Drugs 47 (Suppl. 4): 47-58, 1994 00 12-6667/94/0400-0047/$6.00/0 © Adis International Limited. All rights reserved.

DRSUP3876

Vasodilators in Heart Failure Conclusions from V-HeFT II and Rationale for V-HeFT III

Jay N. Cohn Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA

Summary The Veterans Affairs Vasodilator-Heart Failure Trials (V-HeFT I and II) provided information about heart failure treated with conventional therapy, and evaluated the long term efficacy of vasodilators. In V-HeFT I, the combination of hydralazine and isosorbide dinitrate provided a beneficial effect on prognosis in heart failure. V-HeFT II demonstrated that enalapril had a more favourable effect on 2-year survival than a combination of hydralazine plus isosorbide dinitrate. However, the hydralazine-isosorbide dinitrate combination exerted the most favourable short term impact on exercise performance and left ventricular ejection fraction.

The V-HeFT studies showed that, although not all vasodilators are alike, their differing effects might be beneficial when used in combination. Determination of the potential additive effect of the calcium antagonist felodipine, a vasodilator, when used in combination with an ACE inhib­itor, is the major goal of V-HeFT III.

The Vasodilator-Heart Failure Trials (V-HeFT) were planned 14 years ago, when few data were available on the prognosis of patients with heart failure. Previous haemodynamic studies had dem­onstrated a marked haemodynamic effect of va­sodilator drugs when administered to patients with chronic congestive heart failure (Awan et al. 1981; Chatterjee et al. 1978; Cohn & Franciosa 1977; Guiha et al. 1974; Pierpont et al. 1978); however, the effects of these drugs on prognosis had not been explored.

The two V-HeFT trials (V-HeFT I and V-HeFT II) provide a database of patients with heart failure treated with digoxin and diuretic whose progress was followed for an average period of 2.3 years (V-HeFT I) and 2.5 years (V-HeFT II). During this time, comparative assessments of the effects of pla­cebo, prazosin, and the combination of hydrala-

zine plus isosorbide dinitrate (V-HeFT I), as well as of the effects of enalapril and the combination of hydralazine plus isosorbide dinitrate (V-HeFT II), were made. The V-HeFT trials encompass physiological assessments with morbidity and mortality end-points in rigorously selected patient groups of modest size. Other studies focusing on mortality as the only end-point have included less rigorously selected groups of heart failure patients. However, it is most likely that the lower sample sizes used in the V-HeFT trials contributed to the modest p-values obtained in these trials.

The philosophy behind the approach taken in the V-HeFT trials was that therapy for patients with heart failure should focus not only on improved survival, but on intermediate end-points that may correlate with patient quality-of-life. A physiolog­ically rational therapy producing beneficial effects

48

on morbidity would be clinically justifiable even if the confidence interval for a favourable effect on mortality did not exceed 90% 'or 95%.

When designing large scale heart failure st\ldies, one presupposes that the disease affects the patient population in a homogeneous manner. It is as­sumed that a response among individual subjects that is sufficiently uniform to allow a global rec­ommendation demonstrates the efficacy of an in­tervention. Little is known, however, about the de­terminants of therapeutic responses; many questions need to be answered before the thera­peutic approach to heart failure is considered to be rational. Moreover, it is highly unlikely that mod­ification of a single mechanism will fundamentally alter the natural history of the disease. The q\lest for a single therapeutic intervention may therefore be counterproductive. Instead, therapy derived from the results of V-HeFT and similar clinical trials aspires to create a process of'bu,ilding blocks', whereby a single treatment is added to another in an effort to modify the progress of the disease.

V-HefT measured the majority of evaluable critical variables influ,encing the prognosis of patients with heart failure and its response to therapy. It was hoped that the physiological para­meters monitored, in addition to long term follow­up prognostic information, would provide a rich database from which new insights would arise and new hypotheses would be generated for further in­vestigation. Moreover, the sequential design of the two V-HeFT studies in identical patient popula­tions allowed observations from the V -HeFT I data set to be retested in the V-HeFT II data set. This retesting technique provided greater confidence in the assessment of the quantitative importance of left ventricular ejection fraction, peak oxygen con­sumption, cardiothoracic ratio, and Holter moni­toring in the prognosis of patients with heart fail­ure. Other methods of evaluating heart failure, such as quality-of-life assessments and exercise testing, were also addressed .. Although a great deal has been learned from the first two V-HeFT trials, they still offer a significant database for further analysis.

V-HeFT I (Cohn et al. 1986) was undertaken to gain insight into the natural history of heart failure

Drugs 47 (Suppl. 4) 1994

treated with conventional therapy, and to eval\late the long term efficacy of 2 vasodilator regimens in heart failure when compared with placebo. Com­pleted in 1985, V-HeFT I demonstrated a favour­able effect of hydralazine plus isosorbide dinitrate combination therapy on prognosis in male patients with heart failure. The study established a clear rationale for vasodilator therapy in heart failure.

Given the popularity of angiotensin converting enzyme (ACE) inhibitor therapy as 'vasodilator therapy', it was important to compare the hydral­azine-isosorbide dinitrate combination with an ACE inhibitor in the subsequent study, V-HeFT II. En­alapril, which had significantly reduced mortality in the CONSENSUS trial (CONSENSUS Trial Study Group 1987), was chosen as the comparator. A placebo group was not included in V-HeFT II because the results of V-HeFT I no longer justified the exposure of a large population of patients with heart failure to therapy that did not include vasodilators.

V-HeFT II (Cohn et al. 1991) demonstrated a more favourable effect with enalapril than with hy­dralazine and isosorbide dinitrate on 2-year sur· vival in male patients with chronic heart failure. In both V -HeFT trials, the vasodilators prolonged s\lrvival by varying degrees. In V-HeFT I, survival was 66% at 2 years in the placebo group. A similar survival rate was noted 10 months later in the hy­dralazine plus isosorbide dinitrate groups in both V-HeFT I and V-HeFT II, and 17 months later in the enalapril arm of V-HeFT II (fig. 1). However, the hydralazine plus isosorbide dinitrate combin­ation exerted a more favourable effect on exercise performance and left ventricular ejection fraction than enalapril.

The lesson from the V -HeFT studies is that not all vasodilators are alike; prazosin, which exerted a sustained vasodilator effect in V -HeFT I, did not favourably affect survival, whereas the hydralazine and isosorbide dinitrate combination did. The ACE inhibitor enalapril, which probably produces less vasodilation than the hydralazine isosorbide dini­trate combination, exerted a more favourable ef­fect on survival.

Vasodilators, therefore, should not be viewed as

Vasodilators in Heart Failure: V-HeFT Trials

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V-HeFT II Enalapril Hyd-Iso

49

0.00 +--,.----,;--~-_+-~--..JLr_-~__.-~-__r___, o 6 12 18 24 30 36 42 48 54 60 66

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Fig. 1. Survival curves for patients in Veterans Affairs Vasodilator-Heart Failure Trials (V-HeFT) I and II. Hyd-Iso = hy­dralazine-isosorbide dinitrate. (After Cohn 1993a. Reproduced with permission. Circulation. Copyright 1993, American Heart Association. )

a group of homogeneous compounds, but rather as a heterogeneous group of agents affecting the com­plex syndrome of heart failure in significantly dif­ferent ways. An evaluation of the effects of thera­peutic regimens on various indices of the severity of heart failure may provide some clues concern­ing the degree of heterogeneity associated with vasodilators.

1. Effects of Vasodilator Therapy on Left Ventricular Ejection Fraction

Left ventricular ejection fraction (L VEF) has been identified as one of the most important pre­dictors of mortality in heart failure (Cohn & Rec­tor 1988; Keogh et al. 1990). Although most stud­ies have analysed L VEF at one point during a study period, L VEF may vary throughout the course of the disease. The implications of variations detected when assessing serial L VEF in heart failure patients have not been determined with any certainty.

L VEF was one of the sequential physiological measurements performed in V-HeFT (at baseline, 8 weeks, 28 weeks, 1 year and every 6 months thereafter in V-HeFT I; at baseline, 13 weeks, and yearly thereafter in V-HeFT II; Cintron et al. 1993). In V-HeFT I, L VEF fell progressively among sur-

vivors in the placebo group over 4 years. This de­cline reflected a progressive worsening of left ven­tricular function, which was viewed as remodelling of the left ventricle. Moreover, in V-HeFT I, pra­zosin (an lXI-blocker) exerted no significant effect on the progressive decline in ventricular function in survivors, and therefore did not have any anti­remodelling action. In contrast, the hydralazine­isosorbide dinitrate combination exhibited a fa­vourable effect on L VEF in V-HeFT I, which re­sulted in a highly significant improvement for the first 2 years. After 4 years, there was still no pro­gressive evidence of remodelling in survivors who were re-treated with hydralazine plus isosorbide dinitrate. V-HeFT I results therefore indicated a correlation between the change in ejection fraction and the mortality benefit observed with hydrala­zine plus isosorbide dinitrate.

Indeed, when the change in ejection fraction in V-HeFT I was assessed as a predictor of subse­quent survival, regardless of therapy, the ejection fraction change from baseline to 6 months was closely associated with the subsequent course of the disease (fig. 2; Cintron et al. 1993). In patients whose ejection fraction rose by a minimum of 10%, there was a very favourable effect on long term sur­vival after the 6-month measurement. In patients

50

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Fig. 2. Proportion of survivors over 72 months in patient groups determined by change in ejection fraction (%) from baseline to 6 months (p < 0.0001 for all curves) in the Vet­erans Affairs Vasodilator-Heart Failure Trial (V-HeFT) I. EF = ejection fraction. (After Cintron et al. 1993. Reproduced with permission. Circulation. Copyright 1993, American Heart Association.)

whose ejection fraction rose by between 5 and 10%, there was an intermediately favourable effect on survival, whereas the worst outcome was seen in those whose ejection fraction remained unchanged or fell in the 6-month period. Therefore, changes in ejection fraction, which reflect haemodynamic responses to both the vasodilatory and anti-re­modelling effects of vasodilators, are likely to be important determinants of the subsequent course of congestive heart failure.

In V-HeFT II, the hydralazine-isosorbide dini­trate combination improved ejection fraction for the first 2 years to a greater extent than enalapril (fig. 3). This further attests to the potentially more effective haemodynamic response to hydralazine plus isosorbide dinitrate than to enalapril (Cintron et al. 1993). In subjects receiving hydralazine plus isosorbide dinitrate, a significant improvement in ejection fraction and a less favourable effect on survival were observed.

The apparent differences in the effects of ena­lapril and hydralazine plus isosorbide dinitrate could possibly be explained by observing the re­lationship between the change in ejection fraction and subsequent mortality. Figure 4 describes this relationship in V-HeFT II (from baseline to 1 year) after randomisation in the 2 treatment arms. The

Drugs 47 (Suppl. 4) 1994

left-hand side shows the frequency of patients fall­ing into I of the following 4 groups: group I, those whose ejection fractions declined; group II, those whose ejection fractions stayed the same; group III, those whose ejection fractions increased moder­ately; and group IV, those whose ejection fractions increased by more than 10% over 1 year. The en­alapril treatment group had more patients in group II (unchanged ejection fractions) and fewer patients in groups III and IV (improved ejection fractions) than the hydralazine-isosorbide dinitrate treatment group. Thus, hydralazine plus isosorbide dinitrate had a better effect on ejection fraction than enalapril. In 3 of the 4 groups (i.e. I, II and III), I-year cumulative mortality rates were lower with enalapril than with hydralazine plus isorbide di­nitrate. Moreover, enalapril had a better effect on prognosis for the same degree of improvement in ejection fraction. This improved prognosis with enalapril is the central message from V-HeFT II. Importantly, there is more than one treatment­related factor contributing to improved prognosis.

2. Exercise Performance and Prognosis in Heart Failure

Reduced exercise capacity, a hallmark of chronic heart failure, is commonly associated with a de­crease in the quality-of-life of patients with this dis-

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Fig. 3. Mean change in ejection fraction (%) over 2 years in patients receiving the hydralazine-isosorbide dinitrate (Hyd­Iso) combination or enalapril in the Veterans Affairs Vaso­dilator-Heart Failure Trial (V-HeFT) II. * p < 0.0001 vs base­line;t p < 0.05 Hyd-Iso vs enalapril.

Vasodilators in Heart Failure: V-HeFf Trials 51

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Fig. 4. Percentage of patients in each treatment subgroup by change in ejection fraction (EF) [left] and I-year mortality for treatment subgroups by change in EF (right) in Veterans Affairs Vasodilator-Heart Failure Trial (V-HeFT) II. Group I: EF decreased by greater than 5%; Group II: EF did not change; Group III: EF increased by greater than 5%; Group IV: EF increased by greater than 10%. Hyd-Iso = hydralazine-isosorbide dinitrate.

ease. An inadequate understanding of the mech­anisms influencing exercise tolerance (Sullivan et al. 1989) and the lack of association between acute systemic haemodynamic improvement and an im­mediate increase in peak exercise capacity (Fran­ciosa & Cohn 1979a,b; Kugler et al. 1982; McGrath et al. 1985; Rubin et al. 1979) explain why the mechanism by which drug treatment may produce a delayed increase in exercise capacity is not understood. Furthermore, the relationship between a patient's ability to perform daily activities and his or her change in peak exercise capacity has not been completely defined (Cohn & Rajfer 1990). Nonetheless, peak exercise capacity was found to be an independent prognostic marker of mortality in heart failure (Cohn et al. 1993; Szlachcic et al. 1985). Moreover, exercise performance has been favourably altered by drug therapy in several pla­cebo-controlled short term trials in heart failure patients (Aronow et al. 1977; Captopril Multicen­ter Research Group 1983; Colucci et al. 1980; Creager et al. 1985; Drexler et al. 1989; Enalapril Congestive Heart Failure Investigators 1985; Fran­ciosa & Cohn 1979a,b; Franciosa et al. 1980, 1982; Kramer et al. 1983; Leier et al. 1983; Rubin et al. 1979; Sharpe et al. 1984). The therapeutic regimens in V -HeFT I and II were evaluated, in terms of

their influence on exercise tolerance, in order to define the effects of long term vasodilator therapy on exercise performance in patients with chronic congestive heart failure. Serial bicycle ergometric exercise tests were performed with gas exchange measurements during progressive incremental work rates to a symptom-limited peak end-point. In V­HeFT II, gas exchange anaerobic threshold (AT ge)

measurements were also made. In V-HeFT I, the increase in mean peak oxygen

uptake (V02) in patients treated with the hydral­azine plus isosorbide dinitrate combination ap­proached significance (compared with values in placebo recipients) at 2 months (p < 0.16) and was significant at I year (p < 0.04).

In V-HeFT II, a discrepancy between survival and peak exercise capacity over the first 2 years was observed (fig. 5; Ziesche et al. 1993). For the first 26 weeks, and again at 2 years, the hydrala­zine-isosorbide dinitrate combination had a more favourable effect on peak exercise performance than enalapril. This evidence presents another paradox, which is that the use of one drug combination may improve exercise performance more than another combination, without necessarily having as great an impact on long term survival. The profiles of the 2 regimens studied in V-HeFT II (i.e. ACE in-

52

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Drugs 47 (Supp/. 4) 1994

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Fig. 5. Mean change from baseline in peak oxygen consumption over 2 years per treatment arm in the Veterans Affairs Vasodilator-Heart Failure Trial (V-HeFT) II. Hyd-Iso = hydralazine-isosorbide dinitrate. * p < 0.0001 vs baseline; t p < 0.05 vs enalapril.

hibitors and vasodilators) therefore appear to differ significantly in heart failure.

3. Heart Failure Treatment with a Single Agent is Not Ideal

The differing effects of heart failure treatments can be used to advantage. At least 2 independent processes occur in the long term course of heart failure (fig. 6). The first process takes place in the myocardium, where ventricular dysfunction leads to progressive remodelling, which is hypothesised to contribute to both pump failure and sudden death. Superimposed on this progressive process in the left ventricle are a host of peripheral factors, including neurohormonal stimulation, vasocon­striction, volume retention, etc. These peripheral factors contribute to exercise intolerance and to the symptoms of heart failure, and may also lead to progressive remodelling via neurohormonal stimu­lation, autocrine-paracrine factors, or left ventricle

loading by vasoconstriction-induced impedance. Because these factors contribute to remodelling, they are all liable to increase the severity of symp­toms and the possibility of death.

Do the V-HeFT trials explain the more favour­able effect of enalapril treatment on survival than on improvement in left ventricular function in the first 2 years? The explanation could be ascribed to the beneficial effect of enalapril on neurohormonal mechanisms. In V-HeFT II, plasma noradrenaline levels for the first year after randomisation were significantly lower in patients treated with en ala­pril than in those treated with hydralazine plus iso­sorbide dinitrate (fig. 7). However, both groups showed a progressive rise in plasma noradrenaline over time. This suggests a progression of heart fail­ure. While plasma noradrenaline levels can be at­tenuated for a period of time in response to ACE inhibitor therapy, none of these drugs have alone been successful in attenuating or completely block­ing progression of the disease. In heart failure

Vasodilators in Heart Failure: V-HeFT Trials

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53

Fig. 6. Processes involved in the long term progression of heart failure. (After Cohn 1993b. Reproduced with permission. Circulation. Copyright 1993, American Heart Association.)

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Fig. 7. Mean change from baseline in plasma noradrenaline (pg/ml) over 48 months by treatment group in the Veterans Affairs Vasodilator-Heart Failure Trial (V-HeFT) II. Hyd-Iso = hydralazine-isosorbide dinitrate; * p < 0.05. (After Francis et al. 1993. Reproduced with permission. Circulation. Copyright 1993, American Heart Association.)

54

patients, exercise performance and quality-of-Iife progressively fall over time. Despite multiple drug treatment, the mortality rate associated with heart failure remains unacceptably high. Thus, the mag­nitude of the effect of current therapies is modest at best.

There are 2 important target organs in the man­agement of heart failure: the myocardium and the systemic vasculature (fig. 8). The progressive changes that take place in these organs are most probably related to the influence of a combination of haemodynamic load, neurohormonal stimula­tion, and growth factors. Interference with all of these factors may be critical for producing a fa­vourable effect in the long term treatment of heart failure.

Attempts to block growth factors depend on the ability to identify the critical factors involved. Mo­lecular biology clearly plays an important role in this regard. Although the effects of haemodynamic load are prominent with vasodilators, other com­binations may be more effective than those in use today. For instance, attempts to block neurohor­monal stimulation have taken many forms. There are several potential mechanisms for inhibiting the processes that appear to contribute to the progres­sion of heart failure.

Drugs 47 (Suppl. 4) 1994

4. Goals of V-HeFT III

We can conclude from V-HeFT II that both en­alapril and hydralazine plus isosorbide dinitrate exert favourable effects on the course of heart fail­ure. The greater benefit of enalapril on mortality, and of hydralazine plus isosorbide dinitrate on other end-points, suggests that these agents could have additive benefits in the management of patients treated with digoxin and diuretic. Deter­mination of these additive effects constitutes one of the goals of V-HeFT III.

The desired attributes of a vasodilator under consideration for addition to an ACE inhibitor in a heart failure trial are outlined in table I. The va­sodilator should reduce impedance to left ventric­ular ejection, and should preferably increase ven­ous capacitance, although the latter may have already been accomplished by the ACE inhibitor. The targeted vasodilator should improve left ven­tricular ejection fraction and reduce heart size, both of which are factors that are critical to inhibition of progression of the syndrome. While preferably not activating neurohormonal mechanisms, the vasodilator should have an anti proliferative effect, which slows the progression of left ventricular dys­function by inhibiting cardiac and vascular remo­delling. The potential antiproliferative effects of

Neurohormonal stimulation

Growlh factors

I Hypertrophy

// t I Myocardium I

Perfusion

Haemodynamlc load

Fig. 8. Effects on the heart and the systemic vasculature, target organs in heart failure.

Growlh factors

I Hypertrophy

+ remodelling

Vasodilators in Heart Failure: V-HeFT Trials

Table I. Desirable pharmacodynamic effects of vasodilators in heart failure trials

Reduced impedance to left ventricular ejection

Increased venous capacitance Increased left ventricular ejection fraction and reduced heart

size

Absence of stimulation of neurohormonal mechanisms Slowed progression of left ventricular dysfunction (inhibition

of cardiac and ventricular remodelling)

various vasodilator drugs at a clinical level are not yet entirely known. The hydralazine-isosorbide di­nitrate combination meets a number of the above criteria, and thus would be an appropriate com­bination for use with an ACE inhibitor. However, in V-HeFT III, the vasoselective calcium antag­onist felodipine was chosen, because it is believed to have certain advantages over the hydralazine­isosorbide dinitrate combination.

Concerns about the use of calcium antagonists as monotherapy in heart failure may not apply to the combined use of a calcium antagonist with an ACE inhibitor, especially if an antagonist with minimal negative inotropic effects, such as felo­dipine, were used. Such a vasodilator would be li­able to have a favourable effect on left ventricular performance. If a pure vasodilator were admini­stered to a heart failure patient 'operating' on a lower part of the impedance vs stroke volume curve, that patient would ascend the curve and experience strikingly improved left ventricular systolic per­formance (fig. 9, curve A). Use of a calcium ant­agonist with a negative inotropic effect might de­press the impedance vs stroke volume curve, because of reduced impedance from the potent va­sodilator and an improved stroke volume (fig. 9, curve B). The beneficial effects of a calcium ant­agonist and an ACE inhibitor combination may well be related to favourable effects on left ventricular systolic performance, even in the face of decreased contractility. If contractility were not lowered, a more favourable effect on systolic performance would be expected.

Felodipine, the calcium antagonist in V-HeFT

55

III, should compare favourably with the hydrala­zine-isosorbide dinitrate combination used in V­HeFT I and II. There should be fewer side effects associated with felodipine, allowing a larger per­centage of the patients to remain on 'full' dosages of the drug. With hydralazine plus isosorbide di­nitrate, a reduction in dosage was required because of headache in about 20 to 30% of the patient population. In addition, the twice-daily felodipine dosage regimen is simpler than the 4-times daily regimens of hydralazine and isosorbide dinitrate that were necessary in the earlier V-HeFT trials. It is believed that nitrate tolerance should also be less of a concern with felodipine than with the hydral­azine-isosorbide dinitrate combination.

Several mechanisms may be involved in the fa­vourable response produced by the combination of enalapril and felodipine. The calcium antagonist, added to the ACE inhibitor, will undoubtedly aug­ment the vasodilator effect. Since the calcium ant­agonist is a potent relaxant of the coronary conduit arteries, the combination should have a favourable effect on myocardial perfusion; there should be fur­ther improvement in L VEF. Left ventricular hy­pertrophy and remodelling may be further inhib­ited by the vasodilator and ACE inhibitor working independently. The ACE inhibitor should inhibit any neurohormonal activation by the calcium ant­agonist; felodipine, administered alone, may ac-

Impedance

A = No inotropic effect B = Negative inotrope

Fig. 9. Effect of calcium antagonists on left ventricular func­tion in heart failure. Ca++ antagonist = calcium antagonist.

56

LV dysfunction

Drugs 47 (Supp/. 4) 1994

? ACE inhibitors ? Growth Inhibitors Nitrates

ACE Inhibitors -----.J ~ LVdilatat,on _______

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Fig. 10. Physiological basis for multiple therapies in heart failure . LV = left ventricular; EF = ejection fraction; RBF = renal blood flow; ACE = angiotensin converting enzyme; Na+ = sodium.

tually suppress the neurohormonal mechanisms. Administration of an ACE inhibitor with felodi­pine could also avert some of the sodium retention that might otherwise occur.

Results from the V-HeFf trials indicate that therapy for heart failure requires multiple drugs. Heart failure is a polypharmacy syndrome (fig. 10), with many progressive mechanisms in which drugs may intervene. One of the objectives of heart fail­ure treatment is to prevent the left ventricle from progressive remodelling in patients with left ven­tricular dysfunction. ACE inhibitors and growth inhibitors can potentially prevent this progression; nitrates may also help. Once the left ventricle is dilated and ejection fraction lowered, inotropic agents could be used to improve systolic perform­ance. Therefore, improved systolic performance by inotropic agents might favourably impact on the processes that develop in response to poor systolic performance. Currently, there are no inotropic agents available that can be prescribed with impunity.

Reductions in ejection fraction appear to be ac­companied by neurohormonal activation. How­ever, a host of hormonal inhibitors could poten­tially halt progressive processes in the peripheral vasculature and myocardium that are adversely af-

fected by neurohormonal activation. The processes may include hypertrophy and dilation of the left ventricle, and hypertrophy and stiffening of the peripheral vasculature.

The use of diuretics remains essential in heart failure in patients in whom renal blood flow and sodium retention appear to be adversely affected. Volume expansion further increases preload unless venodilators such as nitrates and ACE inhibitors are used to reduce the filling pressure of the heart, to favourably affect loading conditions, and to block some of the progressive positive feedback loops that develop in the failing heart.

The goals ofV-HeFf III are to evaluate the ad­dition of the vasodilator calcium antagonist felo­dipine to the ACE inhibitor enalapril, and to eval­uate the potential role of digoxin as an inotrope, in the setting of chronic heart failure. We are con­fident that V-HeFf III, like the earlier V-HeFf trials, will continue to provide useful information that will help clinicians develop the best treatment for patients suffering from heart failure.

References Aronow WS, Greenfield RS, Alimadadian H, Danahy DT. Effect

of the vasodilator trimazosin versus placebo on exercise per­formance in chronic left ventricular failure. American Journal of Cardiology 40: 789-793, 1977

Vasodilators in Heart Failure: V-HeFT Trials

Awan NA, Needham KE, Evenson MK, Amsterdam EE, Mason DT. Therapeutic application of prazosin in chronic refractory congestive heart failure: tolerance and 'tachyphylaxis' in per­spective. American Journal of Medicine 71: 153-160,1981

Captopril Multicenter Research Group. A placebo-controlled trial of captopril in refractory chronic congestive heart failure. Jour­nal of the American College of Cardiology 2: 755-763, 1983

Chatterjee K, Massie B, Rubin S, Gelberg H, Brundage BH, et al. Long-term outpatient vasodilator therapy of congestive heart failure: consideration of agents at rest and during exercise. American Journal of Medicine 65: 134-145, 1978

Cintron G, Johnson G, Francis G, Cobb F, Cohn JN, et al. Prog­nostic significance of serial changes in left ventricular ejection fraction in patients with congestive heart failure. Circulation 87 (Suppl. VI): 17-23, 1993

Cohn IN. Introduction. Circulation 87 (Suppl. VI): 1-4, 1993a Cohn IN. Physiological variables as markers for symptoms, risk,

and interventions in heart failure. Circulation 87 (Suppl. VII): VII-IIO-VII-114, 1993b

Cohn IN, Archibald 00, Ziesche S, Franciosa JA, Harston WE, et al. Effect of vasodilator therapy on mortality in chronic con­gestive heart failure: results of a Veterans Administration Co­operative Study (V-HeFT). New England Journal of Medicine 314: 1547-1552, 1986

Cohn JN, Franciosa JA. Vasodilator therapy of cardiac failure. New England Journal of Medicine 297: 27-31; 254-258, 1977.

Cohn JN, Johnson GR, Shabetai R, Loeb H, Tristani F, et al. Ejection fraction, peak exercise oxygen consumption, cardi­othoracic ratio, ventricular arrhythmias, and plasma norepi­nephrine as determinants of prognosis in heart failure. Cir­cl!lation 87 (Suppl. VI): VI-5-VI-16, 1993

Cohn IN, Johnson G, Ziesche S, Cobb F, Francis G, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. New Eng­land Journal of Medicine 325: 303-310, 1991

Cohn JN, Rajfer SF. Evaluation of functional capacity in heart failure. A concensus conference. Heart Failure 6: 169-173, 1990

Cohn JN, Rector TS. Prognosis of congestive heart failure and predictors of mortality. American Journal of Cardiology 62: 25A-30A, 1988

Colucci WS, Wynne J, Holman RL, Braunwald E. Long-term therapy of heart failure with prazosin: A randomized double blind trial. American Journal of Cardiology 45: 337-344, 1980

CONSENSUS Trial Study Group. Effects of enalapril on mor­tality in severe congestive heart failure. New England Journal of Medicine 316: 1429-1435, 1987

Creager MA, Massie BM, Faxon DP, Friedman SD, Kramer BL, et al. Acute and long-term effects of enalapril on the cardio­vascular response to exercise and exercise tolerance in patients with congestive heart failure. Journal of the American College of Cardiology 6: 163-170, 1985

Drexler H, Banhardt U, Meinertz T, Wollschlager H, Lehmann M, et al. Contrasting peripheral short-term and long-term ef­fects of converting enzyme inhibition in patients with con­gestive heart failure: a double-blind, placebo-controlled trial. Circulation 79: 491-502, 1989

Enalapril Congestive Heart Failure Investigators. Long-term ef­fects of enalapril in patients with congestive heart failure: a multicenter placebo-controlled trial. Heart Faih,lre 3: 107-110, 1985

Frances GS, Cohn IN, Johnson G, Rector TS, Goldman S, et al. Plasma norepinephrine, plasma renin activity, and congestive heart failure: relations to survival and the effects of therapy in V-HeFT II. Circulation 87 (Suppl. VI): 40-48, 1993

Franciosa JA, Cohn IN. Effect ofisosorbide dinitrate on response to submaximal and maximal exercise in patients with con­gestive heart failure. American Journal of Cardiology 43: 1009-1014, 1979a

Franciosa JA, Cohn IN. Immediate effects of hydralazine-isosor-

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bide dinitrate combination on exercise capacity and exercise hemodynamics in patients with left ventricular failure. Cir­culation 59: 1085-1091, 1979b

Franciosa JA, Goldsmith SR, Cohn IN. Contrasting immediate and long term effects of isosorbide dinitrate on exercise ca­pacity in congestive heart failure. American Journal of Med­icine 69: 559-566, 1980

Franciosa JA, Weber KT, Levine B, Kinasewitz GT, Janicki JS, et al. Hydralazine in long term treatment of chronic heart fail­ure: Lack of difference from placebo. American Heart Journal 104: 587-594, 1982

Guiha NH, Cohn JN, Mikulic E, Franciosa JA, Limas 0. Treat­ment of refractory heart failure with infusion of nitroprusside. New England Journal of Medicine 2.91: 587-592, 1974

Keogh AM, Baron DW, Hickie JB. Prognostic guides in patients with idiopathic or ischemic dilated cardiomyopathy assessed for cardiac transplantation. American Journal of Cardiology 65: 903-908, 1990

Kramer BL, Massie BM, Topic N. Controlled trial of captopril in chronic heart failure: a rest and exercise hemodynamic study. Circulation 67: 807-816, 1983

Kugler J, Maskin C, Frishman W, Sonnenblick E, LeJemtel T. Regional and systemic metabolic effects of angiotensin-con­verting enzyme inhibition during exercise in patients with sev­ere heart failure. Circulation 66: 1256-1261, 1982

Leier CV, Huss P, Magorien RD, Unverferth DV. Improved ex­ercise capacity and differing arterial and venous tolerance dur­ing chronic isosorbide dinitrate therapy for congestive heart failure. Circulation 67: 817-822, 1983

McGrath BP, Arnolda L, Matthews PG, Jackson B, Jennings G, et al. Controlled trial of enalapril in congestive cardiac failure. British Heart Journal 54: 405-414, 1985

Pierpont GL, Cohn IN, Franciosa JA. Combined oral hydrala­zine-nitrate therapy in left ventricular failure: hemodynamic equivalency to sodium nitroprusside. Chest 73: 8-13, 1978

Rubin SA, Chatterjee K, Ports TA, Ge1berg HJ, Brundage BH, et al. Influence of short-term oral hydralazine therapy on exercise hemodynamics in patients with severe chronic heart failure. American Journal of Cardiology 44: 1183-1189, 1979

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Sullivan MJ, Knight D, Higginbotham MB, Cogg FR. Relation between central and peripheral hemodynamics during exercise in patients with chronic heart failure: muscle blood flow is reduced with maintenance of arterial perfusion pressure. Cir­culation 80: 769-781, 1989

Szlachcic J, Massie BM, Kramer BL, Topic N, Tabau J. Corre­lates and prognostic implication of exercise capacity in chronic congestive heart failure. American Journal of Cardiology 55: 1037-1042, 1985

Ziesche S, Cobb FR, Cohn IN, Johnson G, Tristani F, et al. Hy­dralazine and isosorbide dinitrate combination improves ex­ercise tolerance in heart failure: results from V -HeFT I and V­HeFT II. Circulation 87 (Suppl. VI): VI-56-VI-64, 1993

Correspondence and reprints: Dr Jay N. Cohn. Cardiovascu1ar Division, Department of Medicine, University of Minnesota Medical School, Box 488, 420 Delaware Street, S.E., Minneapolis, Minnesota, USA 55455-0392.

Discussion Question: Your studies proved that the vaso­

dilator combination hydralazine plus isosorbide dinitrate and the ACE inhibitor enalapril work in

58

different ways. What do you think, then, is the ideal treatment for heart failure patients?

Dr J.N. Cohn: I think that the ideal treatment regimen for patients with heart failure has not yet been discovered. Heart failure is complex, and continues to be associated with a high mortality rate. However, on the basis of the information we have today, the ideal treatment would include dig­oxin, diuretics and an ACE inhibitor. Certainly, this makes sense if mortality is the major end-point. However, if other end-points are as important, the effects of the hydralazine-isosorbide dinitrate com­bination on exercise and ejection fraction are com­pelling. I believe that an ACE inhibitor combined with a vasodilator such as a calcium antagonist may provide the best currently available treatment. We are evaluating this combination in V-HeFT III. Inotropic agents (once they have been proven to be safe) have potential as well.

Question: In your study, did you find any cor­relation between patient characteristics on entry into the study and mortality?

Dr Cohn: In V-HeFT II we examined the base­line variables to determine their impact not only on the risk of mortality, but also on the relative response of patients with these variables to phar­macological treatment. We found that patients with severe ventricular arrhythmias, low baseline ejec­tion fractions, low peak oxygen consumptions, or low systolic blood pressures had a significantly higher mortality rate. These results could have been expected. In addition, the mortality rate was higher in patients with high cardiothoracic ratios, greater

Drugs 47 (Suppi. 4) 1994

impairment on a quality-of-life questionnaire, high plasma noradrenaline or renin levels, or those in New York Heart Association classes I and II. Patient age, coronary artery disease, or duration of heart failure at baseline were not predictive of mortality. At 2 years, treatment with enalapril re­sulted in a significant (28%) reduction in mortality relative to the combination of hydralazine plus iso­sorbide dinitrate. The patient subgroups that ex­perienced lower mortality with enalapril treatment included the following: patients with high plasma renin or noradrenaline levels; patients with low cardiothoracic ratios; patients with :s:;: 10 premature ventricular contractions per hour, or without ven­tricular arrhythmias; and patients in New York Heart Association classes I and II. In no patient subgroup was the mortality rate higher with ena­lapril treatment than with the hydralazine-isosor­bide dinitrate combination.

Question: Was your analysis conducted with re­gard to mortality due to sudden cardiac death and drug treatment?

Dr Cohn: Yes, we observed a decrease in sud­den deaths in the patient group treated with ena­lapril, which corresponded directly with a reduc­tion in the prevalence of ventricular tachycardia. Enalapril reduced the incidence of ventricular tachycardia by 40% at the end of 2 years; more­over, new ventricular tachycardia was reduced by 48% over the same period. This evidence points to the usefulness of enalapril in preventing the pro­gression of heart failure, and in reducing the in­cidence of sudden death in heart failure patients.