Effects of two different enalapril dosages on clinical

European Heart Journal (1996) 17, 1223-1232

Effects of two different enalapril dosages on clinical, haemodynamic and neurohumoral response of patients with severe congestive heart failure R. Pacher, B. Stanek, S. Globits, R. Berger, M. Hulsmann, M. Wutte, B. Frey, M. Schuller*, E. Hartter* and E. Ogrist Department of Cardiology and * Occupational Medicine, University of Vienna, ^Danube Hospital, Vienna, Austria

(18%) deaths, eight on low dose and seven on high dose. After 48 weeks, functional capacity by New York Heart Association class improved more on the high dose than on the low dose (P=004). In contrast, alterations in invasive haemodynamic variables at rest and exercise as well as maximal exercise capacity were comparable in both groups. Diastolic blood pressure decreased and the change between both groups was statistically significant (/ J =001). Changes in plasma creatinine levels did not differ between high and low dose treatment and no patients had to be withdrawn because of deterioration in kidney function. With regard to neurohumoral activity, a tendency to a discrepant response to both treatments was observed with a blunted increase in noradrenaline on high versus low enalapril dose. Thus, high-dose enalapril treatment proved superior to low dose as regards symptomatology in severe heart failure after long-term treatment, despite similar effects on haemodynamics and on maximal exercise capacity. (Eur Heart J 1996; 17: 1223-1232)

Introduction

There are few studies showing clinical benefit with low doses of angiotensin converting enzyme inhibitors and few studies comparing the effects of low versus high doses of angiotensin converting enzyme inhibitors in heart failure131. A dose-response relationship was found in a dose ranging study with quinapril in doses ranging from 5 to 20 mg twice daily, patients receiving higher doses having greater increments in exercise performance14'. In contrast, no dose-dependent increase in exercise tolerance was detected with cilacapri! in doses ranging from 0-5 to 2-5 mg daily in one study*51, whereas in another study with higher cilacapril dosages exercise variables were found to be improved'61. The only randomized dose ranging study so far reported with enalapril included only 27 patients, but the results showed that patients treated with enalapril 15 mg twice

Angiotensin converting enzyme inhibitors improve symptoms and reduce mortality in congestive heart failure1'21. However, in clinical practice, many heart failure patients take doses of angiotensin converting enzyme inhibitors that are far below the doses that have been used in the studies that conclusively showed the symptomatic and prognostic benefits of these drugs. Revision submitted and accepted 10 January 1996. This work was supported by funds from Merck & Co. Correspondence: Richard Pacher, Department of Cardiology, University of Vienna, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. 0195-668X/96/081223+10 $18.00/0

Key Words: Angiotensin converting enzyme inhibition, low and high dose enalapril, severe heart failure, symptomatology, noradrenaline, big endothelin.

1996 The European Society of Cardiology

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Angiotensin converting enzyme inhibitors improve symptoms and prolong life in congestive heart failure, but the dose in the individual patient is uncertain. A randomized, 48-week, double-blind study was performed to investigate the safety and efficacy of 'high' in comparison to continued 'low' angiotensin converting enzyme inhibitor therapy in severe heart failure. Eighty-three patients (56 ± 1 1 years; 69 men, 14 women) in New York Heart Association functional class III/TV on digoxin, furosemide and 'low' angiotensin converting enzyme inhibitors (captopril ^ 5 0 m g . d a y ~ ' or enalapril ^ 10 mg . d a y " ' ) were included. After a 5; 14 day run-in on l O m g . d a y ^ ' enalapril, digitalis and furosemide, right heart catheterization at rest and exercise was performed. All patients presented with atrial pressure >10mmHg and/or pulmonary artery pressure >35mmHg, and/or cardiac index 03 N

2

'eo c

Haemodynamics

X

Exercise

X

Neurohormones

X

X

Clin. exam.

X X X X X

X

X

Lab.

X X X X X

X

X

mgday

Figure 1 Flow chart. E, enalapril; BID, twice daily doses; Clin. exam., clinical examination; Lab., routine laboratory.

Laboratory measurements Venous blood samples were drawn from indwelling catheters after a 30 min supine rest for determination of noradrenaline (by high pressure liquid chromatography), renin activity (radioimmunoassay), aldosterone (radioimmunoassay), atrial natriuretic peptide (radioimmunoassay) and big endothelin-1, which is a major component of total immunoreactive endothelin-1 in plasma of heart failure patients'101. For determination of big-endothelin, C-terminal big-endothelin-1 was measured by an extraction based radioimmunoassay, as described in detail elsewhere1111.

Statistical methods Continuous variables are expressed as means ± SEM. Patient characteristics were compared using the Fisher's exact test for dichotomous variables or the Wilcoxon rank-sum test for ordered categorical data. The comparability of the treatment groups at baseline was assessed by the McCullagh's method with treatment as factor for the New York Heart Association score, by ANOVA with treatment as factor effect for diastolic and systolic blood pressure and right heart catheterization, and by means of ANOVA on the ranked values with treatment as factor for neurohumoral activity. The efficacy analyses were performed using an 'intention to treat' approach; that is, all patients with efficacy data both at baseline and on treatment were analysed including protocol violators or drop-outs. If in the 'intention to treat' approach a patient's data were missing at weeks 24 or 48, the last observation prior to that week was carried forward and used in the analyses. Patients who died during the study or within 14 days after the end of the study for a reason other than congestive heart failure worsening, were assigned the New York Heart Association score of their previous visit while patients who died because of congestive heart

failure worsening were put in the worst category. Patients who underwent heart transplantation were given the score of their previous visit since they were already a candidate for heart transplant at the start of the study. The comparison between the two groups was made using McCullagh's method (for ordered categorical variables) with baseline and treatment as model effects and with ANOVA on the ranks with treatment as model effect. Within group comparisons, to assess the significance of the change from baseline in the two treatment groups separately, were made using the Wilcoxon signed-rank test and paired t-test. Efficacy ordered categorical variables were analysed by McCullagh's method. Treatment groups were compared with regard to the incidence of clinical and laboratory adverse effects by means of Fisher's exact test. Kaplan Meier survival estimates and the log-rank test were used to compare survival between groups. A / > =004) between the two groups with respect to aetiology; more patients in the low-dose group had idiopathic cardiomyopathy and more patients in the high-dose group had ischaemic heart disease. No other significant differences between groups

comprised 40 patients for analysis of New York Heart Association class. Both groups were comparable with regard to New York Heart Association score at baseline. At weeks 12, 24 and 48, NYHA class decreased from baseline in the low-dose group as well as in the high-dose group, but the magnitude of change from baseline was not different between the groups at weeks 12 and 24. At week 48, however, the improvement in New York Heart Association class was larger (— 0-9) in the high-dose group than in the low-dose group (— 0-5), resulting in a significantly different change (P=004) between both treatments (Fig. 3). As a consequence, at week 48, the proportion of patients with New York Heart Association class III—IV was higher in the low-dose group (54%) than in the high-dose group (35%) (P-00\).

Systolic and diastolic blood pressure Both groups were comparable with regard to systolic and diastolic blood pressure at baseline (Table 2). At weeks 12 and 24 systolic blood pressure decreased and Eur Heart J, Vol. 17, August 1996

Drop-outs n=1

High dose n = 41 \

WeekO

n = 41

n = 40

n=8

n=8 if n = 34

Week 12

n = 33

n= 14

n = 11

Week 24

n = 28

n = 30

n = 23

n = 17

Week 48

n = 19

n = 24

'Study completing cohort'

Figure 2 Number of all randomized patients, 'all patients-treated' cohort and 'study completing cohort' and number of 'drop-outs' at weeks 0, 12, 24 and 48, as allocated to the low-dose group and the high-dose group.

0.0

Week 12

Week 24

Week 48

-= -0.5 -

-1.0= 0.04

Figure 3 Mean changes in New York Heart Association (NYHA) functional class from baseline to weeks 12, 24 and 48 in the low-dose group (open bars, n=41) and in the high-dose group (hatched bars, n=40).

the changes from baseline were significantly more pronounced in the high-dose group than in the low-dose group (/ > =001 and / > =005, respectively). At week 48, however, changes in systolic blood pressure from baseline were no longer different between the treatments.


Age (years) Male/Female NYHA status Class II Class III Class IV Aetiology of heart failure' Idiopathic cardiomyopathy Ischaemic heart disease Heart transplant candidates Sinus rhythm Atnal fibrillation Left bundle branch block Pacemaker AICD Essential hypertension Diabetes mellitus Treatment ACE-inhibitors Digitalis Nitrates Aspirin (100 mg . day ~ ') Diuretics Furosemide (mg . day" ') Spironolactone Ethacrynic acid

Low dose n =42

Effects of enalapril on severe heart failure

Table 2

Baseline haemodynamic and exercise variables

Variable

Low dose

High dose

Week 12

Week 24

= 0.01

P = 0.05

= 0.01

= 0.01

1227

Week 48

61 3

(a) At rest HR (bpm) Syst BP (mmHg) Diast BP (mmHg) Mean BP (mmHg) RAP (mmHg) PAP syst (mmHg) PAP diast (mmHg) PAP mean (mmHg) PCWP (mmHg) SVI (ml. m " 2 ) CI (1 . min~ ' . m~ 2 ) SVRI (dyn.s" 1 .cm PVRIfdyn.s" 1 cm

(n=41) 92 ±2-7 121 ± 2 7 83 ± 1 -4 95 ± 1-7 10 ±0-8 52 ±2 31 ±1-4 40± 1-6 30±l-3 28 ± 1-6 2-5 ±011 2890 ±113 345 ±27

(n=41) 67-8 ±3-9 151 ± 4 1 92 ±1-7 140 ±3-6

(n = 39) 65-5 ±3-5 157 ±4-0 95 ±2-1 133 ±3-5

HR, heart rate; Syst BP, systolic blood pressure; Diast BP, diastolic blood pressure; RAP, right atnal pressure; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; SVI, stroke volume index; CI, cardiac index; SVRI, systemic vascular resistance index; PVRI, pulmonary vascular resistance index. Data are mean ± SEM. No significant differences between groups.

Diastolic blood pressure decreased at weeks 12, 24 and 48 and the magnitude of change from baseline was significantly different between both treatments at all weeks (P-00\) (Fig. 4).

0-

-4-8-12

-10= 0.01

Figure 4 Mean changes from baseline to weeks 12, 24 and 48 in systolic and diastolic blood pressure in the low-dose group (open bars, n=41) and in the high-dose group (hatched bars, n = 39) and in plasma creatinine in the low-dose group (open bars, n=38) and in the high-dose group (hatched bars, n=34).

Haemodynamic results Baseline right heart catheterization was performed in 41 of 42 patients in the low-dose group and in all 41 patients in the high-dose group. In one patient right heart catheterization was technically impossible. There was no significant difference in haemodynamic variables at rest between the treatment groups (Table 2). Due to 23 drop-outs, as shown in Fig. 2, a second haemodynamic test was performed in 29 patients on the low dose and in 31 patients on the high dose at week 24. In addition, at week 48 haemodynamic data are missing in four of 19 study-completing patients on the low dose and in one of 24 study-completing patients on the high-dose because of technical problems. Baseline haemodynamic variables at rest were comparable in the two subsets with sequential haemodynamic data and changes in haemodynamic variables from baseline at weeks 24 and 48 were not significantly different between either treatment. Pulmonary capillary wedge pressure, however, showed a tendency to a more pronounced decrease on the high dose (P—006) (Table 3).

Exercise capacity In 41 of 42 patients in the low-dose group and in 39 of 41 patients in the high-dose group maximal exercise capacity was established. In two patients in the highdose group exercising was technically impossible. There was no difference in exercise capacity at baseline between either treatment group (Table 2). Due to 23 drop-outs, as shown in Fig. 2, a second exercise test was performed in 29 patients on the low dose and in 31 patients on the high dose at week 24. In addition, at week 48 exercise data are missing in four of 19 studycompleting patients on the low dose because of technical problems. Baseline exercise variables were comparable in the two subsets with sequential exercise data and changes from baseline in exercise variables, including mean pulmonary artery pressure, were not significantly different between either treatment at weeks 24 and 48. At week 48, maximal workload and respective exercise time showed a tendency to a more pronounced increase on high dose (/ ) =008 and P=007 between both treatments) (Table 4). Eur Heart J, Vol. 17, August 1996


(b) At exercise Workload (W) Syst BP (mmHg) Diast BP (mmHg) HR (bpm)

"2)

(n=41) 94 ±2-8 121 ±2-7 81 ± •4 94± •7 10±()-8 50 ± •7 31 ± •3 39 ± •4 28 ± •1 28 ± •6 2-5 ±014 2902±138 382 ±34

1228 R. Pacher et al.

Table 3 Haemodynamic response to low or high enalapril treatment Variable

High dose (n = 31)

P valuet

92 ± 3 1 90 ±3-4 92 ± 3-2

91 ±2-5 88 ±2-8 87 ±2-7

ns ns ns

94 ± 2 1 93 ± 2 8 92 ± 3 1

96 ±1-9 91 ± 2 1 * 90± 1 9*

ns ns ns

10 ±0-9 9 ±0-8 9 ±0-9

9 ±0-5 8 ± 1-1 8 ±0-9

ns ns ns

39 ± 1 5 36 ± 1-6 36 ± 1-9

40± 1-7 33 ± 2 2** 34 ±2-0**

ns ns ns

2 7 ± 1-1 25 ± 1-5 25 ± 1-6

29 ±1-3 22 ± 1-7** 24 ± 1-5"

ns 006 ns

29 ±1-7

30 ± 1 6

24 weeks 30 ± 2 1 48 weeks 30 ± 2 1 2 CI (1. min ~ ' . m ~ ) Baseline 2-5 ± 0 1 24 weeks 2-7 ± 0 1 48 weeks 2-6 ± 0 1 1 5 SVRI ( d y n . s " . c m - . m " 2 ) Baseline 2902 ±162 24 weeks 2751 ± 168 48 weeks 2666±150 PVRI ( d y n . s ~ ' c m - ' . m " 2 ) Baseline 382 ± 3 4 24 weeks 367 ± 35 48 weeks 343 ± 3 6

32 ± 1-6 34 ±2-0*

ns ns ns

2-6 ±0-1 2-7 ± 0 1 2-8 ±0-1

ns ns ns

2774 ±135 2576 ± 89 2463 ± 101*

ns ns ns

340 ±32 359 ±41 325 ± 39

ns ns ns

fSignificance of between-group changes. Abbreviations: HR, heart rate; MAP, mean arterial pressure; RAP, right atrial pressure; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; SVI, stroke volume index; CI, cardiac index; SVRI, systemic vascular resistance index; PVRI, pulmonary vascular resistance index. Data are mean ± SEM; */>