Long-term control of congestive heart failure with captopril

Long-Term Control of Congestive Heart Failure With Captopril

FETNAT M. FOUAD, MD, FACC ROBERT C. TARAZI, MD, FACC EMMANUEL L. BRAVO, MD NEIL J. HART, MD, FACC LON W. CASTLE, MD, FACC ERNEST0 E. SALCEDO, MD, FACC Cleveland,

Ohio

From the Research Division and Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio. Address for reprints: Fetnat M. Fouad, MD, Research Division, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44106.

The long-term effects of captopril therapy were assessed by sequential hemodynamic studies over a 6 month period in 19 patients with resistant congestive heart failure. Initial improvement during the first week of therapy was noted only in 11 and was marked by significant (p
Disturbances of the renin-angiotensin system in heart failure have been described for over 30 years, both in man and in experimental animals.imii They have been related to various factors including diminished perfusion pressure, 12,13reduced renal blood flow14J5 and hyponatremia1”J7 and have been said to vary with the stage or rate of development of decompensation.4J7Js The end-result was differently viewed either as a compensatory mechanism1g*20 to help maintain arterial pressure despite a falling cardiac output, or as a potentially harmful vicious circle in which peripheral vasoconstriction and secondary aldosteronism led to further cardiac overload.lg The implications of these discussions took on added significance with the introduction in practice of agents that interfere effectively with the effects of angiotensin II. These included both specific analogs that acted as competitive inhibitors at the receptor leve121 and converting enzyme inhibitors that interfered with the generation of angiotensin II from angiotensin I.22-2g Early studies in man demonstrated a favorable hemodynamic response to both types of agents in heart failure,21J3,27-:30 suggesting that hyperreninemia and hypoaldosteronism could contribute to the persistence of cardiac decompensation and its resistance to classic therapy in some cases. Preliminary experience was, by necessity, limited to either acute responses to intravenous administration of angiotensin antagonists or to a few determinations of some hemodynamic indexes after oral treatment

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TABLE I

TABLE II

Early Hemodynamic Effects (1 Week) of Captopril Therapy (mean f standard error of the mean)

Baseline Characteristics of the Groups Investigated (mean f standard error of the mean)

Group I (n = 11) AMAP (mm Hg) AHR (beatslmin) ACO &i/&n) ’ zz2; ATPR (u . m*) $&(z+J, ACPV (ml) ACPVITBV (% )

-12.9 -11.0 +280 +9 -4.7 -12 - 1.4 +2.77 -180 -3.7

f f f f f f f f i f

3.14’ 2.86’ 96’ 1.77‘ 1.48” 2.57” 0.567 2.86 65t 1.537

Group II (n = 8) -5.5 +3 +31 -0.6 +1.9 -3.6 +O. 18 +6.97 f1.6 +0.81

f f f f f f f f i f

1.987 2.2 116 1.64 1.83 2.27 0.67 3.13 87 1.15

NS <0.005 NS <0.005 <0.02 <0.05 >0.05 NS NS <0.05

lp =

0.001 to 0.005, t p = 0.01 to 0.05, from control. Group I = marked improvement at week 1; Group II = little improvement at week 1. CO = cardiac output; CPV = cardiopulmonary volume; HI? = heart rate; MAP = mean arterial pressure; MTT = pulmonary mean transit time; NS = not significant; %N = percent of normal; PV = plasma volume; TBV = total blood volume; TPR = total peripheral resistance; SV = stroke volume; WT = weight.

with captopril. With regard to the latter, most reported studies described only the response of either pulmonary wedge pressure,3l cardiac output31 or ejection fraction28>2gafter variable periods (1 to 4 months) of treatment. Valuable as this early information was, it is obvious that sequential rather than single determinations are needed and that these should not be restricted to hemodynamic indexes but should also include some measure of body fluid volume and neurohumoral factors. The advent of noninvasive radionuclide methods for the study of cardiac performance allowed the needed sequential hemodynamic studies; to this was added the simultaneous determination of blood volume and of plasma catecholamines, renin activity and aldosterone, as well as creatinine clearance. A total of 19 patients were followed up by regular monthly studies for 6 months. Methods Study patients: Nineteen patients (7 women and 12 men) were included in the study. All had persistent heart failure, class III or IV of the New York Heart Association, despite optimal therapy with digitalis, diuretics and vasodilators (usually prazosin or hydralazine). Age varied from 34 to 77 years. The cause of heart disease was either coronary artery disease or primary myocardial disease. Protocol: All patients were hospitalized to ensure bed rest and regular diet; administration of vasodilators was discontinued, and the doses of digitalis and diuretics were adjusted for optimal effectiveness before starting captopril therapy. From then on, and throughout the period of follow-up, the doses of digitalis and diuretics were kept unchanged. Captopril was begun in a dose of 25 mg three times a day and kept unchanged in all but three patients; in these three patients the dose was increased to 50 to 100 mg three times a day by the end of the first month to achieve better control.

Hemodynamic studies: Radionuclide studies were obtained first before starting captopril and then sequentially at

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P

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MAP (mm Hg) HI? (beatsjmin) CO (liters/Tin) ;;;t).m 1 EF (%) PV (%N) CPV (ml) SC (mgl 100 PRA (ng/ml) PA (ng/dl) PC (ng/liter)

ml)

97 88 3.16 55 18 18 100.5 1,063 1.65 5.2 26.4 663

f f f f f f f zt i f f f

5.68 3.64 0.23 4.04 2.04 1.6 4.80 106 0.24 0.96 3.97 92

Group II (n = 8) 88 90 2.77 55 21 13 101.2 840 1.30 10.6 42.3 637

f f f f f f f f f f f f

2.73 3.84 0.20 5.51 2.12 2.0 11.82 139 0.18 4.56 13.28 76

P NS NS NS NS NS NS NS NS

NS NS NS NS

Group I = marked improvement at week 1; Group II = minimal improvement at week 1. EF = eiection fraction; PA = plasma aldosterone; PC = plasma catecholahines; PRA = plasma rehin activity; SC = serum crebtinine; other abbreviations as in Table I.

the end of 1 week and of 1, 3 and 6 months of maintenance therapy. The studies were based on intravenous injection of technetium-99m-human serum albumin and recording of precordial activity by an Anger camera as described in detail previously.32p33 Each study was analyzed in two ways: analysis of the first pass curve allowed the measurement of cardiac output, pulmonary mean transit time and cardiopulmonary volume34; then gated blood pool analysis yielded the ejection fraction35 from the same circulating radioisotope. All tests were performed in the morning with the patient fasting and after at least 30 minutes’ rest in the supine position. Plasma volume was determined (using radioactive iodinated serum albumin) and blood volume was calculated as previously described in detail.36 Before each hemodynamic study, plasma renin activity, plasma aldosterone, plasma catecholamines and serum electrolytes were determined from samples obtained in the supine position. Blood pressure was recorded using a sphygmomanometer cuff at least four times during each study and the average value was used for calculations. Heart rate was obtained from electrocardiographic lead II during the hemodynamic study. Plasma renin, aldosterone and catecholamines: These determinations were made by the appropriate procedures as described in detail in previous reports.s7+3s Normal values in our laboratory for patients on regular sodium intake averaged 1.2 f 0.4 (standard error) ng/ml/h for plasma renin activity, 10 f 4 (standard deviation) ng/dl for plasma aldosterone and 260 f 120 ng/liter for plasma catecholamines. Informed consent was obtained from all patients after full explanations were given before starting therapy; the protocol used was approved by the Institutional Review Committee of the Cleveland Clinic Foundation.

Results Clinical Follow-Up One week to 3 months: After the addition of captopril to digitalis and diuretics, any improvement in the patient’s condition was gradual and usually not noticeable before 2 to 3 days, at least. By the end of the first week in the hospital, only 11 of the 19 patients had

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TABLE III

(mmHg)

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MAP

Hemodynamfc Changes (mean f standard error of the mean) in Eight Patients With Maintained Improvement on Captopril Therapy Control MAP (mm Hg) HR (beats/min)

99 f 6.75 82 f 11.42

Week 1

Month 3

a7 f 4.18’ 62 f 12.23’

90 f 3.76 71 f 3.49’ MTT (set)

2.Z ((rlfty/min) M-f-f (s) CPV (ml)

0.27 3.35 38 f 3.81 20.9 f 1.41 1,164 f 126

3.67 47 f 4.28’ 0.29’ 15.9 f 1.24’ 957 f 95’

3.46’ 3.64 51 f 0.24’ 13.5 f 0.86’ 802 f 73’

p <0.05 from control. Abbreviations as in Table I. l

14 .

improved as judged by cessation of oxygen therapy, disappearance of shortness of breath at rest and increased exercise tolerance, as well as marked reduction or disappearance of edema and ascites. Subsequently, six of the eight who had shown only minimal response began to show definite clinical improvement between months 1 and 3; one patient was withdrawn because of noncompliance and one died at week 2. Six months: At the end of 6 months, 12 of the 19 patients continued to take the same treatment; of these 12 patients, the clinical response was still borderline in 1 (Case 14), but in all the others heart failure had become well controlled. Of the remaining 7 of the original 19 patients, captopril had to be discontinued in 5: in 1 patient because of poor compliance, in 1 because of severe angina necessitating other forms of therapy, in 1 because of progressive deterioration of renal function due to antecedent nephrosclerosis and possibly added interstitial nephritis, in 1 because of incidental hepatitis and in the fifth because of diarrhea of unknown cause. The remaining two patients died suddenly while apparently improving on captopril therapy. Mortality: Mortality during this 6 month period was thus not negligible: 5 of 19 patients died (25 percent). The two who died suddenly had coronary artery disease and ventricular premature beats, both initially and during captopril treatment; in both the serum potassium level was within normal range. The other three died 1 to 2 weeks after the drug had been discontinued. Hemodynamic

Results

Early (1 week) results (Table I): Arterial pressure remained significantly reduced in the first week of therapy (93 % 3.58 [mean f standard error of the mean] to 83 f 2.32 mm Hg, p
(ml)

(ml)

CPV

1200r Q

r

FIGURE 1. Sequential hemodynamic effects during longterm treatment of congestive heart failure with captopril. Note the late response in patients in Group II (see text). = p <0.05 (from control); C = control; CPV = cardiopulmonary volume; HR = heart rate; Ms = month 3; MAP = mean arterial pressure; MTT = pulmonary mean transit time; SV = stroke volume; W, = week 1. Open circles and dashed lines represent Group I (early responders; n = 8). Black circles and continuous lines represent Group II (late responders; n = 5). l

showed insignificant changes in patients with little clinical improvement but which increased significantly in Group I. The baseline hemodynamic characteristics of the two groups showed no statistically significant differences (Table II) that could predict early responsiveness to captopril. Late results at 3 and 6 months of continued therapy (Table III): Of the 11 patients who had shown marked initial improvement at the end of the first week of therapy (Group I), 8 were still on treatment and continued to manifest good control of heart failure; of the remaining 3,1 died at week 1,1 could not come for the study, and in the third captopril was discontinued because of concomitant hepatitis. Although blood pressure reduction was less marked than at the end of week 1 in the eight improved patients, cardiac output was still higher and the slowing in heart rate and shortening of mean transit time were more obvious. More importantly, there was a change in response in the patients who had shown little improvement initially (Group II). At the end of 3 months of follow-up, mean transit time shortened and cardiopulmonary volume was reduced significantly in the six patients who were still taking captopril (Fig. 1). The most important hemodynamic signs of improvement in all patients as a whole during this period

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TABLE IV Hemodynamic and Humoral Changes (mean f standard error of the mean) in Seven Patients Treated for 6 Months Before Captopril HI? (beatsjmin) MAP (mm Hg) CO (liters/min) SV (ml) TPR (U - m2) MTT (s) EF (%) WT (kg) ;;j 7i-J) 00 CPV (ml) CPVlTBV (%) PRA (nglml) PA (ng/dl)

93 95 3.31 37 50 19.4 16 63.3 94.1 96.7 1,048 33.9 5.0 30.6

f f f f f f f f f f f f f f

1 Week 86 86 3.61 44 42 17.1 20 62.4 93.6 101.7 988 22.5 8.0 17.8

5.20 4.60 0.17 2.90 4.0 2.0 0.01 4.20 4.00 4.60 76 1.70 1.50 2.7

f f f f f f f f f f f f f f

3 Months 76 87 3.44 46 44 12.4 26 61.6 82.8 89.9 708 18.2 9.3 14.0

6.50 2.40 0.20 3.90 2.80 2.80 0.01 4.00 3.60 4.40 107 2.40 1.70 2.60”

f f f f f f f f f f f f f f

6 Months

4.50’ 3.00 0.19 3.90 2.90 0.90’ 0.06 5.00 4.30’ 6.90 59’ 0.7’ 1.90 2.20’

77 93 3.35 45 49 11.7 21 64 85.5 SO.2 637 16.1 22.0 20.1

f f f f f f f f f f f f f f

5.50’ 2.00 0.31 6.10 3.20 0.70’ 0.04 4.90 5.40’ 6.40 48’ 0.8’ 7.80’ 3.0’

-

p <0.05. These seven patients who had sequential studies over 6 months include four patients of Group I and three of Group II. The changes in plasma volume (PV) at 3 and 6 months differ significantly from plasma volume at week 1. Abbreviations as in Tables I and II. l

were the persistent reduction of heart rate (76 f 4.86 versus a control average of 89 f 2.59 beats/min) and normalization of mean transit time (11.9 f 0.8 seconds at month 3; normal of laboratory 6 to 10 seconds). Ejection fraction showed statistically significant improvement at months 1 and 3; however, the change was very small (+0.02 to +0.04, p <0.05) and thus of doubtful biologic significance. At the end of this study, 12 of the original 19 patients were still receiving captopril6 months after the initiation of the protocol; 2 had died suddenly, and in 5 the drug had been discontinued because of side effects, noncompliance or associated disease. Since 5 of the 12 patients did not have a hemodynamic study at 6 months, the data reported in Table IV summarize findings in the other 7.

Humoral Changes

Plasma renin and aldosterone: The significant increase in plasma renin activity seen at the end of the first week (7.3 f 1.89 to 14 f 3.28 ng/ml/h, p <0.05) was maintained throughout the follow-up period (12.1 f 3.16 at month 1,15.7 f 5.1 at month 3 and 20.1 f 0.5 at

2or

9

month 6; p
MI

20

r =-0.79

p~0.001 0

h.

MS

*= -0.92

p
l*

LOG PA

LOG PA

LOG PA

FIGURE 2. Reduction in plasma aldosterone (PA) in relation to initial level. WI = week 1; MI and Me = months 1 and 3, respectively.

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4.3 f 0.12 at 1 week; and 4.04 f 0.14, 4.13 f 0.14 and 3.93 f 0.17 at 1, 3 and 6 months, respectively; p not significant for all). The serum sodium level remained normal throughout the follow-up. The concomitant increase in plasma renin activity and reduction in plasma aldosterone led to a highly significant decrease in the plasma aldosteronelrenin activity ratio during therapy (from a mean value of 24.75 f 4.93 before captopril to 2.61 f 0.60 at 1 week, and 1.86 f 0.29, 1.61 f 0.31 and 3.09 f 1.59 at months 1, 3 and 6, respectively; p <0.005 for all). This reduction of the ratio could be taken as an index of the continued absorption of the drug and patient compliance. Plasma catecholamines: There was a tendency toward a gradual reduction in plasma catecholamines, but it did not attain statistical significance at any stage in this group (650 f 57 ng/liter before captopril, 604 f 65 at 1 week, 490 f 78 at 1 month, 554 f 88 at 3 months and 624 f 155 at 6 months). Renal function: Renal excretory function was generally maintained during the 6 month follow-up period in all 19 patients. The serum creatinine level, which was slightly above normal to start with (1.52 f 0.16 mg/lOO ml), remained unchanged (1.60 f 0.19 at week 1, 1.47 f 0.19 at month 1 and 1.66 f 0.22 at month 3). Only one patient had a significant elevation of serum creatinine (from 3.5 initially to 9.8 mg/lOO ml at 6 months). This patient had a history of hypertension and nephrosclerosis; renal failure was attributed to complicating interstitial nephritis, possibly due to concomitant administration of allopurinol. She was taken off the protocol at that point, but died a few weeks later from heart failure despite conventional therapy. For the other patients the average value for serum creatinine at 6 months was 1.69 f 0.24 mg/lOO ml. Plasma Volume Changes Despite the reduction in body weight observed in the first week and presumably related to diuresis, the average plasma volume was increased significantly (from 100.83 f 4.40 to 105.37 f 4.43 percent of normal, p <0.05), indicating some intravascular fluid shift. However, this expansion was manifest only in 11 patients (+9.81 f 1.86 percent, p <0.005) while in the others plasma volume was not changed significantly (-2.7 f 2.75 percent) irrespective of clinical response. Of importance in that regard was the difference in weight change between these two groups. Those who had an increase in plasma volume in the first week had no concomitant significant change in weight (-0.064 f 0.063 kg, p not significant), while the others had a concomitant reduction in body weight that was significant (- 1.59 f 0.58 kg, p <0.05). Both of these patterns point to the same intravascular shift of fluid volume, probably the result of venodilation. With longer follow-up however, and improvement in failure, plasma volume was reduced progressively (100.8 f 5.50 percent of normal before captopril, 105.4 f 4.43 at week 1,99.6 f 3.88 at month 1, 95.2 f 5.30 at month 3 and 92.3 f 5.88 at month 6 for the group as a whole).

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There was a tendency toward a reduction in cardiopulmonary volume (-103.58 f 55.11, p >0.05) and in the cardiopulmonary/total body volume ratio (-1.88 f 1.16, p not significant) at week 1, but these changes did not reach statistical significance. With longer follow-up, the ratio diminished gradually to normal levels (from 21.2 f 1.34 before captopril to 19.0 f 0.77 at month 1, p >0.05; 17.7 f 0.91 at month 3, p 0.05 at month 6). Correlates of Hemodynamic Changes During Treatment The reduction of arterial pressure was due in all cases to a reduction in total peripheral resistance since cardiac output either had increased or was unchanged. Neither change (blood pressure or total peripheral resistance) was correlated with the pretreatment level of plasma renin activity. In contrast, the maintained reduction in total peripheral resistance correlated significantly at 3 months with the decrease in plasma catecholamines (r = 0.84, p
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failure. They also add to these earlier reports a longterm follow-up with simultaneous determination of hemodynamic and humoral changes, which revealed a more complex pattern than a simple increase in output secondary to a reduction in mean arterial pressure. Hemodynamic effects: Captopril did effectively reduce mean arterial pressure during long-term therapy, presumably secondary to arteriolar dilation. This reduction in systemic pressure was related in all cases to a reduction in total peripheral resistance since cardiac output was increased or at worst left unchanged. However, this effect was not the only hemodynamic consequence of therapy; a significant reduction in cardiopulmonary volume and in cardiopulmonary/total body volume ratio occurred, suggesting an additional venodilator effect. These two consequences would be expected to help increase cardiac performance and consequently cardiac output and stroke volume by reducing the pressure load on the heart and relieving systemic congestion. However, the correlation between changes in stroke volume and in mean arterial pressure was only moderate (r = -0.61, p
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ment and any of the hemodynamic changes produced by captopril. The lack of a significant correlation between pretreatment plasma renin activity and the total peripheral resistance or mean arterial pressure response to converting enzyme inhibition was also noted by Turini et a1.24 This may be related to the complexity of factors influencing plasma renin activity on the one hand and the degree and cause of peripheral vasoconstriction in congestive heart failure on the other. Further, the effects of captopril therapy cannot be related to reduction in peripheral angiotensin II levels alone.44 In fact, recent evidence suggests that captopril may tone down the effects of sympathetic stimulation.4S In that respect, our data regarding changes in plasma catecholamines and their correlation with reduction in total peripheral resistance suggest that a toning down of sympathetic activity might have played a role in the improvement in our patients. That reduction in adrenergic tone could theoretically result from the multifaceted relation between angiotensin II and the sympathetic nervous system.4”-50 However, the delayed reduction in plasma catecholamines probably suggests that the improvement in failure itself might have led to the gradual toning down of adrenergic stimulation. This same explanation may hold for the gradual decrease in cardiopulmonary/total body volume ratio (venodilation) since there is some doubt regarding a direct effect of angiotensin II in veins. 5o The close interrelation between the renin-angiotensin and the adrenergic systems is such that it is very difficult from clinical observations alone to separate the influence of one from that of the other in patients, even with the use of specific blockers. Clinical implications: The combination of hemodynamic, humoral and volume changes suggests that the major influence of captopril was exerted on the peripheral circulation, with secondary improvement in cardiac pump function. In fact, studies of renal blood flow and renal dynamics by our groups51 in these patients showed that improvement in renal hemodynamic function resulted in better handling of sodium load at lower levels of arterial pressure. Also, improvement in hepatic circulation would be expected to enhance aldosterone clearance. These peripheral (systemic and regional) circulatory changes suggest that clinical improvement resulted from unloading of the heart induced by reducing peripheral resistance and extracellular fluid volume. There was no evidence, on the other hand, of a direct action of captopril on the myocardium. What was also evident from our data was the value of pulmonary mean transit time in documenting the progress of our patients. Cardiac output, stroke volume and blood pressure varied with long-term follow-up, but the more consistent objective sign of cardiac function was the normalization of pulmonary mean transit time. It was, in our experience, the single best sign correlating with the clinical progress of our patients. Despite its beneficial effects, captopril was not a panacea. The survival rate was only 83 percent at the end of 3 months of therapy and 75 percent at the end of

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6 months of treatment. The blockade of angiotensin II synthesis improved peripheral circulation and unloaded the heart, but the initial cardiac damage remained unchanged. Foci of arrhythmia and sensitivity of the injured myocardium to electrolyte imbalance, digitalis toxicity or overloading by fever, excess volume or increased pressure remained threatening factors. However, the drug has been tried only in end-stage heart failure; it is possible that better long-term results could be obtained by earlier relief of the cardiac load.

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Acknowledgment We express our gratitude to the Squibb Institute of Medical Research and Dr. Leonard Dennick for the supply of captopril and for his help and assistance. Statistical analysis was accomplished using the PROPHET computer system, which is supported in part by the Division of Research Resources of the National Institutes of Health. We also thank Mary Kay Kruchan, Susan Vaughn and Kathy Rojc for their technical assistance, and Kathy Akiya and Aldona Raulinaitis for secretarial assistance.

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