “Appendix.”
- Received December 31, 1996.
- Revision received May 14, 1997.
- Accepted May 15, 1997.
- Copyright © 1997 by American Heart Association
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Culling W, Ruttley MSM, Sheridan DJ. Acute hemodynamic effects of felodipine during β-blockade in patients with coronary artery disease. Br Heart J. 1984;52:431-434.
Cheng C-P, Igarashi Y, Pettersson K, Little WC. Effect of felodipine on left ventricular performance in conscious dogs: assessment by left ventricular pressure-volume analysis. J Pharm Exp Ther. 1991;257:163-169.
Massie BM, Berk MR, Brozena SC, Elkayam U, Plehn JF, Kukin M, Packer M, Murphy BE, Neuberg GW, Steingart RM, Levine TB, deHaan H, for the FACET Investigators. Can further benefit be achieved by adding flosequinan to patients with congestive heart failure who remain symptomatic on diuretic, digoxin, and an angiotensin converting enzyme inhibitor? Circulation. 1993;88:492-501.
Packer M, Rouleau J, Swedberg K, Pitt B, Fisher L, Klepper M, for the PROFILE Investigators. Effect of flosequinan on survival in chronic heart failure: preliminary results of the PROFILE study. Circulation. 1993;88(suppl I):I-301. Abstract.
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Littler WA, Sheridan DJ, for the UK Study Group. Placebo controlled trial of felodipine in patients with mild to moderate heart failure. Br Heart J. 1995;73:428-433.
Packer M, O’Connor CM, Ghali JK, Pressler ML, Carson PE, Belkin RN, Miller AB, Neuberg GW, Frid D, Wertheimer JH, Cropp AB, DeMets DL, for the Prospective Randomized Amlodipine Survival Evaluation Study Group. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med. 1996;335:1107-1114.
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