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Efficacy and tolerability of nicardipine slow release and enalapril in elderly hypertensive patients: Results of a multicenter study
CURRENT THERAPEUTIC RESEARCH VOL. 54, NO. 2, AUGUST1993
EFFICACY AND TOLERABILITY OF NICARDIPINE SLOW RELEASE AND ENALAPRIL IN ELDERLY HYPERTENSIVE PATIENTS: RESULTS OF A MULTICENTER STUDY R. NAMI,1 D. CARUSO,e A. DORMI,3 A. MARIANI,3 W. MARIOTTI,3 G. MONTANARI,~ P. VOLPE, 3 G. ZAMBALDI,4 AND A. FERRIERI 5 1Universitd degli Studi di Siena, Cattedra di Cardiologia, Siena, 20spedale Cardarelli, XII Divisione Medicina Generale, Naples, 3USL 8, Divisione di Cardiologia, Senigallia, 40spedale S. Maria Nuova, UTIC, Florence, and 5Direzione Medica, Istituto Wassermann, Alfa Wassermann S.p.A., Bologna, Italy
ABSTRACT In an open, multicenter, randomized clinical study, the antihypertensive efficacy and tolerability of nicardipine slow release (SR) and enalapril were evaluated in 561 patients aged 60 years and older with mild to moderate essential hypertension. After a 2- to 3-week washout period, the patients were randomly assigned to receive nicardipine SR 40 mg twice daily or enalapril 20 mg once daily for 6 months. After 2 months of treatment, if the patient's blood pressure remained elevated, hydrochlorothiazide (HCTZ) 12.5 to 25 mg/day was added to the monotherapy. The results of this study confirmed the antihypertensive efficacy and tolerability of nicardipine SR and enalapril when given as monotherapy or in combination with HCTZ. However, in the nicardipine group, the number of responders to monotherapy and the degree of reduction in systolic and diastolic blood pressures during monotherapy was greater than that in the enalapril group. Thus the need for combined therapy was lower in the nicardipine group. Heart rate did not change significantly in either group. The incidence of side effects was higher in the nicardipine group (ankle edema, headache, facial flushing, and palpitations) when compared with the enalapril group (fatigue, cough, taste disturbance, and dizziness), but the number of drug-related withdrawals was significantly higher in the enalapril group, mainly because of cough. These results support the hypothesis t h a t the antihypertensive efficacy of calcium antagonists is age dependent and related to pretreatment blood pressure values. Thus dihydropyridine calcium antagonists, such as nicardipine SR, appear to be p a r t i c u l a r l y effective and well tolerated in the t r e a t m e n t of elderly hypertensive patients. INTRODUCTION
Hypertension in the elderly is a significant problem in clinical practice. In industrialized countries, about 40% of the population older than age 60 suffers from elevated blood pressure. Epidemiologic studies have shown Address correspondenceto: Prof. Renato Nami, Cattedra di Cardiologia,Istituto di PatologiaSpeciale Medica, PiazzaDuomo2, 53100 Siena, Italy. Received for publication on June 3, 1993. Printed in the U.S.A. Reproductionin whole or part is not permitted. 221
0011-393X/93/$3.50
NICARDIPINE AND ENALAPRIL IN ELDERLY HYPERTENSIVE PATIENTS
that elderly hypertensive patients are at increased risk for stroke, congestive heart failure, myocardial infarction, and angina. 1 Moreover, isolated systolic hypertension is common in older patients as a result of increasing rigidity of the arterial wall with age and a corresponding decrease in the compliance of large arteries. 2 Isolated systolic hypertension, once regarded as a physiologic consequence of aging, is now well recognized as a significant risk factor for cerebral and cardiovascular events in the elderly. Clinical studies 3'4 have clearly demonstrated that active treatment reduces cerebral and cardiovascular morbidity and mortality in elderly hypertensive patients. A variety of effective antihypertensive drugs, such as calcium antagonists and angiotensin converting enzyme (ACE) inhibitors, have become available in the last 2 decades. However, some risks are associated with antihypertensive treatment in the elderly. A rapid decrease in blood pressure may result in cardiac and cerebral hypoperfusion. Thus a gradual decrease in blood pressure is recommended in older patients. Moreover, the many age-related changes in the cardiovascular system, such as reduced cardiac output, stroke volume, heart rate, systemic and regional perfusion, and baroreflex sensitivity, 5'6 may be worsened by some antihypertensive drugs. Central or peripheral sympatholytic agents can aggravate orthostatic hypotension,7 and diuretics, which provoke salt and fluid depletion, can reduce the already diminished blood volume in elderly hypertensive patients, s In addition, diuretics can negatively affect electrolyte balance and glucose and lipid metabolism, which may already be impaired in the elderly. Cardiovascular complications of long-term hypertension and coexisting chronic disease unrelated to hypertension often complicate the choice of antihypertensive treatment in older patients. To avoid worsening the patient's quality of life, the antihypertensive agent must be well tolerated. On the basis of these considerations, calcium antagonists and ACE inhibitors appear to satisfy the criteria for antihypertensive treatment in elderly patients. These two drug classes appear to offer many therapeutic advantages when compared with other commonly available antihypertensive drugs. 9'1° Calcium antagonists and ACE inhibitors generally do not modify the hemodynamic and metabolic profile of hypertensive patients, thus maintaining their quality of life. 9'1° The aim of our study was to evaluate the efficacy and tolerability of the dihydropyridine calcium antagonist nicardipine slow release (SR) and the ACE inhibitor enalapril in the treatment of elderly hypertensive patients. PATIENTS
AND METHODS
A total of 561 patients (280 men and 281 women) age 60 years and older (mean age, 68.6 years) with mild to moderate essential uncomplicated hypertension were enrolled in an open, multicenter clinical study. All 222
R. NAMI ET AL.
patients gave informed consent before participating in the study. Exclusion criteria were a sitting diastolic blood pressure > 115 mmHg, secondary or accelerated arterial hypertension, myocardial infarction in the preceding 3 months, angina pectoris, congestive heart failure, valvular cardiopathy, relevant arrhythmias, stroke, hepatic or renal failure (serum transaminases twice the normal range and serum creatinine >1.5 mg/dl), alcoholism, drug abuse, psychosis, or poor compliance. All medication was withdrawn from the 324 previously treated patients 3 weeks before the study. In the 237 previously untreated patients, the washout period lasted 2 weeks. At the end of the washout period, 561 patients with a sitting diastolic blood pressure at rest ranging from 95 to 114 mmHg or a sitting systolic blood pressure at rest >160 mmHg in three subsequent visits were included in the study. These patients were randomly assigned to treatment with nicardipine SR 40 mg twice daily or enalapril 20 mg once daily in the morning for 6 months. After 2 months of treatment, if the blood pressure remained >140/95 mmHg or the decrease in diastolic blood pressure was < 10%, hydrochlorothiazide (HTCZ) 12.5 mg once daily was added to the regimen. After 3 months of therapy, the HCTZ dose was increased to 25 mg once daily in nonresponders and in those patients whose blood pressure was not normalized. Patients were seen at the outpatient clinic of the participating centers during the run-in period without therapy, at the beginning of randomization, and every month during active treatment. Patients were examined in the morning, and blood pressure was measured at rest using a standard mercury sphygmomanometer. Blood pressure values (Korotkoff phases I and V) were recorded in both the supine and standing positions according to World Health Organization guidelines before medication was administered. Routine hematologic and biochemical laboratory tests (red and white blood cell counts, differential leukocyte count, platelets, serum creatinine, glucose, transaminases, alkaline phosphatase, sodium, potassium, total and high-density lipoprotein cholesterol, triglycerides, proteins, and urinalysis) were performed at randomization and at the end of the study. Side effects were reported by the patients using a checklist of the most common adverse events related to the active treatments. All data were reported as mean +- SEM. Student's t test for paired and unpaired data was used for the intragroup and intergroup comparisons. One-way and two-way analyses of variance were used for comparison of the intragroup values over time. P values <0.05 were considered statistically significant. RESULTS
At randomization, no statistical differences between the two treatment groups in demographic or physiologic characteristics were found (Table I). 223
NICARDIPINE AND ENALAPRIL IN ELDERLY HYPERTENSIVE PATIENTS
Data from the 14 patients in the nicardipine SR group and the 18 patients in the enalapril group who withdrew from treatment were not included in the efficacy analysis. During monotherapy, the supine and standing systolic and diastolic blood pressures, which did not differ between groups before active treatment, were significantly reduced (P < 0.001) after the first and second month of treatment in both the nicardipine SR and enalapril groups. At the end of monotherapy, the decrease in systolic and diastolic blood pressures was significantly greater in the nicardipine SR group than in the enalapril group (Figure 1). In addition, the percent of responders to treatment (ie, those patients in whom the diastolic blood pressure reduction was >10 mmHg) was significantly greater in the nicardipine SR group than in the enalapril group at the second month of monotherapy (Figure 2). No significant changes in supine or standing heart rate were observed in the nicardipine SR or enalapril groups when compared with baseline values. At the end of the second month of treatment, HCTZ was added to the regimen of 56 (21.1%) patients in the nicardipine SR group and to that of 102 (38.9%) patients in the enalapril group. At the end of the third month, six (23.3%) additional patients in the nicardipine SR group and 17 (45.5%) additional patients in the enalapril group were given HCTZ. All other patients responded to continued monotherapy. The supine and standing systolic and diastolic blood pressures in the 205 nicardipine SR patients
Table I. Demographic and physiologic characteristics at randomization.
Variables Sex Male Female Mean age (yr) Supine BP (mmHg) Systolic Diastolic Standing BP (mmHg) Systolic Diastolic WHO stage
Nicardipine SR (n = 281)
Enalapril (n = 280)
131 150 68.9 -+ 6.7
149 131 68.8 -+ 6.2
174.7 -- 0.7 101.7 _+ 0.4
173.6 -+ 0.8 101.2 _+ 0,5
173.6 _+ 0.8 101.9 _+ 0.4
172.9 + 0.8 101.3 _+ 0.4
137 75 69
139 63 78
5 45 9
8 51 10
115 161
122 163
I II Unknown Concomitant diseases Metabolic disorders Neuropathy Obstructive emphysema Hypertension Untreated Treated
Data are mean - SD. BP = blood pressure; WHO = World Health Organization.
224
R. NAMIET AL.
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and 143 enalapril patients were significantly reduced from the start until the end of the study, without significant changes in heart rate (Figure 3). In the nicardipine SR group of responders to monotherapy, the supine and standing diastolic blood pressures were significantly lower from the second to the sixth months of therapy than those in the enalapril group of responders. Data on the patients who did not respond to monotherapy and required the addition of HCTZ are reported in Table II. The number of patients who needed HCTZ was significantly higher in the enalapril group than in the nicardipine SR group. The addition of HCTZ induced a significant and 225
NICARDIPINE AND ENALAPRIL IN ELDERLY HYPERTENSIVE PATIENTS
100
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similar fall in the supine and standing systolic and diastolic blood pressures in both groups. No clinically relevant changes in heart rate were seen in the patients receiving combined therapy. During the 6-month period of active treatment, 32 patients withdrew from treatment (Table III). Seventeen patients (3% of the study population) withdrew because of side effects related to therapy; 61% of drug-induced withdrawals occurred during the first 2 months of treatment. During active treatment, 73 (26%) patients in the nicardipine SR group and 63 (22.6%) patients in the enalapril group complained of treatment-related side effects. Ankle edema, headache, facial flushing, and palpitations were reported most frequently in the nicardipine group; fatigue, cough, taste disturbance, and dizziness were the most commonly reported side effects in the enalapril group (Table IV). Both drugs, either as monotherapy or in combination with HCTZ, were well tolerated. Laboratory tests revealed no clinically relevant changes in either individual or mean values. However, serum potassium was slightly but significantly increased and serum total cholesterol was significantly decreased in both groups during treatment. DISCUSSION
The results of our study confirm the efficacy of the calcium antagonist nicardipine SR and the ACE inhibitor enalapril when used as monotherapy or in combination with HCTZ in treating elderly hypertensive patients. However, in the nicardipine SR group, the number of responders to monotherapy and the degree of blood pressure reduction during the 6 226
R. NAMIE T AL.
Nlcardlplne SR (n=205) Suplno position
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Figure 3. Supine and standing systolic blood pressure (diamonds), diastolic blood pressure (circles), and heart rate (squares) in responders to nicardipine SR or enalapril monotherapy. BP = blood pressure; HR = heart rate; SR = slow release.
months of treatment was significantly higher than that in the enalapril group. Thus fewer patients in the nicardipine SR group required combined therapy with HCTZ. Our results support the hypothesis that the antihypertensive efficacy of calcium antagonists is age related. 9':: Hence, the reduction of blood pressure, particularly systolic blood pressure, induced by calcium antagonists appears to increase with advancing age, 12 although other authors :3 disagree. Moreover, the antihypertensive efficacy of calcium antagonists is related to pretreatment blood pressure values. If pretreatment blood pressure values can determine the degree of blood pressure reduction, the antihypertensive efficacy of nicardipine SR should be greatest in patients with the highest blood pressures. In similar patients, other antihypertensive drugs may be ineffective, and a combined therapy would be necessary. During active treatment with nicardipine SR and enalapril, alone or in combination with HCTZ, no rebound hypertension or tachyphylaxis was observed. At the doses used, both drugs appeared to ensure a satisfactory and persistent 24-hour control of blood pressure. No significant changes in heart rate were observed during the study when nicardipine SR or enala227
NICARDIPINE AND ENALAPRIL IN ELDERLY HYPERTENSIVE PATIENTS
Table II. Systolicand diastolicbloodpressures (BP) in patients who required combinedtherapy with hydrochlorothiazide(HCTZ). Nicardipine SR + HCTZ (n = 62)
Day 0 Systolic Diastolic Day 30 Systolic Diastolic Day 60 Systolic Diastolic Day 90 Systolic Diastolic Day 120 Systolic Diastolic Day 150 Systolic Diastolic Day 180 Systolic Diastolic
Enalapril + HCTZ (n = 119)
Supine BP (mmHg)
Standing BP (mmHg)
Supine BP (mmHg)
Standing BP (mmHg)
179.7 ± 1.2 104.4 _+ 0.8
178.3 ± 1.5 103.9 ± 0.7
177.2 _ 1.3 103.1 _ 0.7
176~2 ± 1.2 103.8 ± 0.6
167.0 ± 1.5 95.5 + 0.9
166.7 +- 1.5 95.7 +- 1.0
167.0 _+ 1.2 97.0 ± 0.6
167.7 ± 1.3 97.8 _+ 0.5
165.0 -+ 1.5 95.2 ± 0.9
164.7 _+ 1.4 95.0 ± 1.0
164.7 ± 1.2 96.1 ± 0.6
164.9 ± 1.3 96.6 ± 0.6
157.8 ± 1.2 90.0 ± 1.0
157.3 _+ 1.3 89.6 +- 1.1
157.7 ± 1.3 89.6 ± 1.1
158.1 +_ 1.3 90.3 ± 0.8
154.5 _+ 1.5 88.2 ± 1.1
153.7 ± 1.3 88.4 ± 1.1
154.7 _ 1.3 87.4 _+ 0.8
153.8 ± 1.4 88.4 ± 0.8
155.2 _+ 1.5 87.3 __ 1.0
155.8 -+ 1.5 88.2 +_ 1.0
154.2 ± 1.1 87.3 ± 0.9
153.5 ±_ 1.5 87.9 ± 0.9
153.2 ± 1.3 86.8 ± 1.0
152.6 ± 1.4 87.0 ± 0,9
153.2 ± 1.3 86.9 _+ 0.9
152.0 ± 1.5 87.7 _+ 0.9
Data are mean ± SD.
pril was administered as monotherapy or in combination with HCTZ. Dihydropyridine calcium antagonists can precipitate acute tachycardia, which is secondary to their vasodilatory action and an increase in the reflex sympathetic tone. 14 However, induced tachycardia is a transient occurrence because of a swift baroreflex resetting. 15 It probably is attenuated or absent in older patients due to a reduced baroreflex sensitivity. 16 No significant difference was observed between the supine and standing blood pressures during active treatment, and none of the patients reported orthostatic hypotension. On the basis of their pharmacologic properties, the two drugs appear to have vasodilatory and antihypertensive
Table III. Number of patients withdrawingfrom treatment. Reason for Withdrawal
Nicardipine SR (n = 281)
Enalapril (n = 280)
Poor compliance Hospitalization Side effects Total number of withdrawals
6 3 5 14
5 1 12 18
228
R. NAMI ET AL,
Table IV. Incidence of side effects. Nicardipine SR (n = 281)
Ankle edema Headache Facial flushing Palpitations Fatigue Dizziness Itching Rash Nausea Taste disturbance Diarrhea Cough
Enalapril (n = 280)
No. of Patients
Percent
No. of Patients
39 24 23 16 14 4 4 1 1 1 1 --
13.9 8.5 8.2 5.7 5.0 1.4 1.4 0.3 0.3 0.3 0.3 --
2 5 3 -27 7 4 1 3 8 3 26
Percent 0,7 1.8 1.2 9.6 2.5 1.4 0.3 1.1 2.9 1.1 9.3
SR = slow release.
effects without negatively affecting the homeostatic reflexes of blood pressure control, which in the elderly are already impaired. 7 Combined therapy (nicardipine SR + HCTZ or enalapril + HCTZ) was an effective t r e a t m e n t for those hypertensive patients who did not respond to monotherapy. In our study, the antihypertensive efficacy of nicardipine SR + HCTZ was comparable to that of ACE inhibitors combined with a thiazide diuretic. 17 Therefore, despite negative opinions, is our results confirm the usefulness of the calcium antagonist-thiazide diuretic combination previously evaluated in several clinical studies. 19'2° The side effects reported by the patients in our study were more frequent in the nicardipine SR group than in the enalapril group (26% versus 22.6%), b u t the number of drug-related withdrawals was higher in the enalapril group than in the nicardipine SR group (12 versus 5). Ankle edema, headache, facial flushing, and palpitations were the predominant events reported in the nicardipine SR group. These manifestations are typical of the vasodilatory actions of the drug and were generally mild and well tolerated. Fatigue, cough, taste disturbance, and dizziness were commonly reported in the enalapril group. A frequently irritable and dry cough resistant to symptomatic treatment, alone or together with other side effects, was the most common cause of interruption of therapy or withdrawal. No clinically relevant changes in the laboratory tests were observed with nicardipine SR or enalapril given as monotherapy or in combination with HCTZ. In conclusion, although our study was not placebo controlled, nicardipine SR, as documented for other dihydropyridine calcium antagonists, 21 appeared to be more effective than ACE inhibitors in lowering blood pressure. The potent vasodilatory and antihypertensive activity of nicardipine 229
NICARDIPINEANDENALAPRILIN ELDERLYHYPERTENSIVEPATIENTS
SR, as well as its metabolic and hemodynamic profile, potential anti~ atherogenic properties, 22 and good tolerability, justify its role as a treatm e n t of first choice in elderly hypertensive patients.
Acknowledgment This study was supported by a research grant from Alfa Wassermann S.p.A., Bologna, Italy. References:
1. Kannel WB. Prevalence, incidence and hazards of hypertension in the elderly. Geriatr Cardiovasc Med 1988; 1:5-10. 2. Lakatta EG. Mechanism of hypertension in the elderly. J A m Geriatr Soc 1989; 37:780790. 3. Amery A, Birkehager W, Brixko P, et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet 1985; 1:1349-1354. 4. Coope J, Warrender TS. Randomized trial of treatment of hypertension in elderly patients in primary care. B M J 1986; 293:1145-1148. 5. Walsh R. Cardiovascular effects of the aging process. A m J Med 1987; 82(Suppl 1B):3440. 6. Pfeiffer MA, Weinberg CR, Cook D, et al. Differential changes in autonomic nervous system function with age in man. A m J Med 1983; 75:249-257. 7. Lipsitz LA. Orthostatic hypotension in the elderly. New Engl J Med 1984; 32:952-957. 8. Briggs J, Rowe J. Adverse drug reactions in elderly hypertensive patients. ISI Atlas of Science. Pharmacology 1987; 1:262-265. 9. Kiowski W, Buhler FR, Fadayomi MO. Age, race, blood pressure and renin: Predictors for antihypertensive treatment with calcium antagonists. A m J Cardiol 1985; 56:108-113. 10. Drayer J, Weber MA. Monotherapy of essential hypertension with converting enzyme inhibitor. Hypertension 1983; 5(Part II):108-113. 11. KrakoffLR. Nicardipine monotherapy in ambulatory elderly patients with hypertension. A m Heart J 1989; 117:250-255. 12. Leonetti G, Chiaca R. The effects of nicardipine in elderly hypertensive patients. J Cardiovasc Pharmacol 1990; 16(Suppl 2):$5-$8. 13. Chalmers JP, Smith SA, Wing LMH. Hypertension in the elderly: The role of calcium antagonists. J Cardiovasc Pharmacol 1988; 12(Suppl 8):S147-$155. 14. Kaplan NM. Critical comments on recent literature: Age and response to antihypertensive drugs. A m J Hypertens 1989; 2:213-215. 15. Aoki K, Kondo S, Mochizuki A, et al. Antihypertensive effect of cardiovascular Ca + + antagonist in hypertensive patients in the absence and presence ofbeta-adrenergic blockade. A m Heart J 1978; 96:218-223. 16. Joung MA, Watson RDS, Litter WA. Baroreflex setting and sensitivity after acute and chronic nicardipine therapy. Clin Sci 1984; 66:233-235. 230
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17. Veterans Administration Cooperative Study Group on Hypertensive Agents. Captopril: Evaluation of low doses, twice daily doses and addition of diuretic for treatment of mild to moderate hypertension. Clin Sci 1982; 63:4435-4455. 18. MacGregor GA, Peva House JB, Cappuccio FP, Markandu ND, Nifedipine, diuretics and sodium balance. J Hypertens 1987;5:S127-S131, 19. Ferrara LA, Pasanisi F, Marotta T, et al. Calcium antagonists and thiazide diuretics in treatment of hypertension. J Cardiovasc Pharmacol 1987; 10(Suppl 10):S136-S137. 20. Mancia G, Buoninconti R, Errico M, et al. Efficacia e tollerabilit~ della nicardipina retard e del captopril nell'ipertensione dell'anziano. Risultati di uno studio multicentrico. Minerva Med 1992; 83:1-8. 21. Gennari C, Nami R, Bianchini C, et al. Nitrendipine and the angiotension converting enzyme inhibition in the treatment of hypertension. J Cardiovasc Pharmacol 1987; 9(Suppl 4):$245-$251. 22. Ouchi Y, Orimo H. The role of calcium antagonists in the treatment of atherosclerosis and hypertension. J Cardiovasc Pharrnacol 1990; 16(Suppl 2):S1-$4.
231
EFFICACY AND TOLERABILITY OF NICARDIPINE SLOW RELEASE AND ENALAPRIL IN ELDERLY HYPERTENSIVE PATIENTS: RESULTS OF A MULTICENTER STUDY R. NAMI,1 D. CARUSO,e A. DORMI,3 A. MARIANI,3 W. MARIOTTI,3 G. MONTANARI,~ P. VOLPE, 3 G. ZAMBALDI,4 AND A. FERRIERI 5 1Universitd degli Studi di Siena, Cattedra di Cardiologia, Siena, 20spedale Cardarelli, XII Divisione Medicina Generale, Naples, 3USL 8, Divisione di Cardiologia, Senigallia, 40spedale S. Maria Nuova, UTIC, Florence, and 5Direzione Medica, Istituto Wassermann, Alfa Wassermann S.p.A., Bologna, Italy
ABSTRACT In an open, multicenter, randomized clinical study, the antihypertensive efficacy and tolerability of nicardipine slow release (SR) and enalapril were evaluated in 561 patients aged 60 years and older with mild to moderate essential hypertension. After a 2- to 3-week washout period, the patients were randomly assigned to receive nicardipine SR 40 mg twice daily or enalapril 20 mg once daily for 6 months. After 2 months of treatment, if the patient's blood pressure remained elevated, hydrochlorothiazide (HCTZ) 12.5 to 25 mg/day was added to the monotherapy. The results of this study confirmed the antihypertensive efficacy and tolerability of nicardipine SR and enalapril when given as monotherapy or in combination with HCTZ. However, in the nicardipine group, the number of responders to monotherapy and the degree of reduction in systolic and diastolic blood pressures during monotherapy was greater than that in the enalapril group. Thus the need for combined therapy was lower in the nicardipine group. Heart rate did not change significantly in either group. The incidence of side effects was higher in the nicardipine group (ankle edema, headache, facial flushing, and palpitations) when compared with the enalapril group (fatigue, cough, taste disturbance, and dizziness), but the number of drug-related withdrawals was significantly higher in the enalapril group, mainly because of cough. These results support the hypothesis t h a t the antihypertensive efficacy of calcium antagonists is age dependent and related to pretreatment blood pressure values. Thus dihydropyridine calcium antagonists, such as nicardipine SR, appear to be p a r t i c u l a r l y effective and well tolerated in the t r e a t m e n t of elderly hypertensive patients. INTRODUCTION
Hypertension in the elderly is a significant problem in clinical practice. In industrialized countries, about 40% of the population older than age 60 suffers from elevated blood pressure. Epidemiologic studies have shown Address correspondenceto: Prof. Renato Nami, Cattedra di Cardiologia,Istituto di PatologiaSpeciale Medica, PiazzaDuomo2, 53100 Siena, Italy. Received for publication on June 3, 1993. Printed in the U.S.A. Reproductionin whole or part is not permitted. 221
0011-393X/93/$3.50
NICARDIPINE AND ENALAPRIL IN ELDERLY HYPERTENSIVE PATIENTS
that elderly hypertensive patients are at increased risk for stroke, congestive heart failure, myocardial infarction, and angina. 1 Moreover, isolated systolic hypertension is common in older patients as a result of increasing rigidity of the arterial wall with age and a corresponding decrease in the compliance of large arteries. 2 Isolated systolic hypertension, once regarded as a physiologic consequence of aging, is now well recognized as a significant risk factor for cerebral and cardiovascular events in the elderly. Clinical studies 3'4 have clearly demonstrated that active treatment reduces cerebral and cardiovascular morbidity and mortality in elderly hypertensive patients. A variety of effective antihypertensive drugs, such as calcium antagonists and angiotensin converting enzyme (ACE) inhibitors, have become available in the last 2 decades. However, some risks are associated with antihypertensive treatment in the elderly. A rapid decrease in blood pressure may result in cardiac and cerebral hypoperfusion. Thus a gradual decrease in blood pressure is recommended in older patients. Moreover, the many age-related changes in the cardiovascular system, such as reduced cardiac output, stroke volume, heart rate, systemic and regional perfusion, and baroreflex sensitivity, 5'6 may be worsened by some antihypertensive drugs. Central or peripheral sympatholytic agents can aggravate orthostatic hypotension,7 and diuretics, which provoke salt and fluid depletion, can reduce the already diminished blood volume in elderly hypertensive patients, s In addition, diuretics can negatively affect electrolyte balance and glucose and lipid metabolism, which may already be impaired in the elderly. Cardiovascular complications of long-term hypertension and coexisting chronic disease unrelated to hypertension often complicate the choice of antihypertensive treatment in older patients. To avoid worsening the patient's quality of life, the antihypertensive agent must be well tolerated. On the basis of these considerations, calcium antagonists and ACE inhibitors appear to satisfy the criteria for antihypertensive treatment in elderly patients. These two drug classes appear to offer many therapeutic advantages when compared with other commonly available antihypertensive drugs. 9'1° Calcium antagonists and ACE inhibitors generally do not modify the hemodynamic and metabolic profile of hypertensive patients, thus maintaining their quality of life. 9'1° The aim of our study was to evaluate the efficacy and tolerability of the dihydropyridine calcium antagonist nicardipine slow release (SR) and the ACE inhibitor enalapril in the treatment of elderly hypertensive patients. PATIENTS
AND METHODS
A total of 561 patients (280 men and 281 women) age 60 years and older (mean age, 68.6 years) with mild to moderate essential uncomplicated hypertension were enrolled in an open, multicenter clinical study. All 222
R. NAMI ET AL.
patients gave informed consent before participating in the study. Exclusion criteria were a sitting diastolic blood pressure > 115 mmHg, secondary or accelerated arterial hypertension, myocardial infarction in the preceding 3 months, angina pectoris, congestive heart failure, valvular cardiopathy, relevant arrhythmias, stroke, hepatic or renal failure (serum transaminases twice the normal range and serum creatinine >1.5 mg/dl), alcoholism, drug abuse, psychosis, or poor compliance. All medication was withdrawn from the 324 previously treated patients 3 weeks before the study. In the 237 previously untreated patients, the washout period lasted 2 weeks. At the end of the washout period, 561 patients with a sitting diastolic blood pressure at rest ranging from 95 to 114 mmHg or a sitting systolic blood pressure at rest >160 mmHg in three subsequent visits were included in the study. These patients were randomly assigned to treatment with nicardipine SR 40 mg twice daily or enalapril 20 mg once daily in the morning for 6 months. After 2 months of treatment, if the blood pressure remained >140/95 mmHg or the decrease in diastolic blood pressure was < 10%, hydrochlorothiazide (HTCZ) 12.5 mg once daily was added to the regimen. After 3 months of therapy, the HCTZ dose was increased to 25 mg once daily in nonresponders and in those patients whose blood pressure was not normalized. Patients were seen at the outpatient clinic of the participating centers during the run-in period without therapy, at the beginning of randomization, and every month during active treatment. Patients were examined in the morning, and blood pressure was measured at rest using a standard mercury sphygmomanometer. Blood pressure values (Korotkoff phases I and V) were recorded in both the supine and standing positions according to World Health Organization guidelines before medication was administered. Routine hematologic and biochemical laboratory tests (red and white blood cell counts, differential leukocyte count, platelets, serum creatinine, glucose, transaminases, alkaline phosphatase, sodium, potassium, total and high-density lipoprotein cholesterol, triglycerides, proteins, and urinalysis) were performed at randomization and at the end of the study. Side effects were reported by the patients using a checklist of the most common adverse events related to the active treatments. All data were reported as mean +- SEM. Student's t test for paired and unpaired data was used for the intragroup and intergroup comparisons. One-way and two-way analyses of variance were used for comparison of the intragroup values over time. P values <0.05 were considered statistically significant. RESULTS
At randomization, no statistical differences between the two treatment groups in demographic or physiologic characteristics were found (Table I). 223
NICARDIPINE AND ENALAPRIL IN ELDERLY HYPERTENSIVE PATIENTS
Data from the 14 patients in the nicardipine SR group and the 18 patients in the enalapril group who withdrew from treatment were not included in the efficacy analysis. During monotherapy, the supine and standing systolic and diastolic blood pressures, which did not differ between groups before active treatment, were significantly reduced (P < 0.001) after the first and second month of treatment in both the nicardipine SR and enalapril groups. At the end of monotherapy, the decrease in systolic and diastolic blood pressures was significantly greater in the nicardipine SR group than in the enalapril group (Figure 1). In addition, the percent of responders to treatment (ie, those patients in whom the diastolic blood pressure reduction was >10 mmHg) was significantly greater in the nicardipine SR group than in the enalapril group at the second month of monotherapy (Figure 2). No significant changes in supine or standing heart rate were observed in the nicardipine SR or enalapril groups when compared with baseline values. At the end of the second month of treatment, HCTZ was added to the regimen of 56 (21.1%) patients in the nicardipine SR group and to that of 102 (38.9%) patients in the enalapril group. At the end of the third month, six (23.3%) additional patients in the nicardipine SR group and 17 (45.5%) additional patients in the enalapril group were given HCTZ. All other patients responded to continued monotherapy. The supine and standing systolic and diastolic blood pressures in the 205 nicardipine SR patients
Table I. Demographic and physiologic characteristics at randomization.
Variables Sex Male Female Mean age (yr) Supine BP (mmHg) Systolic Diastolic Standing BP (mmHg) Systolic Diastolic WHO stage
Nicardipine SR (n = 281)
Enalapril (n = 280)
131 150 68.9 -+ 6.7
149 131 68.8 -+ 6.2
174.7 -- 0.7 101.7 _+ 0.4
173.6 -+ 0.8 101.2 _+ 0,5
173.6 _+ 0.8 101.9 _+ 0.4
172.9 + 0.8 101.3 _+ 0.4
137 75 69
139 63 78
5 45 9
8 51 10
115 161
122 163
I II Unknown Concomitant diseases Metabolic disorders Neuropathy Obstructive emphysema Hypertension Untreated Treated
Data are mean - SD. BP = blood pressure; WHO = World Health Organization.
224
R. NAMIET AL.
Supine BP Enalapril
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and 143 enalapril patients were significantly reduced from the start until the end of the study, without significant changes in heart rate (Figure 3). In the nicardipine SR group of responders to monotherapy, the supine and standing diastolic blood pressures were significantly lower from the second to the sixth months of therapy than those in the enalapril group of responders. Data on the patients who did not respond to monotherapy and required the addition of HCTZ are reported in Table II. The number of patients who needed HCTZ was significantly higher in the enalapril group than in the nicardipine SR group. The addition of HCTZ induced a significant and 225
NICARDIPINE AND ENALAPRIL IN ELDERLY HYPERTENSIVE PATIENTS
100
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T60 Figure 2. Percentage of responders after 60 days (T60) of monotherapy with nicardipine slow release (SR) or enalapril. ***P < 0.001.
similar fall in the supine and standing systolic and diastolic blood pressures in both groups. No clinically relevant changes in heart rate were seen in the patients receiving combined therapy. During the 6-month period of active treatment, 32 patients withdrew from treatment (Table III). Seventeen patients (3% of the study population) withdrew because of side effects related to therapy; 61% of drug-induced withdrawals occurred during the first 2 months of treatment. During active treatment, 73 (26%) patients in the nicardipine SR group and 63 (22.6%) patients in the enalapril group complained of treatment-related side effects. Ankle edema, headache, facial flushing, and palpitations were reported most frequently in the nicardipine group; fatigue, cough, taste disturbance, and dizziness were the most commonly reported side effects in the enalapril group (Table IV). Both drugs, either as monotherapy or in combination with HCTZ, were well tolerated. Laboratory tests revealed no clinically relevant changes in either individual or mean values. However, serum potassium was slightly but significantly increased and serum total cholesterol was significantly decreased in both groups during treatment. DISCUSSION
The results of our study confirm the efficacy of the calcium antagonist nicardipine SR and the ACE inhibitor enalapril when used as monotherapy or in combination with HCTZ in treating elderly hypertensive patients. However, in the nicardipine SR group, the number of responders to monotherapy and the degree of blood pressure reduction during the 6 226
R. NAMIE T AL.
Nlcardlplne SR (n=205) Suplno position
Enalaprll (n=143) Supine position
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months of treatment was significantly higher than that in the enalapril group. Thus fewer patients in the nicardipine SR group required combined therapy with HCTZ. Our results support the hypothesis that the antihypertensive efficacy of calcium antagonists is age related. 9':: Hence, the reduction of blood pressure, particularly systolic blood pressure, induced by calcium antagonists appears to increase with advancing age, 12 although other authors :3 disagree. Moreover, the antihypertensive efficacy of calcium antagonists is related to pretreatment blood pressure values. If pretreatment blood pressure values can determine the degree of blood pressure reduction, the antihypertensive efficacy of nicardipine SR should be greatest in patients with the highest blood pressures. In similar patients, other antihypertensive drugs may be ineffective, and a combined therapy would be necessary. During active treatment with nicardipine SR and enalapril, alone or in combination with HCTZ, no rebound hypertension or tachyphylaxis was observed. At the doses used, both drugs appeared to ensure a satisfactory and persistent 24-hour control of blood pressure. No significant changes in heart rate were observed during the study when nicardipine SR or enala227
NICARDIPINE AND ENALAPRIL IN ELDERLY HYPERTENSIVE PATIENTS
Table II. Systolicand diastolicbloodpressures (BP) in patients who required combinedtherapy with hydrochlorothiazide(HCTZ). Nicardipine SR + HCTZ (n = 62)
Day 0 Systolic Diastolic Day 30 Systolic Diastolic Day 60 Systolic Diastolic Day 90 Systolic Diastolic Day 120 Systolic Diastolic Day 150 Systolic Diastolic Day 180 Systolic Diastolic
Enalapril + HCTZ (n = 119)
Supine BP (mmHg)
Standing BP (mmHg)
Supine BP (mmHg)
Standing BP (mmHg)
179.7 ± 1.2 104.4 _+ 0.8
178.3 ± 1.5 103.9 ± 0.7
177.2 _ 1.3 103.1 _ 0.7
176~2 ± 1.2 103.8 ± 0.6
167.0 ± 1.5 95.5 + 0.9
166.7 +- 1.5 95.7 +- 1.0
167.0 _+ 1.2 97.0 ± 0.6
167.7 ± 1.3 97.8 _+ 0.5
165.0 -+ 1.5 95.2 ± 0.9
164.7 _+ 1.4 95.0 ± 1.0
164.7 ± 1.2 96.1 ± 0.6
164.9 ± 1.3 96.6 ± 0.6
157.8 ± 1.2 90.0 ± 1.0
157.3 _+ 1.3 89.6 +- 1.1
157.7 ± 1.3 89.6 ± 1.1
158.1 +_ 1.3 90.3 ± 0.8
154.5 _+ 1.5 88.2 ± 1.1
153.7 ± 1.3 88.4 ± 1.1
154.7 _ 1.3 87.4 _+ 0.8
153.8 ± 1.4 88.4 ± 0.8
155.2 _+ 1.5 87.3 __ 1.0
155.8 -+ 1.5 88.2 +_ 1.0
154.2 ± 1.1 87.3 ± 0.9
153.5 ±_ 1.5 87.9 ± 0.9
153.2 ± 1.3 86.8 ± 1.0
152.6 ± 1.4 87.0 ± 0,9
153.2 ± 1.3 86.9 _+ 0.9
152.0 ± 1.5 87.7 _+ 0.9
Data are mean ± SD.
pril was administered as monotherapy or in combination with HCTZ. Dihydropyridine calcium antagonists can precipitate acute tachycardia, which is secondary to their vasodilatory action and an increase in the reflex sympathetic tone. 14 However, induced tachycardia is a transient occurrence because of a swift baroreflex resetting. 15 It probably is attenuated or absent in older patients due to a reduced baroreflex sensitivity. 16 No significant difference was observed between the supine and standing blood pressures during active treatment, and none of the patients reported orthostatic hypotension. On the basis of their pharmacologic properties, the two drugs appear to have vasodilatory and antihypertensive
Table III. Number of patients withdrawingfrom treatment. Reason for Withdrawal
Nicardipine SR (n = 281)
Enalapril (n = 280)
Poor compliance Hospitalization Side effects Total number of withdrawals
6 3 5 14
5 1 12 18
228
R. NAMI ET AL,
Table IV. Incidence of side effects. Nicardipine SR (n = 281)
Ankle edema Headache Facial flushing Palpitations Fatigue Dizziness Itching Rash Nausea Taste disturbance Diarrhea Cough
Enalapril (n = 280)
No. of Patients
Percent
No. of Patients
39 24 23 16 14 4 4 1 1 1 1 --
13.9 8.5 8.2 5.7 5.0 1.4 1.4 0.3 0.3 0.3 0.3 --
2 5 3 -27 7 4 1 3 8 3 26
Percent 0,7 1.8 1.2 9.6 2.5 1.4 0.3 1.1 2.9 1.1 9.3
SR = slow release.
effects without negatively affecting the homeostatic reflexes of blood pressure control, which in the elderly are already impaired. 7 Combined therapy (nicardipine SR + HCTZ or enalapril + HCTZ) was an effective t r e a t m e n t for those hypertensive patients who did not respond to monotherapy. In our study, the antihypertensive efficacy of nicardipine SR + HCTZ was comparable to that of ACE inhibitors combined with a thiazide diuretic. 17 Therefore, despite negative opinions, is our results confirm the usefulness of the calcium antagonist-thiazide diuretic combination previously evaluated in several clinical studies. 19'2° The side effects reported by the patients in our study were more frequent in the nicardipine SR group than in the enalapril group (26% versus 22.6%), b u t the number of drug-related withdrawals was higher in the enalapril group than in the nicardipine SR group (12 versus 5). Ankle edema, headache, facial flushing, and palpitations were the predominant events reported in the nicardipine SR group. These manifestations are typical of the vasodilatory actions of the drug and were generally mild and well tolerated. Fatigue, cough, taste disturbance, and dizziness were commonly reported in the enalapril group. A frequently irritable and dry cough resistant to symptomatic treatment, alone or together with other side effects, was the most common cause of interruption of therapy or withdrawal. No clinically relevant changes in the laboratory tests were observed with nicardipine SR or enalapril given as monotherapy or in combination with HCTZ. In conclusion, although our study was not placebo controlled, nicardipine SR, as documented for other dihydropyridine calcium antagonists, 21 appeared to be more effective than ACE inhibitors in lowering blood pressure. The potent vasodilatory and antihypertensive activity of nicardipine 229
NICARDIPINEANDENALAPRILIN ELDERLYHYPERTENSIVEPATIENTS
SR, as well as its metabolic and hemodynamic profile, potential anti~ atherogenic properties, 22 and good tolerability, justify its role as a treatm e n t of first choice in elderly hypertensive patients.
Acknowledgment This study was supported by a research grant from Alfa Wassermann S.p.A., Bologna, Italy. References:
1. Kannel WB. Prevalence, incidence and hazards of hypertension in the elderly. Geriatr Cardiovasc Med 1988; 1:5-10. 2. Lakatta EG. Mechanism of hypertension in the elderly. J A m Geriatr Soc 1989; 37:780790. 3. Amery A, Birkehager W, Brixko P, et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet 1985; 1:1349-1354. 4. Coope J, Warrender TS. Randomized trial of treatment of hypertension in elderly patients in primary care. B M J 1986; 293:1145-1148. 5. Walsh R. Cardiovascular effects of the aging process. A m J Med 1987; 82(Suppl 1B):3440. 6. Pfeiffer MA, Weinberg CR, Cook D, et al. Differential changes in autonomic nervous system function with age in man. A m J Med 1983; 75:249-257. 7. Lipsitz LA. Orthostatic hypotension in the elderly. New Engl J Med 1984; 32:952-957. 8. Briggs J, Rowe J. Adverse drug reactions in elderly hypertensive patients. ISI Atlas of Science. Pharmacology 1987; 1:262-265. 9. Kiowski W, Buhler FR, Fadayomi MO. Age, race, blood pressure and renin: Predictors for antihypertensive treatment with calcium antagonists. A m J Cardiol 1985; 56:108-113. 10. Drayer J, Weber MA. Monotherapy of essential hypertension with converting enzyme inhibitor. Hypertension 1983; 5(Part II):108-113. 11. KrakoffLR. Nicardipine monotherapy in ambulatory elderly patients with hypertension. A m Heart J 1989; 117:250-255. 12. Leonetti G, Chiaca R. The effects of nicardipine in elderly hypertensive patients. J Cardiovasc Pharmacol 1990; 16(Suppl 2):$5-$8. 13. Chalmers JP, Smith SA, Wing LMH. Hypertension in the elderly: The role of calcium antagonists. J Cardiovasc Pharmacol 1988; 12(Suppl 8):S147-$155. 14. Kaplan NM. Critical comments on recent literature: Age and response to antihypertensive drugs. A m J Hypertens 1989; 2:213-215. 15. Aoki K, Kondo S, Mochizuki A, et al. Antihypertensive effect of cardiovascular Ca + + antagonist in hypertensive patients in the absence and presence ofbeta-adrenergic blockade. A m Heart J 1978; 96:218-223. 16. Joung MA, Watson RDS, Litter WA. Baroreflex setting and sensitivity after acute and chronic nicardipine therapy. Clin Sci 1984; 66:233-235. 230
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17. Veterans Administration Cooperative Study Group on Hypertensive Agents. Captopril: Evaluation of low doses, twice daily doses and addition of diuretic for treatment of mild to moderate hypertension. Clin Sci 1982; 63:4435-4455. 18. MacGregor GA, Peva House JB, Cappuccio FP, Markandu ND, Nifedipine, diuretics and sodium balance. J Hypertens 1987;5:S127-S131, 19. Ferrara LA, Pasanisi F, Marotta T, et al. Calcium antagonists and thiazide diuretics in treatment of hypertension. J Cardiovasc Pharmacol 1987; 10(Suppl 10):S136-S137. 20. Mancia G, Buoninconti R, Errico M, et al. Efficacia e tollerabilit~ della nicardipina retard e del captopril nell'ipertensione dell'anziano. Risultati di uno studio multicentrico. Minerva Med 1992; 83:1-8. 21. Gennari C, Nami R, Bianchini C, et al. Nitrendipine and the angiotension converting enzyme inhibition in the treatment of hypertension. J Cardiovasc Pharmacol 1987; 9(Suppl 4):$245-$251. 22. Ouchi Y, Orimo H. The role of calcium antagonists in the treatment of atherosclerosis and hypertension. J Cardiovasc Pharrnacol 1990; 16(Suppl 2):S1-$4.
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