Journal of Cardiovascular Pharmacology:
Cardiovascular Remodeling and the Role of ACE Inhibition in Heart Failure
Quality of Life with ACE Inhibitors in Chronic Heart Failure
Bulpitt, Christopher J.
Division of Geriatric Medicine, Royal Postgraduate Medical School, London, England
Address correspondence and reprint requests to Prof. C. J. Bulpitt at Division of Geriatric Medicine, Royal Postgraduate Medical School, Du Cane Road, London W12 ONN, England.
Summary: The randomized trials assessing the effect of angiotensin-converting enzyme (ACE) inhibitors in chronic heart failure (CHF) are reviewed. The Minnesota Living with Heart Failure Questionnaire has demonstrated the benefits of enalapril in some but not all circumstances and the Yale Dyspnea-Fatigue Index improves with lisinopril. A recent trial of both cilazapril and captopril vs. placebo employed the Sickness Impact Profile and supports the concept that ACE inhibitors have a small (and in this trial nonsignificant) beneficial effect on mobility. Other vasodilators and inotropes may also have small benefits on quality of life, such that comparisons of an ACE inhibitor with vasodilators, as was done in the V-HeFT II trial, fail to reveal any different effects on quality of life.
Patients with chronic heart failure (CHF) are interested in living long and well, and are therefore interested in survival with a good quality of life (QOL). QOL is determined by the presence or absence of symptoms, the ability to undergo exertion and hence carry out activities, the enjoyment of social participation, and the preservation of psychological well-being. Patients are interested in exercise tolerance to the extent to which it relates to their activity.
In CHF, psychological adjustment to illness is associated with the New York Heart Association (NYHA) grade (1,2), the 6-min walk test, self-reported functional status, depression, and hostility (3). QOL is not related to ejection fraction but rather is related to exercise capacity. However, the latter is determined by the physical and psychological well-being of the patient. QOL and the results of exercise tests are therefore related. In one trial comparing the effects of digoxin, xamoterol, and placebo (4), improvements in both QOL and exercise capacity were observed in all three groups, the results of increased attention from the medical and research staff. As expected, QOL is higher in NYHA class I patients than in classes II and III; however, ejection fraction is not (5). Therefore, the measurement of QOL is a better measure of well-being than objective measures of cardiac function. In patients with angina, measures of QOL are also higher in the less severs NYHA grades (6).
The treating physician aims either to increase survival while preserving or improving QOL or to increase QOL while preserving survival. It is possible that a patient will accept a reduced survival in return for a greatly increased QOL, but this is a very controversial area. The patient will be prepared to make some sacrifices for an increased survival, e.g., to endure some side effects of drug treatment or to accept a small risk of an adverse drug reaction, but there will obviously be a limit to the risks that are acceptable.
The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) (7), the Second Vasodilator Heart Failure Trial (V-HeFT II) (8), and the Studies of Left Ventricular Dysfunction (SOLVD) (9) trials have demonstrated a reduction in mortality with angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors also improve survival when heart failure follows acute myocardial infarction (10), and reinfarction rates may be reduced (11,12).
METHODS OF MEASURING QOL IN CHF
The NYHA functional classification
This classification (1,2) is an incomplete and surrogate measure of QOL that identifies the degree of limitation of physical activity as perceived by the clinician. Classes I to IV range from least severe to most severe.
The Mahler Index of Dyspnea-Fatigue
This index (13) includes three subscales, often known as the Yale Index, which assess functional impairment, tasks required to produce breathlessness, and effert required to produce breathlessness.
Minnesota Living With Heart Failure Questionnaire
This questionnaire (14) provides a comprehensive measure of QOL with 21 questions focusing on physical, psychological, and socioeconomic consequences of CHF.
The Chronic Heart Failure Questionnaire (CHQ)
This questionnaire (15) chooses the five activities associated with shortness of breath that subjects perform frequently and are also the most important in their daily lives. Patients are then repeatedly asked the extent of their dyspnea in those five activities.
Sickness Impact Profile (SIP)
This profile (16) consists of 12 dimensions: ambulation, mobility, body care and movement, social interaction, communication, alertness behavior, emotional behavior, sleep and rest, eating, work, home management, and recreation and pastimes.
Profile of Mood States (POMS)
This profile (17) consists of six subscales relating to tension-anxiety, depression-dejection, angerhostility, vigor-activity, fatigue-inertia, and confusion-bewilderment.
Surrogate measures that address certain aspects of QOL
These measures include withdrawal from study medication and rate of occurrence of adverse drug effects (18), and results of timed walk tests. The latter correlate with measures of QOL (4,19).
RESULTS IN RANDOMIZED TRIALS
Treatment other than ACE inhibitors
In 1985, Lipkin and Poole-Wilson (20) identified 17 trials in which the NYHA grading had been an outcome measure. They examined the data to determine the effect of the drugs on NYHA grade and exercise capacity. With various agents such as amrinone, prenalterol, acebutolol, and metoprolol, no trial reported a benefit, despite two trials that involved 37 and 52 patients and follow-up durations of 26 and 12 weeks, respectively. Because these drugs had no effect on NYHA grade or exercise capacity, they are unlikely to improve QOL. Care must be taken, however, not to extrapolate such findings to other cardiac conditions. For example, Olsson and colleagues (21) reported an improved QOL when metoprolol was employed after a myocardial infarction. With the vasodilators-nitrates, hydralazine, prazosin, and minoxidil-three of six trials demonstrated a definite or possible improvement in exercise capacity.
The NYHA classification is not a sufficient measure of QOL, and more comprehensive measures are required, with detailed assessments of symptomatology, activity, social participation, and psychological well-being (22). The CHQ (15) was employed in a double-blind, randomized crossover trial of digoxin against placebo in 20 patients (23). The CHQ revealed an improvement in dyspnea with digoxin and a tendency (p = 0.09) toward an improvement in emotional function. However, fatigue was not reduced (Table 1).
Interestingly, premature termination of placebo treatment was required in seven of the 20 patients compared with none during digoxin treatment (p = 0.016). In contrast, Blackwood et al. (4) compared 60 patients receiving xamoterol with 30 receiving digoxin and 27 receiving placebo, and failed to find a change in limitation of activity or social functioning using new and possibly unvalidated methods. However, they did employ the POMS to evaluate emotional well-being (Table 2). There were no differences psychological well-being among the groups.
More recently, the Minnesota Living with Heart Failure Questionnaire has been shown to be responsive to the effects of pharmaceutical agents. The questionnaire (14) revealed a before and after improvement in QOL of 21% when a new inotrope was introduced in an uncontrolled study (24). An improvement of 22% was also noted in the SIP (16), a well-established instrument for assessing QOL. There is no doubt that QOL improved, but this may have been due to the effects of increased attention and entry into this uncontrolled study. Exercise capacity did not improve. Most importantly, in double-blind trials the Minnesota Living with Heart Failure Questionnaire has proven to be sensitive to the benefit of the inotropic agent pimobendan (25). In this trial a significant improvement with 5 mg/day compared to placebo was accompanied by an increase in treadmill exercise duration (Table 3). A tendency to improve with 10 mg/day was also accompanied by an improvement in exercise capacity. A smaller trial has also suggested an improvement with the inotrope enoximone, but only 10 patients were followed in a crossover trial of 3-week treatment (26).
Treatment with ACE inhibitors
Lipkin and Poole-Wilson (20) also reviewed four trials with patients receiving ACE inhibitors, and although two trials were small and one trial was rated as being too short, they all suggested an increase in exercise capacity.
Patients in the SOLVD trial (9) had QOL assessed with the Minnesota Questionnaire, and the physical and total scores improved with enalapril (27). This was not true for the arm of the SOLVD trial concerned with prevention rather than treatment of CHF (28) (Table 4). The Yale scale of dyspnea-fatigue (13) has been employed in comparing QOL in patients receiving lisinopril with captopril (27) and lisinopril with placebo (29). In both trials, the Yale scale improved more with lisinopril (30) (Table 5). An earlier version of the Minnesota Questionnaire was employed in the V-HeFT II trial but did not distinguish between QOL with enalapril and QOL with hydralazine plus isosorbide dinitrate (31).
In a trial comparing the long-acting ACE inhibitor cilazapril and the short-acting captopril with placebo, both ACE inhibitors prolonged exercise tolerance on a bicycle ergometer (32). However, the 6-min walk test did not improve significantly compared with placebo (increase after 12 weeks was 33 meters for cilazapril, 30 for captopril and 23 meters for placebo). Measures of QOL in this trial included the SIP, POMS, and the Mahler or Yale Dyspnea-Fatigue Index (33). Table 6 gives the changes from baseline to 12 weeks for areas of the SIP. As for the walking test, the results during active treatments were not statistically significantly better than during placebo. The effect size (ES) is also calculated in Table 6 (34). The ES is the effect of treatment with active drug minus the effect of treatment with placebo, divided by the pooled standard deviation at baseline. After 12 weeks, positive effect sizes of 0.12-0.16 were observed with active treatment for both ambulation and mobility. These effect sizes would be judged as small (34). The treatments did not improve the total psychosocial score compared with placebo.
Surrogate measures of QOL in the treatment and placebo groups of three of the survival trials of ACE inhibitors are shown in Table 7. The table gives the proportion of patients who withdrew from study medication or who experienced a serious adverse event. The increase in syncope and hypotension may have adversely effected the QOL, but only in about 3% of patients. Impairment of renal function may or may not have affected the QOL of the patients.
It is important for the measurement of QOL to be comprehensive and to cover all relevant health-related areas that are of concern in the short term. Such an evaluation should exclude financial and marital status, areas that are unlikely to change over 3 months, but should include ambulation, mobility, sleep and rest, eating, work, recreation, social interaction, and emotional behavior. These areas are measured using the SIP. This was used in a trial of transdermal nitroglycerine for angina, applied throughout the 24-h period and compared with placebo (35). Tolerance to the active drug occurred and QOL therefore did not improve. Surprisingly, tolerance to the adverse effect of headaches did not occur, and headaches reduced social interaction during active treatment. Measures of QOL therefore allow an assessment of both the benefits and the adverse effects of treatment.
Another method of measuring QOL in CHF appears promising: the Minnesota Living with Heart Failure Questionnaire. This questionnaire does appear to be sensitive to the benefit of drug treatment. The place of the Yale Index of dyspnea-fatigue and the CHQ has yet to be established. There is surprisingly little evidence for changes in psychological well-being as a result of treating CHF. However, evidence is accumulation of small benefits in this dimension (33).
Vasodilators improve both survival and QOL in CHF, and this is especially true for the ACE inhibitors, which improve exercise tolerance and mobility. This effect is shared by some inotropes, such as digoxin and pimobendan, and probably by long-acting nitrates. Benefits from all active treatments may explain the similar effects of enalapril and hydralazine plus isosorbide dinitrate in the V-HeFT II trial.
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Quality of life; ACE inhibitors; Inotropes
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