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Antihypertensive Effect of Enalapril as First-Step Treatment of Mild and Moderate Uncomplicated Essential Hypertension
Antihypertensive Effect of Enalapril as First-Step Treatment of Mild and Moderate Uncomplicated Essential Hypertension Evaluation by Two Methods of Blood Pressure Measurement
PAOLO SASSANO, M.D. GILLES CHAT!:LLIER, M.D. FRANCOIS ALHENC-GELAS, M.D. PIERRE CORVOL, M.D. JOEL MENARD, M.D. Paris, France
From the Service d'Hypertension Arterielle, Hopital Broussais, Paris, France. Requests for reprints should be addressed to Dr. Joel Menard, INSEAM U 36 17 Rue de Fer a Moulin 75005 Paris, France.
18
~uguat
20, 1984
The new angiotensin converting enzyme inhibitor enalapril (MK421 ), was given in a single daily dose of 20 mg to 53 patients with uncomplicated essential hypertension. Its effects were compared with those of a placebo given to 47 patients on a double-blind randomized basis. The blood pressure was measured in all patients by a physician, using a mercury sphygmomanometer, and by an automatic device in the absence of the physician. After 15 days of treatment, enalapril induced a significant reduction in systolic blood pressure (161.4 ± 13 versus 145.1 ± 15, p < 0.001) and in diastolic blood pressure (103.3 ± 6 versus 92.9 ± 8, p < 0.001) measured by the physician. The magnitude of the fall in blood pressure was identical after 30 days of active treatment. The reduction in blood pressure induced by enalapril was similarly detected by both methods of measurement, despite the fact that blood pressure values were higher when measured by the physician. A placebo effect was observed with the physician's values that was not present with the automatically recorded values. A very significant correlation between blood pressure values obtained by these two methods was observed. However, among nine of 53 patients treated with enalaprll, a difference In the decrease of blood pressure of 10 mm Hg or more was noted between the two methods of measurement. The decre~tse in !3lood pressure occurred with no chan~e noted in the pulse rate 9r orthostatic hypotension. Plasma renin activity increased after treatment. No changes were observed in creatinine clearance and plasma electrolyte levels. Even though several controlled trials have shown a reduction in cardiovascular mortality and morbidity in treated hypertensive patients [1],use of the presently available drugs is limited by the relatively high incidence of their clinical or biologic side effects [2] and their relative lack of efficacy [3]. Therefore, it is expected that new therapeutic agents, such as converting enzyme inhibitors or calcium channel blockers, will be more effi· cacious and have fewer side effects. The precise quantification of the antihypertensive efficacy of a new drug is made difficult by the variations in blood pressure recorded during the day [4,5] and by the spontaneous decline _in blood pressure that is observed during successive visits in placebo-treated outpatients [6]. In order to quantify the antihypertensive effect of the new converting enzyme inhibitor MK-421 (enalapril), we conducted a double-blind randomized study in which the effects of enalapril (20 mg once a day) were compared with those of a placebo. The blood pressure was evaluated by
The American Journal of Medicine
CONVERTING ENZVME INHIBITION-SASSANO ET AL
then performed by the same observer during the entire trial. The point of disappearance of the fifth Korotkoff sound was taken as the diastolic blood pressure. Analytical Methods. Blood sampling was performed after one hour in the supine position for measurement of plasma renin activity and for control of the biochemical parameters usually selected to detect any toxic effect of a new drug. Plasma renin activity was measured by angiotensin I radioimmunoassay [7]. In our laboratory, the normal value (mean ± SE) for supine plasma renin activity is 0.82 ± 0.48 ng/ml per hour (n = 18) at a urinary sodium excretion of 145 ± 47 mEq per day. Statistical Methods. Results are expressed as mean ±SD. Either the Student t test or a paired t test was used to compare groups or measurements made in the same person. Correlation coefficients were obtained by the least-squares method.
two different methods of measurement: a 30-minute recording of blood pressure by an automatic oscillometric device (Sentron) in the absence of a physician, and two measurements of blood pressure performed by a physician with a mercury sphygmomanometer. · The results of this trial demonstrate and quantify the antihypertensive effect of MK-421, given once a day, as first-step therapy of mild and moderate uncomplicated essential hypertension. PATIENTS AND METHODS Patients. Among 1,243 new patients with hypertension who were referred to the clinic during one year, 118 (80 men and 38 women, aged 27 to 64 years) were selected for this trial according to the following criteria: a diastolic blood pressure of 95 to 120 mm Hg, the absence of cardiovascular complications, no treatment for at least two weeks prior to the start of the therapy, a body weight of less than 95 kg, age 18 to 65 years, and the absence of chronic conditions. A minimum of 15 days without treatment after the first visit was allowed before complete work-up in the hospital. Then, all patients were given a placebo for 15 days. At the end of this period, both blood pressure and heart rate were evaluated six to eight hours after placebo ingestion. One hundred patients with an uncomplicated essential hypertension completed the study. Fifteen patients were excluded because their blood pressure fell to less than 95 mm Hg after 15 days of placebo therapy. Two other patients were excluded because they were suspected of having secondary hypertension. One patient was withdrawn from the trial after 15 days of enalapril therapy because of a 15-fold increase in serum aspartate aminotransferase (SGOT) and in serum alanine aminotransferase (SGPT), both of which reverted back to normal 90 days after the cessation of therapy and which again increased 10-fold when enalapril was reintroduced for 13 days. This patient admitted that he was drinking 2 liters of beer a day at the time of the first increase in his hepatic enzymes. Blood pressure and heart rate were monitored during one hour at five-minute intervals by an automatic device based on the oscillometric method (Sentron). The blood pressure value considered was the mean of the last five measurements. Two successive measurements of supine blood pressure were
TABLE I
RESULTS Group Comparability. The placebo-treated group included 47 patieiits (31 men and 16 women), mean age 46.8 years (range 31 to 64 years), mean body weight 71.8 kg (range 52 to 95 kg). The enalapril-treated group included 53 patients (40 men and 13 women), mean age 47.4 years (range 27 to 63 years), mean body weight 73.6 kg (range 51 to 93 kg). The two groups were comparable for the following variables, all of which were considered before treatment (systolic and diastolic blood pressure, plasma sodium and potassium levels, creatinine clearance, and urinary sodium and potassium excretion). Blood Pressure. Mean blood pressure values after the placebo period, and after 15 and 30 days of treatment are shown in Tables I and II. When the decrease in blood pressure induced by enalapril is calculated from the automated values and from the physician's values, there is no statistical difference between the results obtained by the two methods of measurement. When the blood pressure values measured by the physician (Table I) are analyzed, a placebo-induced fall in blood pressure is detectable for both systolic and diastolic blood pressure after the first 15 days of placebo therapy, whereas no further fall is observed after 30 days. This
Blood Pressure Results Systolic Blood Pressure (mm Hg)
Diastolic Blood Pressure (mm Hg)
Days
Enalapril
Placebo
pt
Enalapril
Placebo
pt
0
161.4±13.0
163.5 ± 13.8
NS
103.3 ± 6.3
104.6 ± 7.0
NS
15
145.1 ± 15.6 NS 143.8 ± 13.8
158.8 ± 13.6 NS 158.4 ± 13.7
92.9 ± 8.4 NS 91.8 ± 8.4
100.3 ± 9.9 NS 100.7 ± 9.2
30
Blood pressure was measured by the same physician with a mercury sphygmomanometer before and after 15 and 30 days of treatment; means ISO are expressed. tt test or paired t test: * p < 0.05; •• p < 0.01; ***p < 0.001; NS = not significant.
August 20, 1984
The American Journal of Medicine
19
CONVERTING ENZYME INHIBITION-SASSANO ET AL
Blood Pressure Results
TABLE II
Diastolic Blood Pressure (mm Hg)
Systolic Blood Pressure (mm Hg); Days
Enalapril
Placebo
pt
Enalapril
Placebo
pt
0
149.7 ± 13.3
NS
92.1 ± 10.1
131.4 ± 12.8 NS 131.6 ± 12.9
91.2 ± 9.9 NS 89.4 ± 12.0 NS 89.6 ± 10.6
NS
15
149.1 ± 12.9 NS 148.5 ± 13.8 NS 148.1 ± 13.7
30
79.7 ± 8.8 NS 79.9 ± 8.3
Blood pressure was measured with an automatic device before and after 15 and 30 days of treatment; means ± SD are expressed. tt test or paired t test: * p < 0.05; ** p < 0.01; ***p < 0.001; NS = not significant.
.
+ 10
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= 0.45
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Ll Diastolic B.P. Physician
< 0.0005
Figure 1. Correlation between the decrease in diastolic blood pressure measured by continuous automatic recording of blood pressure and by the physician.
TABLE Ill
Change in Systolic Blood Pressure Induced by Upright Position
Days
Enalaprll (mm Hg)
Placebo (mm Hg)
0 15 30
-4.1 ± 9.9 -3.5 ± 10.4 -4.6 ± 7.5
-6.8 ± 9.2 -4.8 ± 11.6 -2.1 ± 7.9
Blood pressure was measured by the physician with a mercury sphygmomanometer before and after 15 and 30 days of treatment, after one minute with the patient in the upright position. Means ± SD are expressed.
20
August 20, 1984
The American Journal of Medicine
placebo effect is not observed with blood pressure values obtained by automatic measurement (Table II). The enalaprir:induced fall in systolic and diastolic blood pressure calculated from the values given by the Sentron machine is very significantly correlated to the decrease calculated from ,the values measured by the physician (r = 0.43, p < 0.0002 for systolic blood pressure; r = 0.45, p < 0.0005 for diastolic blood pressure) (Figure 1.) Nevertheless, if response is defined by a fall in diastolic blood pressure of 10 mm Hg and more by the two methods of measurement, 27 patients can be classified as responders and 10 patients as non responders. In 16 of the 53 patients, the discrepancy between the values provided by the two methods of measurement does not allow the exact antihypertensive effect of enalapril to be precisely defined. Among those 16 patients, eight patients would have been classified as responders according to the automatic method and as nonresponders according to the sphygmomanometric values, whereas the opposite result would have been seen in the other eight patients. In placebo-treated patients, there was no correlation between the variations in blood pressure measured by the automatic device and those measured by the physician. A fall in blood pressure of more than 10 mm Hg as measured by the two methods was obtained only in four of 47 patients after 30 days of placebo therapy. As shown in Table Ill, no orthostatic hypotension was observed during enalapril treatment. The pulse rate, with the patient in both recumbent and upright positions, did not show any change during the treatment period (enalapril-treated group: supine 72 ± 9 versus 71 ± 10, upright 86 ± 10 versus 86 ± 12; placebo-treated group: supine 74 ± 8 versus 73 ± 9, upright 8~ ± 11 versus 85 ± 10). No serious complaints were reported by the patients, and the double-blind characteristic of the study was completely preserved for both the physician and the patient during this one-month period. Plasma Renin Activity. Whereas the placebo did not change plasma renin activity from 0.72 ± 0.8 to 0.75 ± 0.9 ng/ml per hour, enalapril increased plasma renin activity from 0.69 ± 0.6 to 5.1 ± 6.9 ng/ml per hour. Plasma
CONVERTING ENZYME INHIBITION-SASSANO ET AL
TABLE IV
Plasma Sodium and Potassium Levels and Creatinine Clearance before and after Treatment Enalapril
Sodium (mmol/liter) Potassium (mmol/liter) Creatinine clearance (ml/minute)
Placebo
Before
Aller
Before
Aller
141.4±2.4 4.0 ± 0.3
140.7 ± 2.5 3.9 ± 0.3
140.4 ± 2.6 3.9 ± 0.3
141.2 ± 2.0 3.9 ± 0.3
105.5 ± 33.2
103.1 ± 31.5
96.5 ± 28.5
98.2 ± 27.1
renin activity increased in 46 of 53 patients receiving enalapril. Except for the one patient already described, no other changes in the biochemical parameters were detected during the course of this study (Table IV). COMMENTS Enalapril was shown in other clinical trials to be able to suppress angiotensin converting enzyme activity as well as the formation of angiotensin II for several hours after a single oral dose of 2.5 to 40 mg [8-1 0]. The choice of a once-a-day dose of 20 mg made for this trial is based on these data and has been confirmed by the similar efficacy and tolerability of once-a-day and twice-a-day regimens of a daily 20 mg enalapril dosage [11]. These results again illustrate the difficulties encountered in blood pressure measurements during such trials. Quantification of the fall in blood pressure is, on the average, identical by both methods, and the fall in blood pressure is also significantly correlated between both methods for each patient. Nevertheless, the continuous recording of blood pressure in the absence of the physician provides blood pressure values that are 10 to 14 mm Hg lower than those obtained by the physician. Moreover, discrepancies larger than 10 mm Hg are observed in one patient among five, which makes a precise quantification of the benefits of the treatment for each patient difficult. Despite a minimum of three successive visits before randomization, a placebo effect was still detected by the physician during the first 15 days of treatment. On the contrary, this placebo effect was not observed with the blood pressure values measured by the automatic device in the absence of a physician and while the patient was lying quietly. Gould et al [12] have already reported that a placebo effect does not exist when 24-hour ambulatory intra-arterial measurement of blood pressure is performed. Mancia et al [13] also showed a constant but quite variable increase in blood pressure when a patient undergoing continuous intra-arterial recording of blood pressure is confronted by his physician. It is likely that the interference of the physician explains the higher values measured in the present study and that the placebo effect occurs when the patient gets to know the physician better.
After 15 days of treatment, a maximal efficacy of enalapril at this dose is observed, and there is no further decrease in blood pressure between 15 and 30 days of active treatment. The decrease in systolic and diastolic blood pressure induced by enalapril is not accompanied by orthostatic hypotension or an accelerated heart rate. This confirms observations made in other studies of normal volunteers in which tachycardia was not observed during converting enzyme inhibition and was without any alteration in autonomic reflex [14, 15]. The magnitude of the fall in blood pressure observed in this study (17/11 mm Hg) was obtained in hypertensive patients whose sodium intake was moderate since their mean natriuresis was 123 ± 63 mEq per day before treatment and 125 ±59 mEq per day after treatment. If we consider the results obtained in the 37 patients for whom the interpretation of blood pressure measurements is not ambiguous, the mean decrease in blood pressure induced by enalapril during a once-a-day regimen was -17/11 mm Hg. In 57 percent of the patients, the decrease is diastolic blood pressure was below 90 mm Hg. The magnitude of the fall in diastolic blood pressure was similar to that observed in trials with diuretics or beta blockers as initial treatment [16]. However, the main advantages of enalapril treatment were the absence of orthostatic hypotension, the absence of change in pulse rate, and the total absence of clinical and biochemical side effects. This fact could be of great importance in the long-term treatment of hypertension since side effects of drugs can minimize compliance. The increase in hepatic enzymes observed in one patient who was a heavy drinker cannot be interpreted in the context of this small study but should be interpreted in relation to the large number of patients who have been exposed to this drug throughout the world and who did not show any increase in their hepatic enzymes during treatment [17]. ACKNOWLEDGMENT We are grateful to Dr. J. Espie and Mrs. P. Airoldi of the Merck Sharp and Dohme Company for their helpful assistance in this work.
August 20, 1984
The American Journal of Medicine
21
CONVERTING ENZYME INHIBITION-SASSANO ET AL
REFERENCES 1. 2.
3. 4. 5. 6. 7.
8. 9.
22
WHO/ISH Mild Hypertension Liaison Committee: Trials of treatment of mild hypertension. An interim analysis. Lancet 1982; 1: 149-156. Medical Research Council Working Party on Mild to Moderate Hypertension: Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension. Lancet 1981; 1: 539-543. Menard J, Chatellier G, Degoulet P, Plouin PF, Corvol P: How much can blood pressure be lowered? Hypertension 1983; 5 (suppl Ill): 21-25. Millar-Craig MW, Bishop CN, Raftery EB: Circadian variation of blood pressure. Lancet 1978; 1: 795-797. Mancia G: Methods for assessing blood pressure values in humans. Hypertension 1983; 5 (suppl Ill): 5-13. Australian Therapeutic Trial in Mild Hypertension: Untreated mild hypertension. Lancet 1982; 1: 185-191. Menard J, Corvo! P, Allegrini J, Breminer J: Mesure de lactivite ranine plasmatique de lhomme par le dosage radioimmunologique de langiotensine I. In : Colloques INSEAM, eds. Techniques radioimmunologiques. Paris: INSEAM, 1972; 459-470. Gavras H, Biollaz J, Waeber B, Brunner HR, Gavras I, Davies RO: Antihypertensive effect of the new oral angiotensin converting enzyme inhibitor "MK 421." Lancet 1981; II: 543-547. Biollaz J, Burnier M, Turini GA, et al: Three new long-acting converting enzyme inhibitors: relationship between plasma converting enzyme activity and response to angiotensin I. Clin
August 20, 1984
The American Journal of Medicine
10. 11.
12. 13. 14.
15.
16.
17.
Pharmacol Ther 1981; 11:461-467. Brunner HR, Waeber B, Nussberger J, Schaller MD, Gomez HJ: Long-term clinical experience with enalapril in essential hypertension. J Hypertension 1983; 1 (suppl 1): 103-107. Bergstrand R, Johanasson S, Wedin A, Wilhelmsson L: Comparison of once-a-day and twice-a-day dosage regimens of enalapril (MK421) in patients with mild hypertension. Br J Clin Pharmacol 1982; 14: 136P-137P. Gould BA, Mann S, Davies AB, Altman DG, Raftery EB: Does placebo lower blood pressure? Lancet 1981; 11: 1377-1381. Mancia G, Ferrari A, Gregorini L, et al: Blood pressure variability in man: its relation to high blood pressure, age and baroreflex sensitivity. Clin Sci 1980, 59: 401s-406s. MacGregor GA, Markandu ND, Bayliss J, Roulston JE, Squires M, Morton JJ: Non-sulfhydryl-containing angiotensin converting enzyme inhibitor (MK421 ): evidence for role of renin system in normotensive subjects. Br. Med J 1982; 283:401-403. Millar JA, Derkx FHM, Mclean K, Reid J: Pharmacodynamics of converting enzyme inhibition: the cardiovascular, endocrine and autonomic effects of MK 421 (enalapril) and MK 521. Br J Clin Pharmacol 1982; 14: 347-355. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension. JAMA 1982; 16: 1996-2003. Dollery CT: Safety and efficacy of enalapril. Summing up the evidence. J Hypertension 1983, 1 (suppl 1): 155-157.
PAOLO SASSANO, M.D. GILLES CHAT!:LLIER, M.D. FRANCOIS ALHENC-GELAS, M.D. PIERRE CORVOL, M.D. JOEL MENARD, M.D. Paris, France
From the Service d'Hypertension Arterielle, Hopital Broussais, Paris, France. Requests for reprints should be addressed to Dr. Joel Menard, INSEAM U 36 17 Rue de Fer a Moulin 75005 Paris, France.
18
~uguat
20, 1984
The new angiotensin converting enzyme inhibitor enalapril (MK421 ), was given in a single daily dose of 20 mg to 53 patients with uncomplicated essential hypertension. Its effects were compared with those of a placebo given to 47 patients on a double-blind randomized basis. The blood pressure was measured in all patients by a physician, using a mercury sphygmomanometer, and by an automatic device in the absence of the physician. After 15 days of treatment, enalapril induced a significant reduction in systolic blood pressure (161.4 ± 13 versus 145.1 ± 15, p < 0.001) and in diastolic blood pressure (103.3 ± 6 versus 92.9 ± 8, p < 0.001) measured by the physician. The magnitude of the fall in blood pressure was identical after 30 days of active treatment. The reduction in blood pressure induced by enalapril was similarly detected by both methods of measurement, despite the fact that blood pressure values were higher when measured by the physician. A placebo effect was observed with the physician's values that was not present with the automatically recorded values. A very significant correlation between blood pressure values obtained by these two methods was observed. However, among nine of 53 patients treated with enalaprll, a difference In the decrease of blood pressure of 10 mm Hg or more was noted between the two methods of measurement. The decre~tse in !3lood pressure occurred with no chan~e noted in the pulse rate 9r orthostatic hypotension. Plasma renin activity increased after treatment. No changes were observed in creatinine clearance and plasma electrolyte levels. Even though several controlled trials have shown a reduction in cardiovascular mortality and morbidity in treated hypertensive patients [1],use of the presently available drugs is limited by the relatively high incidence of their clinical or biologic side effects [2] and their relative lack of efficacy [3]. Therefore, it is expected that new therapeutic agents, such as converting enzyme inhibitors or calcium channel blockers, will be more effi· cacious and have fewer side effects. The precise quantification of the antihypertensive efficacy of a new drug is made difficult by the variations in blood pressure recorded during the day [4,5] and by the spontaneous decline _in blood pressure that is observed during successive visits in placebo-treated outpatients [6]. In order to quantify the antihypertensive effect of the new converting enzyme inhibitor MK-421 (enalapril), we conducted a double-blind randomized study in which the effects of enalapril (20 mg once a day) were compared with those of a placebo. The blood pressure was evaluated by
The American Journal of Medicine
CONVERTING ENZVME INHIBITION-SASSANO ET AL
then performed by the same observer during the entire trial. The point of disappearance of the fifth Korotkoff sound was taken as the diastolic blood pressure. Analytical Methods. Blood sampling was performed after one hour in the supine position for measurement of plasma renin activity and for control of the biochemical parameters usually selected to detect any toxic effect of a new drug. Plasma renin activity was measured by angiotensin I radioimmunoassay [7]. In our laboratory, the normal value (mean ± SE) for supine plasma renin activity is 0.82 ± 0.48 ng/ml per hour (n = 18) at a urinary sodium excretion of 145 ± 47 mEq per day. Statistical Methods. Results are expressed as mean ±SD. Either the Student t test or a paired t test was used to compare groups or measurements made in the same person. Correlation coefficients were obtained by the least-squares method.
two different methods of measurement: a 30-minute recording of blood pressure by an automatic oscillometric device (Sentron) in the absence of a physician, and two measurements of blood pressure performed by a physician with a mercury sphygmomanometer. · The results of this trial demonstrate and quantify the antihypertensive effect of MK-421, given once a day, as first-step therapy of mild and moderate uncomplicated essential hypertension. PATIENTS AND METHODS Patients. Among 1,243 new patients with hypertension who were referred to the clinic during one year, 118 (80 men and 38 women, aged 27 to 64 years) were selected for this trial according to the following criteria: a diastolic blood pressure of 95 to 120 mm Hg, the absence of cardiovascular complications, no treatment for at least two weeks prior to the start of the therapy, a body weight of less than 95 kg, age 18 to 65 years, and the absence of chronic conditions. A minimum of 15 days without treatment after the first visit was allowed before complete work-up in the hospital. Then, all patients were given a placebo for 15 days. At the end of this period, both blood pressure and heart rate were evaluated six to eight hours after placebo ingestion. One hundred patients with an uncomplicated essential hypertension completed the study. Fifteen patients were excluded because their blood pressure fell to less than 95 mm Hg after 15 days of placebo therapy. Two other patients were excluded because they were suspected of having secondary hypertension. One patient was withdrawn from the trial after 15 days of enalapril therapy because of a 15-fold increase in serum aspartate aminotransferase (SGOT) and in serum alanine aminotransferase (SGPT), both of which reverted back to normal 90 days after the cessation of therapy and which again increased 10-fold when enalapril was reintroduced for 13 days. This patient admitted that he was drinking 2 liters of beer a day at the time of the first increase in his hepatic enzymes. Blood pressure and heart rate were monitored during one hour at five-minute intervals by an automatic device based on the oscillometric method (Sentron). The blood pressure value considered was the mean of the last five measurements. Two successive measurements of supine blood pressure were
TABLE I
RESULTS Group Comparability. The placebo-treated group included 47 patieiits (31 men and 16 women), mean age 46.8 years (range 31 to 64 years), mean body weight 71.8 kg (range 52 to 95 kg). The enalapril-treated group included 53 patients (40 men and 13 women), mean age 47.4 years (range 27 to 63 years), mean body weight 73.6 kg (range 51 to 93 kg). The two groups were comparable for the following variables, all of which were considered before treatment (systolic and diastolic blood pressure, plasma sodium and potassium levels, creatinine clearance, and urinary sodium and potassium excretion). Blood Pressure. Mean blood pressure values after the placebo period, and after 15 and 30 days of treatment are shown in Tables I and II. When the decrease in blood pressure induced by enalapril is calculated from the automated values and from the physician's values, there is no statistical difference between the results obtained by the two methods of measurement. When the blood pressure values measured by the physician (Table I) are analyzed, a placebo-induced fall in blood pressure is detectable for both systolic and diastolic blood pressure after the first 15 days of placebo therapy, whereas no further fall is observed after 30 days. This
Blood Pressure Results Systolic Blood Pressure (mm Hg)
Diastolic Blood Pressure (mm Hg)
Days
Enalapril
Placebo
pt
Enalapril
Placebo
pt
0
161.4±13.0
163.5 ± 13.8
NS
103.3 ± 6.3
104.6 ± 7.0
NS
15
145.1 ± 15.6 NS 143.8 ± 13.8
158.8 ± 13.6 NS 158.4 ± 13.7
92.9 ± 8.4 NS 91.8 ± 8.4
100.3 ± 9.9 NS 100.7 ± 9.2
30
Blood pressure was measured by the same physician with a mercury sphygmomanometer before and after 15 and 30 days of treatment; means ISO are expressed. tt test or paired t test: * p < 0.05; •• p < 0.01; ***p < 0.001; NS = not significant.
August 20, 1984
The American Journal of Medicine
19
CONVERTING ENZYME INHIBITION-SASSANO ET AL
Blood Pressure Results
TABLE II
Diastolic Blood Pressure (mm Hg)
Systolic Blood Pressure (mm Hg); Days
Enalapril
Placebo
pt
Enalapril
Placebo
pt
0
149.7 ± 13.3
NS
92.1 ± 10.1
131.4 ± 12.8 NS 131.6 ± 12.9
91.2 ± 9.9 NS 89.4 ± 12.0 NS 89.6 ± 10.6
NS
15
149.1 ± 12.9 NS 148.5 ± 13.8 NS 148.1 ± 13.7
30
79.7 ± 8.8 NS 79.9 ± 8.3
Blood pressure was measured with an automatic device before and after 15 and 30 days of treatment; means ± SD are expressed. tt test or paired t test: * p < 0.05; ** p < 0.01; ***p < 0.001; NS = not significant.
.
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Figure 1. Correlation between the decrease in diastolic blood pressure measured by continuous automatic recording of blood pressure and by the physician.
TABLE Ill
Change in Systolic Blood Pressure Induced by Upright Position
Days
Enalaprll (mm Hg)
Placebo (mm Hg)
0 15 30
-4.1 ± 9.9 -3.5 ± 10.4 -4.6 ± 7.5
-6.8 ± 9.2 -4.8 ± 11.6 -2.1 ± 7.9
Blood pressure was measured by the physician with a mercury sphygmomanometer before and after 15 and 30 days of treatment, after one minute with the patient in the upright position. Means ± SD are expressed.
20
August 20, 1984
The American Journal of Medicine
placebo effect is not observed with blood pressure values obtained by automatic measurement (Table II). The enalaprir:induced fall in systolic and diastolic blood pressure calculated from the values given by the Sentron machine is very significantly correlated to the decrease calculated from ,the values measured by the physician (r = 0.43, p < 0.0002 for systolic blood pressure; r = 0.45, p < 0.0005 for diastolic blood pressure) (Figure 1.) Nevertheless, if response is defined by a fall in diastolic blood pressure of 10 mm Hg and more by the two methods of measurement, 27 patients can be classified as responders and 10 patients as non responders. In 16 of the 53 patients, the discrepancy between the values provided by the two methods of measurement does not allow the exact antihypertensive effect of enalapril to be precisely defined. Among those 16 patients, eight patients would have been classified as responders according to the automatic method and as nonresponders according to the sphygmomanometric values, whereas the opposite result would have been seen in the other eight patients. In placebo-treated patients, there was no correlation between the variations in blood pressure measured by the automatic device and those measured by the physician. A fall in blood pressure of more than 10 mm Hg as measured by the two methods was obtained only in four of 47 patients after 30 days of placebo therapy. As shown in Table Ill, no orthostatic hypotension was observed during enalapril treatment. The pulse rate, with the patient in both recumbent and upright positions, did not show any change during the treatment period (enalapril-treated group: supine 72 ± 9 versus 71 ± 10, upright 86 ± 10 versus 86 ± 12; placebo-treated group: supine 74 ± 8 versus 73 ± 9, upright 8~ ± 11 versus 85 ± 10). No serious complaints were reported by the patients, and the double-blind characteristic of the study was completely preserved for both the physician and the patient during this one-month period. Plasma Renin Activity. Whereas the placebo did not change plasma renin activity from 0.72 ± 0.8 to 0.75 ± 0.9 ng/ml per hour, enalapril increased plasma renin activity from 0.69 ± 0.6 to 5.1 ± 6.9 ng/ml per hour. Plasma
CONVERTING ENZYME INHIBITION-SASSANO ET AL
TABLE IV
Plasma Sodium and Potassium Levels and Creatinine Clearance before and after Treatment Enalapril
Sodium (mmol/liter) Potassium (mmol/liter) Creatinine clearance (ml/minute)
Placebo
Before
Aller
Before
Aller
141.4±2.4 4.0 ± 0.3
140.7 ± 2.5 3.9 ± 0.3
140.4 ± 2.6 3.9 ± 0.3
141.2 ± 2.0 3.9 ± 0.3
105.5 ± 33.2
103.1 ± 31.5
96.5 ± 28.5
98.2 ± 27.1
renin activity increased in 46 of 53 patients receiving enalapril. Except for the one patient already described, no other changes in the biochemical parameters were detected during the course of this study (Table IV). COMMENTS Enalapril was shown in other clinical trials to be able to suppress angiotensin converting enzyme activity as well as the formation of angiotensin II for several hours after a single oral dose of 2.5 to 40 mg [8-1 0]. The choice of a once-a-day dose of 20 mg made for this trial is based on these data and has been confirmed by the similar efficacy and tolerability of once-a-day and twice-a-day regimens of a daily 20 mg enalapril dosage [11]. These results again illustrate the difficulties encountered in blood pressure measurements during such trials. Quantification of the fall in blood pressure is, on the average, identical by both methods, and the fall in blood pressure is also significantly correlated between both methods for each patient. Nevertheless, the continuous recording of blood pressure in the absence of the physician provides blood pressure values that are 10 to 14 mm Hg lower than those obtained by the physician. Moreover, discrepancies larger than 10 mm Hg are observed in one patient among five, which makes a precise quantification of the benefits of the treatment for each patient difficult. Despite a minimum of three successive visits before randomization, a placebo effect was still detected by the physician during the first 15 days of treatment. On the contrary, this placebo effect was not observed with the blood pressure values measured by the automatic device in the absence of a physician and while the patient was lying quietly. Gould et al [12] have already reported that a placebo effect does not exist when 24-hour ambulatory intra-arterial measurement of blood pressure is performed. Mancia et al [13] also showed a constant but quite variable increase in blood pressure when a patient undergoing continuous intra-arterial recording of blood pressure is confronted by his physician. It is likely that the interference of the physician explains the higher values measured in the present study and that the placebo effect occurs when the patient gets to know the physician better.
After 15 days of treatment, a maximal efficacy of enalapril at this dose is observed, and there is no further decrease in blood pressure between 15 and 30 days of active treatment. The decrease in systolic and diastolic blood pressure induced by enalapril is not accompanied by orthostatic hypotension or an accelerated heart rate. This confirms observations made in other studies of normal volunteers in which tachycardia was not observed during converting enzyme inhibition and was without any alteration in autonomic reflex [14, 15]. The magnitude of the fall in blood pressure observed in this study (17/11 mm Hg) was obtained in hypertensive patients whose sodium intake was moderate since their mean natriuresis was 123 ± 63 mEq per day before treatment and 125 ±59 mEq per day after treatment. If we consider the results obtained in the 37 patients for whom the interpretation of blood pressure measurements is not ambiguous, the mean decrease in blood pressure induced by enalapril during a once-a-day regimen was -17/11 mm Hg. In 57 percent of the patients, the decrease is diastolic blood pressure was below 90 mm Hg. The magnitude of the fall in diastolic blood pressure was similar to that observed in trials with diuretics or beta blockers as initial treatment [16]. However, the main advantages of enalapril treatment were the absence of orthostatic hypotension, the absence of change in pulse rate, and the total absence of clinical and biochemical side effects. This fact could be of great importance in the long-term treatment of hypertension since side effects of drugs can minimize compliance. The increase in hepatic enzymes observed in one patient who was a heavy drinker cannot be interpreted in the context of this small study but should be interpreted in relation to the large number of patients who have been exposed to this drug throughout the world and who did not show any increase in their hepatic enzymes during treatment [17]. ACKNOWLEDGMENT We are grateful to Dr. J. Espie and Mrs. P. Airoldi of the Merck Sharp and Dohme Company for their helpful assistance in this work.
August 20, 1984
The American Journal of Medicine
21
CONVERTING ENZYME INHIBITION-SASSANO ET AL
REFERENCES 1. 2.
3. 4. 5. 6. 7.
8. 9.
22
WHO/ISH Mild Hypertension Liaison Committee: Trials of treatment of mild hypertension. An interim analysis. Lancet 1982; 1: 149-156. Medical Research Council Working Party on Mild to Moderate Hypertension: Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension. Lancet 1981; 1: 539-543. Menard J, Chatellier G, Degoulet P, Plouin PF, Corvol P: How much can blood pressure be lowered? Hypertension 1983; 5 (suppl Ill): 21-25. Millar-Craig MW, Bishop CN, Raftery EB: Circadian variation of blood pressure. Lancet 1978; 1: 795-797. Mancia G: Methods for assessing blood pressure values in humans. Hypertension 1983; 5 (suppl Ill): 5-13. Australian Therapeutic Trial in Mild Hypertension: Untreated mild hypertension. Lancet 1982; 1: 185-191. Menard J, Corvo! P, Allegrini J, Breminer J: Mesure de lactivite ranine plasmatique de lhomme par le dosage radioimmunologique de langiotensine I. In : Colloques INSEAM, eds. Techniques radioimmunologiques. Paris: INSEAM, 1972; 459-470. Gavras H, Biollaz J, Waeber B, Brunner HR, Gavras I, Davies RO: Antihypertensive effect of the new oral angiotensin converting enzyme inhibitor "MK 421." Lancet 1981; II: 543-547. Biollaz J, Burnier M, Turini GA, et al: Three new long-acting converting enzyme inhibitors: relationship between plasma converting enzyme activity and response to angiotensin I. Clin
August 20, 1984
The American Journal of Medicine
10. 11.
12. 13. 14.
15.
16.
17.
Pharmacol Ther 1981; 11:461-467. Brunner HR, Waeber B, Nussberger J, Schaller MD, Gomez HJ: Long-term clinical experience with enalapril in essential hypertension. J Hypertension 1983; 1 (suppl 1): 103-107. Bergstrand R, Johanasson S, Wedin A, Wilhelmsson L: Comparison of once-a-day and twice-a-day dosage regimens of enalapril (MK421) in patients with mild hypertension. Br J Clin Pharmacol 1982; 14: 136P-137P. Gould BA, Mann S, Davies AB, Altman DG, Raftery EB: Does placebo lower blood pressure? Lancet 1981; 11: 1377-1381. Mancia G, Ferrari A, Gregorini L, et al: Blood pressure variability in man: its relation to high blood pressure, age and baroreflex sensitivity. Clin Sci 1980, 59: 401s-406s. MacGregor GA, Markandu ND, Bayliss J, Roulston JE, Squires M, Morton JJ: Non-sulfhydryl-containing angiotensin converting enzyme inhibitor (MK421 ): evidence for role of renin system in normotensive subjects. Br. Med J 1982; 283:401-403. Millar JA, Derkx FHM, Mclean K, Reid J: Pharmacodynamics of converting enzyme inhibition: the cardiovascular, endocrine and autonomic effects of MK 421 (enalapril) and MK 521. Br J Clin Pharmacol 1982; 14: 347-355. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension. JAMA 1982; 16: 1996-2003. Dollery CT: Safety and efficacy of enalapril. Summing up the evidence. J Hypertension 1983, 1 (suppl 1): 155-157.