enalapril for congestive heart failure

Enalapril for Congestive Heart Failure

John Kjekshus, MD, PhD, and Karl Swedberg, MD, PhD, for The Consensus Trial Study Group

In a randomized, double-blind trial, 253 patients with congestive heart failure (New York Heart As- sociation class IV) received either enalapril (n = 127) or placebo (n = 126) in addition to their exist- ing therapeutic regimens (consisting of digitalis, diuretics, and vasodilators other than angiotensin- converting enzyme inhibitors). The study was discontinued prematurely for ethical reasons because of the much lower mortality among the patients receiving enalapril (n = 50) than among those receiving placebo (n = 68) (p <0.003). The important reduction in mortality was observed among patients dying from progressive heart failure. Follow-up ranged from 1 day to 20 months (average IS8 days). The reduction in mortality was associated with general improvements in the symptoms and signs of left and right ventricular heart failure, reduction of heart size, improvements in New York Heart Association classification, reduction of concurrent cardiovascular medication, and reduction of hospital admissions and days spent in the hospital. The overall withdrawal rate was low, and was comparable in the 2 treatment groups (16%; enalapril, n = 22, placebo, n = 18). Symptomatic hypotension was observed in 17% (n = 21) of the enalapril group vs 0% of the placebo group. Hypotension was the reason for withdrawal of enalapril therapy in 7 patients. After the initial dose of enalapril was reduced to 2.5 mg in high-risk patients, hypotension necessitated withdrawal in only 3.2% of the patients. Hyperkalemia was observed exclusively among patients with concurrent use of potassium- sparing agents. At initiation of therapy, serum creatinine levels increased more frequently in the enalapril group than in the placebo group, but was the reason for withdrawal of treatment in only 3 and 2 patients, respectively. A long-term progressive increase in serum creatinine levels was not observed. Hyponatremia at baseline was associated with an increased risk for mortality in patients receiving placebo, but not in those receiving enalapril. It is concluded that enalapril, added to conventional therapy, reduces morbidity and mortality from severe progressive heart failure.

(Am J Cardiol 1989;63:26D-32D)

From the Department of Medicine, N-13 16 Baerum Hospital, Norway. This work was supported by a grant from Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey.

Address for reprints: John Kjekshus, MD, PhD, Department of Medicine, N-1316 Baerum Hospital, Sandrika, Norway.

26D THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

I n patients with congestive heart failure (CHF), the administration of angiotensin-converting enzyme inhibitors (ACE) has been associated with hemody-

namic and symptomatic improvement with long-term use.’ Furberg and Yusuf,2 pooling data from several stud- ies, found no conclusive effect on survival, but suggested that ACE inhibitors might improve prognosis. The study described here details the effect of enalapril on mortality in patients with severe CHF; the main results of this study have been published elsewheres3

METHODS This was a double-blind, parallel, randomized, place-

bo-controlled, multicenter study conducted in Finland, Norway and Sweden. Patients were included if they were in New York Heart Association (NYHA) class IV CHF. The study was performed under the auspices of an independent Ethical and Safety Review Committee and a separate Steering Committee to handle administrative responsibilities. The active treatment period for each patient was to last a minimum of 6 months and until the last patient entered had completed 6 months, The study was stopped prematurely by the Ethical and Safety Review Committee for ethical reasons after approximately 20 months.

Treatment with enalapril or identically matched placebo was begun in the hospital with 5 mg administered twice daily after informed consent had been obtained. After 67 patients had been randomized, the protocol was changed and high-risk patients (those with a serum sodium level <130 mmol/liter, a serum creatinine level of 150 to 300 pmol/liter, an increased dose of diuretics within the previous weeks, or treatment with potassium- sparing agents) were given an initial dose of 2.5 mg/day. If hypotension or an increase in serum creatinine levels did not occur after 3 to 4 days, the dose was increased to 2.5 mg twice daily for the remainder of the first week. After 1 week, therapy was increased to 10 mg twice daily if the patient was not symptomatically hypotensive or had other adverse effects. According to clinical response, a further increase could occur, up to a maximum dose of 20 mg twice daily. The patients were evaluated after 1, 2, 3, 6 and 16 weeks and thereafter at 6,9 and 12 months, as well as at the end of the study.

If, at any time after week 3, the patient’s condition was deteriorating to a degree that the investigator be- lieved additional therapy was required, vasodilator therapy (other than an ACE inhibitor) could be initiated in patients not already receiving such treatment, or a second vasodilator could be added to the regimens of those patients already receiving vasodilatory therapy. A second vasodilator could be added only if the patient had re-

ceived the highest dose of study drug for at least 3 weeks and optimal adjustments of digitalis and diuretic therapy had been made. The vasodilators to be administered were isosorbide dinitrate, prazosin and hydralazine, started in this sequence.

The primary end point in this study was 6-month mortality based on the “intention-to-treat” approach. Other efficacy measures were symptomatology (evaluated by NYHA classification), heart size, physical examination, hospitalization, study drug and concomitant drug usage.

According to the protocol, this study was to enroll 400 patients (200 in each treatment group). Assuming true 6- month mortality rates of 40 and 24% in the placebo and enalapril groups, respectively, the study had 90% power at a 5% significance level.

The protocol allowed for 1 interim analysis after approximately 200 patients had completed 6 months of follow-up; it was on the basis of this interim analysis that the study was prematurely stopped.

RESULTS Two hundred fifty-three patients from 35 centers

were enrolled in this study; 126 patients were randomized to receive placebo and 127 to receive enalapril. Mean age of the patients was 70 years, and 12% were between 60 and 79 years of age. Of the remainder, approximately half were younger than 60 years and half were 80 years or older. Seventy-one percent of the patients were men.

Etiology of congestive heart failure: The most frequent contributing factors for the development of CHF were coronary heart disease (76%), previously document- ed myocardial infarction (52%), valvular heart disease

0 1 2345678 9 IO 11 12 Month

ve percent cQ~~dence ban e~~ion-to-treat analysis.

ble

(23%), hypertension (22%), diabetes (22%), atria1 fibril- lation (50%) and cardiomyopathy (15%). Many patients had more than 1 etiology.

Concurrent therapy: Virtually all patients were receiving both furosemide and digoxin or digitoxin at the start of the study. In addition, 56% were taking a vasodilator (the most frequently used was isosorbide dinitrate), and 71% were taking potssium chloride or a potassium- sparing diuretic.

Mortality and mode of death: Of the 126 placebo patients, 55 (43.6%) died within 6 months and 66 (52.4%) died within 12 months. These findings were comparable to 33 deaths (26.0%) within 6 months and 46 deaths (36.2%) within 12 months among the 127 enalapril patients. The reduction in 6-month mortality (which was the primary end point) due to enalapril was, therefore, 40.5% (p = 0.004). The reduction in ISmonth mortality was 30.9% (p = 0.011).

Using the per-protocol approach, there were 52 deaths within 6 months (4 1.3%) and 62 deaths within 12 months (49.2%) in the placebo group, and 29 deaths within 6 months (22.8%) and 37 deaths within 12 months (29.1%) in the enalapril group. The reduction in mortality due to enalapril was, therefore, 44.7% at 6 months (p = 0.002) and 40.8% at 12 months (p = 0.001). The estimated reduction in mortality due to enalapril is larger in the per- protocol analysis than in the intention-to-treat analysis.

Overall, 118 patients died during the course of the study (68 in the placebo group and 50 in the enalapril group). By far, the most frequent cause of death in both groups was progression of CHF (66 patients, or 56% of all

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THE AMERICAN JOURNAL OF CARDIOLOGY FEBRUARY 21, 1989

A SYMPOSIUM: CONGESTIVE HEART FAILURE-ADVANCES IN TREATMENT

Placebo

150 200 250 300 350 Days

FIGURE 3. Life-table analysis---sudden death (4 hour). (Adapted with permission from Am I Carc/~o/.~

TABLE I Crude Mortality Rates by Subgroup Deaths within 180 days-All Patients Eligible (Intention-to-Treat Analysis)

No.

Placebo

% Mortality No.

Enalaprii

% Mortality % Reduction

in Mortality p Value

Subgroup

Age (years) 565 >65

Sex Male Female

Vasodrlator therapy Yes No

Etiologies Cardiomyopathy

Yes No

Coronary heart drsease Yes No

Valvular heart disease Yes No

Hypertension Yes No

Myocardral Infarction Yes No

Drabetes

Yes No

Atrlal fibnllabon Yes

No Heart size (ml/m*)

<900 >900

Heart rate (beats/min) <SO >80

Laboratory values Serum creatinine (pmol/liter)

5140

>140 Serum potassium (mmol/liter)

54.5 >4.5

Serum sodium (mmol/liter) 5135 >135

37 89

90 36

70 56

20 106

97 29

28 98

28 98

67 59

27 99

61 65

83 39

46 61

96 30

107 19

37 89

48.6 32 41.6 95

489 89 30.6 38

42.9 72 446 55

400 17 443 110

50.5 95 20 7 32

42.9 31 43.9 96

39.3 30 44.9 97

55.2 65 30.5 62

29.6 29 47.5 98

42.6 65 44.6 62

35 71 59 55

35 52 49 58

40.6 81 53.3 46

43 0 110 47.4 17

59 5 34 37.1 93

18.8 61.5 001 28.4 31.6 NS

24.7 494 0.001 29.0 5.3 NS

23.6 44.9 0.02 29.1 45.8 NS

23.5 41 2 NS 264 40.5 0.007

25.3 50.0 0.001 28.1 -35.9 NS

19.4 54.8 NS 28.1 35.9 0.025

26.7 32.1 NS 25.8 42.6 0.007

27.7 49.9 0.002 24.2 20.7 NS

34.5 -16.4 NS 23.5 50.6 0001

29.2 31.4 NS 22.6 49 4 0.014

24 31.4 NS 29 50.8 0.01

23 34.3 NS 28 42.9 0.05

22.2 45.3 0.01 32.6 38.9 NS

236 45.0 0004 41.2 13.1 NS

32.4 45.6 0.03 23.7 36.2 0.05

NS = nons~~nkmt


deaths). Other causes were sudden cardiac death (within 1 hour), 28 patients (24%); death taking 1 to 24 hours, 11 patients (9%); other cardiac death, 3 patients (3%); stroke, 3 patients (3%); other cardiovascular death, 6 patients (5%); and ulcer, 1 patient (1%).

A life-table analysis with 95% confidence bands is shown in Figure 1. The life-table analysis showed that enalapril reduced mortality due to progression of CHF at 6 months by 52.8% (p = O.OOl), and at 12 months by 53.4% (p = 0.001; Fig. 2). Similarly, enalapril reduced mortality due to any cardiac death at 6 months by 42.2%, and at 12 months by 32.1% (both p = 0.001). The reduction in mortality due to sudden cardiac death (within 1 hour) at 6 months was 40% and at 12 months was 2.6% (the difference was not significant; Fig 3).

Results comparing the effects of placebo and enalapril on mortality for 14 subgroups of patients are presented in Table I. The basic conclusion from these analyses is that the effect of enalapril appears to be consistent among the subgroups.

The most important subgroups considered were those patients taking or not taking concomitant vasodilators at the time of randomization. Among patients taking vasodilators, the reduction in 6-month mortality was 47.0% (from 48.5 to 25.9%, p = 0.004), and the reduction in 12- month mortality was 16.7% (from 58.7 to 48.9%, p = 0.026). Among patients not taking concomitant vasodilators, the reduction in 6-month mortality was 3 1.0% (from 48.0 to 33.1%, p = 0.14), and the reduction in 1Zmonth mortality was 37.4% (from 66.9 to 41.9%. p = 0.026).

In only 2 subgroups (patients without coronary heart disease and patients with diabetes) was the 6-month mortality greater in the enalapril group than in the placebo group. In only 3 other groups of women (patients without previous myocardial infarctions and patients with serum potassium levels >4.5 mmol/liter) was the reduction in 6- month mortality <30%.

Right and leti ventricular failure: Results of the baseline physical examination were compared with those obtained at the end of the study. Patients in the enalapril group improved from the prestudy examination with respect to several parameters. There were statistically significant within-group improvements in the enalapril group in abnormalities that concerned right ventricular failure, e.g., edema (p <O.OS), liver size (p <O.Ol) and liver enzyme changes (p <O.OS), as well as abnormalities that concerned left ventricular failure, such as in the lungs and respiration (e.g., rales and dyspnea, p <O.Ol), and in heart size (p <0.05).

~ta~i~atiQ : After adjustment for the different s of follow-up in the 2 treatment groups, patients

in the enalapril group had fewer hospital admissions and spent fewer days in the hospital than did patients in the placebo group.

enalapril and placebo groups began the study taking similar amounts of test drug, those receiving placebo were titrated to considerably larger doses than were those receiving enalapril. At week 6, only 39% of the placebo recipients were taking less than the maximum of 40 mg,

whereas 39% of the enalapril recipients were taking 10 mg or less, and 76% were taking 20 mg or less.

Use of concomitant vasodilators tended to increase in the placebo group and decrease in the enalapril group. Concomitant use of the potassium-sparing diuretics spironolactone and amiloride decreased sharply in the enalapril group (from 44 patients to 23, and from 15 patients to 5, respectively). In the placebo group, 16 patients stopped and 13 patients started taking spironolactone (50 before vs 47 at the end of the study), but the number of patients taking amiloride increased from 7 to 14.

Adverse experiences: The most frequent adverse experiences reported by patients in the enalapril group were worsening of CHF (25 patients) and hypotension (22 patients) (Table II). Worsening of CHF, however, was significantly more frequent in the placebo group (41 patients, p lO.OS), whereas hypotension was significantly less frequent in the placebo group (no patients, p lO.01).

Other frequently reported adverse experiences were vertigo, dizziness, pneumonia, urinary tract infection, heart disorders (cardiac decompensation), fatigue, cough, oliguria and anuria. Although the treatment groups did not differ significantly with respect to most of these adverse effects, the incidence of vertigo and dizziness was higher in the enalapril than in the placebo group.

There were greater decreases in blood pressures in the enalapril group than in the placebo group. Overall, 41 patients taking enalapril (33%) had decreases of at least 20 mm Hg in systolic blood pressure (decreasing below 100 mm Hg), compared with only 3 patients taking placebo (2%). Among the 41 patients taking enalapril, systolic blood pressure decreased below 80 mm Hg in 15 patients, compared with none of the 3 patients taking

- TABLE II Climal Adverse Experiences

Adverse Experience

Placebo (n = 126)

No %

Enalaprll (n = 127)

Between- No. % Group Test

Any adverse experience 107 84.9 103 81.1 Death 68 54.0 50 39.4 p <O.Ol

Chest paln 4 32 4 3.1 Syncope 1 0.8 5 3.9 Angtna pectons 3 24 5 3.9 Worsening congestive 41 32.5 25 19.7 p<OO5

heart failure Hypotenslon 0 0.0 22 17.3 p<OOl

Myocardlal InfarctIon, acute 5 4.0 5 3 9 Transient lschemtc attacks 4 3.2 0 0.0 Dlzzlness 5 40 17 134 Cough 1 08 4 31 Rash 6 4.8 2 1 6 Ollguna and anuna 1 08 4 31 Hyperkalemla 8 6.3 24 189 p<OO1 Hypokalemla 12 95 2 16 p <O.Ol Hyperuncemla 1 0.8 4 3.1 Hyponatremla 14 111 5 3 9 p <0.05 Serum creatlnine Increased 22 175 51 40.2 p <OOl Abnormal liver function test 19 151 8 63 p<OO5 Protelnuna 1 08 4 3.1

Adapted from Am J Cardnlg

i-HE AMERICAN JOURNAL OF CARDIOLOGY FEBRUARY 21, 1989


placebo. Seven patients taking enalapril were withdrawn from the study because of hypotension.

Mean decreases in blood pressure and pulse were greater in the enalapril than in the placebo group. At the end of the study, the mean decrease in supine blood pressure was 10/7 mm Hg in the enalapril group, compared with 412 mm Hg in the placebo group, and the decrease in supine pulse was 5 beats/min in the enalapril group compared with 1 beat/min in the placebo group.

Mean plasma sodium and potassium tended to decrease in the placebo group and increase in the enalapril group.

The directional changes in creatinine levels in any patient receiving enalapril were unpredictable. As a group, however, the patients in the enalapril group expel rienced a larger mean increase in serum creatinine levels than did those in the placebo group, and more of those taking enalapril than placebo had increases >lO pmol/ liter. At the end of the study, 72 patients taking enalapril (59%) had such an increase compared with 38 taking placebo (32%) (p 10.01). The increase in creatinine levels occurred subsequent to the initial dosing and remained unchanged during follow-up, even among those with ele- vated serum creatinine levels at baseline (Fig. 4).

More patients in the enalapril than in the placebo group completed the study (55 to 43%). The numbers of dropouts as a result of adverse experiences and other reasons were similar in the 2 treatment groups (Table III).

DISCUSSION For ethical reasons, this study was discontinued pre-

maturely by the independent Ethical and Safety Review Committee. Although a continuation of the study would have contributed more data and possibly would have made the analysis of subgroups and laboratory variables more meaningful, the scientific value for the main end point of the study, which was mortality, would not have been improved. The groups were remarkably comparable at baseline, and none of the baseline parameters could possibly explain the large differences in mortality between the 2 treatment groups.

Note that this study was not specifically designed to look at patient subgroups, and it may have had very little ability to detect a difference between enalapril and placebo within the subgroups, especially those with small sam- ple sizes. Therefore, the lack of a statistically significant result within any subgroup should not be interpreted as

40- . Enaiaprll

n Placebo

I I I I I I I I I 0 50 100 150 200 250 300 350 400

Follow-Up (Days)

l Enalaprll

n Placebo

-20 1 I I I I I I I I

0 50 100 150 206 250 300 350 401

Follow-Up (Days)

FIGURE 4. Average increase over initial serum creatinine (SC) in patients with initial serum creatinine levels <140 flobli- ter (fop) and 2140 mollliter (bottom).


-

meaning that enalapril is ineffective in that group of patients.

It has been argued that patients with advanced heart failure are so ill and have such extensive myocardial dam- age that no important prolongation of survival can be expected from any treatment and that these patients would not be expected to tolerate converting enzyme inhibitors because of their already low blood pressure and impaired renal function.

This study demonstrates that enalapril, when added to conventional therapy (including digitalis and diuretics, with or without vasodilators [to the exclusion of ACE inhibitors]) in patients with severe CHF reduces 6-month mortality by 21 to 63%. In contrast to what has often been assumed (that ACE inhibitors reduce mortality due to sudden death by their ability to normalize electrolyte and catecholamine levels4), enalapril was shown in this study to reduce mortality resulting from progression of CHF. The reduction in mortality with respect to progression of the disease exceeded 50%. A prolonged reduction of pre- load and afterload appears, therefore, to be instrumental to the results obtained. However, hydralazine and long- acting nitrates reduce long-term mortality among patients with less severe CHF, without reduction of arterial blood pressure.5

Primary arrhythmic death occurred relatively infre- quently compared with progressive heart failure, and the number of patients makes any evaluation of effect of treatment in arrhythmic death obsolete. The depletion of myocardial catecholamine stores and down-regulation of myocardial preceptors may explain the infrequent occur- rence of sudden arrhythmic death relative to progressive heart failure among patients in class IV.

In the treatment of severely ill patients, who are frequently bedridden and hospitalized, prolongation of life alone without improving symptoms may be of doubtful benefit. It is therefore important to look at other variables related to functional capacity. In this study, an improvement was observed in the NYHA classifications of patients treated with enalapril compared with placebo. Eleven percent of the patients taking enalapril and <l% of the patients taking placebo became symptomless (classes I and II), and another 31% became less symptomatic (class III) indoors. There was also a reduced need for hospitalization observed in the enalapril group relative to that in the placebo group.

A significant (10%) reduction in heart size in the enalapril group compared with no change in the placebo group was another objective measure of clinical improvement. A marked reduction in the administration of concomitant medications was also observed. Many patients treated with enalapril stopped taking diuretics, potassium-sparing agents and vasodilators, whereas patients treated with placebo frequently started to take these drugs. Significantly more patients taking enalapril had improvements in findings on physical examination of right and left ventricular failure. Reports of peripheral edema, hepatomegaly and laboratory tests of abnormal liver function became significantly less frequent among the enalapril group than the placebo group.

The most frequent adverse reaction in the enalapril group was hypotension (17.3% vs 0% in the placebo group). Hypotension is associated with the pharmacolog- ic actions of ACE inhibitors and can be anticipated when such therapy is used. This was particularly evident in the initial phase of the study when all patients were receiving a starting dose of 10 mg/day. In these patients, hypotension was the most frequent reason for withdrawal (11.8%; 4 of 34 treated patients). After the protocol was amended and the high-risk patients were identified and therapy was begun with a daily dose of 2.5 mg of enalapril, only 3.2% (3 of 93) of subsequent patients were withdrawn because of hypotension.

Two to 3% of patients with severe CHF do not tolerate ACE inhibitors, irrespective of whether small initial doses are used. Most of these patients will have fixed renal artery stenosis that makes them exceptionally sensitive to such agents. These patients may not tolerate ACE inhibitors at all, or may tolerate them only after drastic reduction in doses of diuretics and potassium-sparing drugs.

In contrast to results obtained with a previous fixed- dose regimen, the present study demonstrates the importance of careful initial dosing of enalapril as well as reduction of concurrent cardiovascular medications.6

An increase in serum creatinine levels was frequently associated with a highly activated renin-angiotensin sys- tem in patients receiving high doses of diuretics or concomitant potassium-sparing agents, or both. As therapy continued, there was a greater increase in serum creatinine levels in the enalapril group (27 vs 8 hmol/liter). It is difficult to interpret the importance of this difference, as the 2 patient groups became less similar as the study progressed. One possibility is that the most severely ill patients in the placebo group died and the relatively healthier placebo recipients lived; in the enalapril group, a greater number of sicker patients survived. Most important, the increase in creatinine levels was not progressive; furthermore, the patients taking enalapril had normaliza- tion of serum sodium, potassium and chloride levels, indi- cating a generally improved electrolyte balance, despite an increase in serum creatinine levels. Treatment with enalapril caused a greater reduction in mortality among patients with high levels of creatinine at baseline compared with those with normal creatinine levels.

Hyponatremia is associated with increased risk of hypotensive reactions to ACE inhibitors.’ However, the ex- cess mortalitylo that we also observed among patients

adverse experience tory adverse experience

THE AMERICAN JOURNAL OF CARDIOLOGY FEBRUARY 21, 1989


with low serum sodium levels was effectively reduced by enalapril.

Hyperkalemia occurred more often in the enalapril group and occurred almost exclusively among patients being treated with potassium-sparing diuretics or potassium supplements. Withdrawal of spironolactone was more frequent in the enalapril group. Frequently, this led to an improvement in renal function and less symptomatic hypotension, probably because enalapril reduces the modu- lating aldosterone mechanism that regulates the effect of spironolactone on blood pressure and renal blood flow, which in some patients can lead to rapid deterioration of glomerular filtration rate. It is therefore advisable to stop treatment with spironolactone before initiating therapy with enalapril. In addition, renal function should be mon- itored before and during enalapril therapy.

CONCLUSION This study has clearly shown that the use of enalapril

in patients with severe CHF (NYHA class IV) is associated with a considerable reduction in overall mortality and clinical improvement when compared with placebo. Enalapril reduces the need for concomitant cardiovascular medications and is generally well tolerated.

REFERENCES 1. Llpkin DP, Poole-Wilson PA. Treatment of chrome heart fadure: a revwv of recent drug trials. Br Med J 1985:291.993-996. 2. Furberg CD. Yusuf S. Effect of vasodilators on survival in chronic congestive heart failure. Am J Card& 1985;55 1110-l 113. 3. CONSENSUS Trial Studv Grouo. Effects of enalamd on mortalitv in severe congestive heart failure N E>gl J ked 1987:316:14~9-1435. 4. McGrath BP, Arnolda LF. Enalapril reduces the catecholamine response to exercise in patients with heart fadure. Eur J Cardrol:1986;30~485-487. 5. Cohn JN, Archibald DG, Ziesche S, Franciosa JA. Harston WE. Tristani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH, Goldman S, Cobb FR, Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Effect of vasodi- later therapy on mortality in chronic congestive heart fadure. N Engl J Med 1986;314:1547-1552. 6. Packer M, Lee WH, Yushak M, Medma N Comparison of captopril and enalaprll in patients with severe chronic heart failure N Engl J Med 1986, 315:847-853 7. Captopril Multicenter Research Group. A placebo-controlled trial of captopril in refractory chronic congestive heart failure. JACC 1983;2:755-763. 8. Swedberg K, Kjekshus J for the CONSENSUS Trial Study Group Effects of enalapril on mortahty in severe. congestive heart failure. results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). Am J Cardiol 1988;62 6OA-66A. 9. Kiekshus J. Swedbera K. for the CONSENSUS Trial Studv Grow. Tolerabil- ity 01 enalapril in congestiie heart failure Am J Cardiol 1488;62:k7Am72A. 10. Packer M, Madina N. Yushak M. RelatIonship between serum sodium

concentrations and the hemodynamic and clinical responses to converting enzyme inhlbition with captopril in severe heart failure. JACC 1984;3:1035-1043.

APPENDIX The investigators (center, number of patients) in the CONSENSUS Trial Study Group are as follows:

Finland: U. Idanpaan-Heikkila, MD (Espoo, 2), J. Remes, MD, T. Hirvonen, MD, K. Pyiirlla, MD (Kuo- pio, lo), U. Korhonen, MD, J. Takkunen, MD, L. Ham& lainen, MD (Oulu, lo), A. Pasternack, MD, M. Nikkila, MD (Tampere, lo), M. Arstila, MD (Turku, 3) M. Lindroos, MD, B. Heikius, MD (Vaasa, 9).

Norway: T. Gundersen, MD, B. Aslaksen, MD (Arendal, ll), L. Gullestad, MD, E. Soyland, MD (Baerum, 1 l), G. Tjonnfjord, MD, A. Ose, MD (Gjovik, 3), P. Aukrust, MD, J. Haerem, MD (Hamar, 7), K. Waage, MD, P. Riddervold, MD (Haugesund, 5), J. Offstad, MD, E. G. Aksnes, MD (Lillehammer, lo), T. Pedersen, MD, P. Sirnes, MD (Oslo, Aker Hospital, 8), A. Westheim, MD, E. Sivertssen, MD, J. Eritsland, MD (Oslo, Ulleval Hospital, 1 l), K. Overskeid, MD, 0. Bru- bakk, MD (Sarpsborg, 4), J. Naesgaard, MD, A. Hallar- aker, MD (Skien, 6), K. Dickstein, MD, V. Bonarjee, MD (Stavanger, lo), H. Wang, MD, E. S. P. Myhre, MD (Tromso, 3).

Sweden: S-A. Forsberg, MD, L. Kareld, MD (Bo- ras, 6), K. Lindvall, MD, S. Eriksson, MD (Danderyd, lo), G. Frithz, MD, A. Stjerna, MD (Eskilstuna, 6), G. Ahlmark, MD, H. Saetre, MD (Falun, 7), B. Andersson, MD, M. Hartford, MD (Goteborg, Sahlgrenska Hospi- tal, 8), R. Bergstrand, MD, P. Held, MD, G. Ulvenstam, MD (Goteborg, Ostra Hospital, 17), L. Lundkvist, MD, P. Andersson, MD (Hudiksvall, 4); U. Dahlstrom, MD, M. Roqvust, MD (Linkoping, 17), A. Henriksson, MD, A. Siiderlind, MD (Lulea, 7), S. Persson, MD (Lund, l), N. Stobaeus, MD (Motala, 2), A. Sjogren, MD, E. Loogna, MD (Nacka, 5), J. FridCn, MD, P.-O. Anders- ton, MD (Norrkiiping, 5), Lars RydCn, MD, P. Smed- gard, MD (Sk&de, 5), I. Liljefors, MD, C. Hofman- Bang, MD (Stockholm, Sabbatsberg Hospital, 3), M. Lycksell, MD, C. Ringqvist, MD (Sundsvall, ll), 0. Johnson, MD, and L.-O. Hemmingson, MD (Umea, 5).

Steering Committee: John Kjekshus, MD, Sand- vika, Norway (Chairman); H. Frick, MD, Helsinki, Fin- land; Karl Swedberg, MD, Gbteborg, Sweden; L. Wil- helmsen, MD, Goteborg, Sweden.

Coordinating Office: Karl Swedberg, MD, &tra Hospital, Goteborg, Sweden (Coordinator); G. Anders- son, RN, Ostra Hospital, Goteborg, Sweden.

Ethical Review Committee: J. Lubsen, MD, The Netherlands (Chairman); D. Julian, MD, Great Britian; B. Levine, MD, USA; W. McFate Smith, MD, USA.

Administration Office: K. Kristianson, PhD, Bromma, Sweden (Head).

Statistical Analysis: S. Snapinn, PhD, Merck Sharp & Dohme Research Laboratories, Brussels, Bel- gium.


enalapril for congestive heart failure

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