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Sustained-release verapamil and trandolapril, alone and in combination, in the treatment of obese hypertensive patients: a double-blind pilot study
CURRENT THERAPEUTIC RESEARCH” VOL. 57, NO. 12, DECEMBER
1996
SUSTAINED-RELEASE VERAPAMIL AND TRANDOLAPRIL, ALONE AND IN COMBINATION, IN THE TREATMENT OF OBESE HYPERTENSIVE PATIENTS: A DOUBLE-BLIND PILOT STUDY Is~Eiw
NALBANTGIL,
Cardiology Department,
REMZI
BINDER,
AND
SANEM
NALBANTGIL
Ege University Medical School, Izmir, Turkey
ABSTRACT
The purpose of this pilot study was to compare the ability of sustainedrelease verapamil (verapamil SR) and trandolapril, both alone and combined in half doses, to reduce blood pressure in obese patients with mild-to-moderate essential hypertension. Twenty patients (13 men and 7 women) took part in the study. Ten (group A) received verapamil SR 240 mg/d, and 10 (group B) received trandolapril 2 mg/d for 6 weeks. All patients were then given both drugs in half-doses for 6 weeks. After combination therapy, group B received verapamil SR 240 mg/d, and group A received trandolapril2 mg/d for 6 weeks. When verapamil and trandolapril were used alone, systolic and diastolic blood pressures decreased significantly in each group. However, systolic and diastolic blood pressures fell further when combination therapy was used and rose slightly when the treatment was changed again to single-drug therapy. Side effects were fewer during the combination therapy. Thus the combination of half doses of verapamil SR and trandolapril was more effective in reducing blood pressure in obese patients with mildto-moderate essential hypertension than a full dose of either drug given alone. INTRODUCTION
The association between high blood pressure and obesity is well documented.’ Evidence for this association is based on two observations: (1) hypertensive patients tend to become obese as the disease progresses2; and (2) obese patients are at higher risk of hypertension than nonobese patients. Therefore, weight gain may indicate whether borderline hypertension has evolved into established hypertension.3 Furthermore, there is a close association among hypertension, obesity, glucose intolerance, and dyslipidemia. In one study,4 more than 80% of identified hypertensive patients were obese, glucose intolerant, or both. Hence, pharmacologic agents that improve-or at least do not worsen-the metabolic abnormalities associated with obesity-related hypertension should be used.5 The internationally accepted recommendation for the treatment of Address correspondence to: Dr. Istemi Nalbantgil, Mithat pasa cad. 75015, 35280, Izmir, Turkey Received forpublication OR September 19, 1996. Printed in the U.S.A. Reproduction in whole or part is not permitted.
990
OOll-393x/96/$3.50
I. NALBANTGIL ET AL
hypertension is to start with a single agent. However, in more than 50% of patients, as demonstrated in all intervention trials,6 combination therapy is necessary. Combinations of two or more drugs can reduce blood pressure via several mechanisms and produce additive or potentiated effects. By using low doses of drugs, side effects are minimized, and this may improve patient compliance. Among the many groups of effective antihypertensive agents that are currently available, angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers present several advantages in terms of favorable hemodynamic and biochemical profiles, as well as patient convenience and quality of life. Both classes of antihypertensives have shown cardioprotective’-’ and nephroprotective effects,” as well as a relative lack of adverse metabolic effects.” Hence, a combination of these drugs could offer benefits over other combined regimens. The efficacy of the calcium channel blocker verapamil in sustainedrelease form (verapamil SR) is well established in hypertension managemen&l2 as is that of trandolapril, a long-acting lipophilic ACE inhibitor.13 We undertook a pilot study to compare the ability of trandolapril and verapamil SR, both alone and combined in half doses, to reduce blood pressure in obese patients with mild-to-moderate essential hypertension. PATIENTS
AND METHODS
Twenty patients (13 men and 7 women), aged between 41 and 64 years, were included in the study. All were overweight (body mass index 227 kg/m2), and had mild-to-moderate essential hypertension (sitting diastolic blood pressure [DBPI between 90 and 99 mm Hg [mild] and 100 and 109 mm Hg [moderate], respectively). Causes of secondary hypertension were excluded by clinical examination; measurement of plasma electrolytes, creatinine, and catecholamine excretion; and intravenous pyelography. Patients with clinical evidence of severe hepatic or renal impairment or any of the known contraindications to the individual study drugs were excluded. Seventeen patients had had previous treatment with several other drugs, but their hypertension remained uncontrolled. No concomitant antihypertensive agents were allowed. The study was approved by each local ethics committee and was conducted in accordance with the Declaration of Helsinki (Hong Kong Revision, 1989). All patients gave written informed consent before study entry. After a washout period of 2 weeks, patients were randomized into two groups of 10; the study was double blind. For 6 weeks, the first group of patients (group A) received verapamil SR 240 mg/d, and the second group (group B) received trandolapri12 mg/d as the standard doses of these drugs. At the end of the 6-week period, all patients were given half doses of both verapamil SR and trandolapril, and this combination was continued for 991
VERAPAMIL
AND TRANDOLAPRIL
IN THE TREATMENT
OF OBESE
HYPERTENSIVE
PATIENTS
another 6 weeks. For the last 6 weeks, the treatment groups were crossed over tie, group A patients received trandolapril 2 mgld and group B patients received verapamil SR 240 mg/d). All drugs, whether used alone or in combination, were given in a single capsule. Patients took the capsule in the morning, and clinical examinations were carried out between 3 and 5 PM. At entry into the study, a medical history was taken, and patients underwent a physical examination. During the M-week treatment period, systolic blood pressure @BP) and DBP and heart rate were recorded each week. Blood pressure and radial pulse rate were measured after the patient had been in the physician’s office for at least 15 minutes and resting for at least 10 minutes. For each patient, SBP and DBP were recorded by the same investigator with a mercury sphygmomanometer at Korotkoff phases I and V, respectively, using the same cuff on the same arm. Each value recorded was the mean of three consecutive readings. Electrocardiographic and echocardiographic examinations were performed at the end of the washout period. Blood tests (hematocrit; hemoglobin; erythrocyte, leukocyte, and platelet counts; and determinations of levels of fasting blood glucose, triglyceride, high-density lipoprotein, low-density lipoprotein, total cholesterol, uric acid, creatinine, aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma-glutamyltransferase, and plasma sodium and potassium) and urinalysis were performed at the end of the washout period and at 6, 12, and 18 weeks after the start of therapy. Adverse events and tolerability were assessed by casual questioning during the scheduled visits. Statistical
Analysis
Changes in blood pressure, heart rate, and blood test results were compared by means of the paired Student’s t test. The results are presented as mean ? SD. A two-tailed P < 0.05 was considered indicative of statistical significance. ‘* RESULTS The demographic data for the 20 patients included in the study are given in Table I. Effects on Blood Pressure In group A, mean SBP was 170.4 & 3.1 mm Hg and mean DBP was 99.2 ? 2.9 mm Hg at the end of the washout period (Table II). After 6 weeks of treatment with verapamil SR 240 mg/d as monotherapy, mean SBP fell to 151.6 ? 4.7 mm Hg (P -=c0.0001) and mean DBP to 93.2 * 2.5 992
I. NALBANTGIL ET AL.
Table I. Demographic data.* Range
Mean %R#n of hypertension (y) Systolic blood pressure (mm Hg) Drastolic blood pressure (mm Hg) Heart rate (beatslmin) Body mass index (kg/m’) Left ventricular mass (g) Left ventricular mass index (g/m*) Previous treatment Unspecified: 10 patients Beta-blockers: 2 patients Diuretics + beta-blockers: 4 patients Beta-blockers + calcium channel blockers:
4.35 55.2 170.8 99.6 76.0 28.54 173.76 92.76
+2 t 2 2 ? -t 2
41-64
7.2 2.78 4.9 3.7 6.2 1.50 42.99 27.63
16k:80 tE 27.0-31.97 111.70-272.36 62.67-171.29
1 patient
* N = 20 (13 men, 7 women).
mm Hg (P < 0.0001). In group B, initial mean SBP was 171.2 +_ 5.1 mm Hg, and mean DBP was 99.8 5 4.8 mm Hg; these fell to 147.4 ‘-c 4.6 mm Hg (P < 0.0001) and 91.0 -+ 2.5 mm Hg (P = 0.0002), respectively, after 6 weeks of treatment with trandolapril. There was no statistical difference between the effects of the two drugs on SBP (P = 0.061 or DBP (P = 0.069). During the 6 weeks of combination therapy, mean SBP in the two groups fell to 140.4 5 4.3 mm Hg (P < 0.00011, and mean DBP fell to 88.1 f 2.4 mm Hg (P < 0.0001). On reverting to monotherapy, mean SBP and DBP in the verapamil
Table II. Systolic blood pressure (SBP, mm Hg), diastolic blood pressure (DBP, mm Hg), and heart rate (HR, beats/min) at the end of the washout period and at 6, 12, and 18 weeks after start of therapy (mean 2 SD). Group Period
Variable
Washout
SBP DBP
6 Weeks monotherapy
EP DBP
6 Weeks combination therapy (12 weeks after start)
!;P DBP
6 Weeks monotherapy $r;tq=.$pped; 18 weeks
Z!P DBP HR
Verapamil SR 170.4 99.2 78.8 151.6 93.2 65.2
r 2 k 5 2 t
3.1 2.9 4.9 4.7’ 2.5’ 4.9*
149.4 2 5.5f 92.6 59.0 -c * 4.7t 5.1t
P < 0.0001 versus end of washout period. t P < 0.05 versus end of combination therapy (12 weeks). l
993
Combination
140.4 2 4.3’ 88.1 2 2.4’ 67.8 -t 5.9’
Trandolapril 171.2 99.8 73.2 147.4 91.0 71.4
2 -+ * 2 4 +
5.1 4.8 7.6 4.6* 2.5* 5.5
143.2 ” 3.7 77.8 2” 3.4t 89.9 1.7
VERAPAMIL
AND TRANDOLAPRIL
IN THE TREATMENT
OF OBESE
HYPERTENSIVE
PATIENTS
SR group (group B) rose to 149.4 % 5.5 and 92.6 -+ 4.7 mm Hg (P = 0.0006 and P = 0.018, respectively). In the trandolapril group (group A), mean SBP rose to 143.2 ? 3.7 and mean DBP to 89.9 5 1.7 mm Hg (P= 0.18 and P = 0.11, respectively). Both SBP and DBP rose more rapidly in the verapamil SR group than in the trandolapril group. This difference was statistically significant for SBP (P = 0.18 for the second week, P = 0.032 for the fourth week, and P = 0.01 for the sixth week) but not for DBP. Effects on Heart Rate At the end of the washout period, mean heart rates were 78.8 + 4.9 beats/min in group A and 73.2 + 7.6 beats/min in group B. At the end of the first 6 weeks, mean heart rate fell to 65.2 ? 4.9 beats/min in the verapamil SR group (group A) (P< 0.0001) and was essentially unchanged in the trandolapril group (group B) (71.4 -C 5.5 beats/min; P = 0.55). After 6 weeks of combination therapy, mean heart rate was 67.8 + 5.9 beatslmin (P = 0.57). In the last 6-week period, mean heart rate fell to 59.0 ? 5.1 beats/min (P= 0.046) in the verapamil SR group (group B) and rose to 77.8 + 3.4 beats/min (P= 0.0003) in the trandolapril group (group A) (Table II). There were no clinically important changes in blood chemistry or hematology, except for a rise in serum potassium in trandolapril users from 4.92 & 0.32 mmol/L at baseline to 5.03 2 0.28 mmol/L (P< 0.05). Side effects (Table III) were less frequent during combination therapy than during monotherapy. Unwanted effects were mild, and all patients continued to take the drugs without need for further therapy to counteract side effects. DISCUSSION
During the first 6-week period, the effect of trandolapri12 mg/d on SBP and DBP was similar to that of verapamil SR 240 mg/d. However, verapamil SR had a heart rate-lowering effect not shown by trandolapril. In the second 6-week period, half-dose combination therapy produced greater decreases in both SBP and DBP than did monotherapy. During the third Table III. Number of patients reporting side effects during verapamil, trandolapril, bination therapy (N = 20).
Verapamil
Trandolapril
Constipation Headache Cough Palpitations Gastrointestinal disorders
994
and com-
Combination
I. NALBANTGIL
ET AL.
6-week period, when monotherapy was again given, the increase in SBP was significant with verapamil SR. With trandolapril alone, SBP and DBP rose progressively, but the changes after 6 weeks were not significant. The purpose of giving half doses of both drugs was to investigate whether the two drugs potentiated each other’s effect. This protocol has been used previously to estimate the combined effect of two different calcium channel blockers.15 If drugs had been combined at the starting doses, then results could have been due to an additive effect. On the other hand, if the half-dose combination produces better results than monotherapy, as it did here, this can be attributed to potentiation. Verapamil SR has been used successfully in the treatment of hypertension for more than 20 years, either as a first-line agent or in combination with other drugs.16 In our study the antihypertensive effect was observed during the first week of treatment and continued progressively throughout the treatment period. Trandolapril has been reported to be efficacious in hypertensive patients with renal dysfunction or insulin reIn this study the beneficial effect of sistance and in elderly patients. 13*17,18 both drugs in overweight hypertensive patients was demonstrated. Verapamil SR and trandolapril had no effect on blood counts or blood chemistry; only serum potassium levels increased significantly after trandolapril treatment. Combination therapy was well tolerated; no side effects other than those generally observed in studies involving verapamil SR or trandolapri113,1gwere reported, and none were severe enough to warrant discontinuation of therapy. Trandolapril was associated with an increased incidence of cough, gastrointestinal disorders, and headache, and verapamil SR was associated with constipation, headache, and palpitations. These side effects are known to occur occasionally with either drug. With combination therapy, these effects were two to three times less frequent, presumably because of the lower doses of each drug. Evaluation of combination therapy in patients with hypertension and comparison with monotherapy require a study design that minimizes variability (observer or patient) and order effects, eliminates bias, and includes sufficient numbers of patients to allow real differences in blood pressure between patient groups to be detected at conventional levels of statistical significance. Crossover study design requires successive examination of different treatments, which may result in a lengthy trial and an increase in the dropout rate. Therefore, the parallel-group design is usually used to compare several active drugs and placebo; this design avoids the potential problems of order and carryover effects and, when the study is of long duration, takes into account short-term and long-term responses to drugs. Crossover trials that incorporate limited periods of treatment for each phase can be carried out with fewer numbers of patients and are more economical with regard to patient resources. However, in this study we cannot exclude carryover effects. Furthermore, a design such as this usu-
VERAPAMIL
AND TRANDOLAPRIL
IN THE TREATMENT
OF OBESE
HYPERTENSIVE
PATIENTS
ally allows comment only on short-term blood pressure responses. Pledger2’ has discussed the primary comparisons of a two-component combination drug trial as AB versus A and AB versus B; if a placebo-treated group is added, this can provide a critical frame of reference for correct interpretation of study results. A placebo-treated group can show whether the individual treatment components provided the expected effects and can provide valuable information for the design of future trials. It can also identify drug interactions tie, antagonism or synergism). However, because of ethical constraints and the well-established antihypertensive effects of each treatment component, we did not include a placebo control; this would also have made the design unwieldy. In the past, we have used this same design effectively.15 With it, we were able to establish that combination therapy with verapamil SR and trandolapril, even in a lower dosage, is superior in effectiveness to monotherapy with either component. CONCLUSION
The combination of half doses of verapamil SR and trandolapril was more effective in reducing blood pressure in obese patients with mild-tomoderate essential hypertension than a full dose of either drug given alone. In the dosage used, the combination was better tolerated than either drug alone. Thus we believe that this combination offers a new option in antihypertensive therapy for obese patients. More studies are required, particularly to investigate the effect on the inappropriately elevated peripheral vascular resistance commonly observed21 in obese patients and the mechanism of connection between obesity and hypertension, because the clinical implications are very clear: Despite having disparate cardiovascular effects, the two conditions take a heavy toll on the heart, particularly when they occur together. Acknowledgment The study was sponsored by Knoll Alman Ltd, Istanbul, Turkey. References: 1. Johnson AL, Cornoni JC, Cassel JC, et al. Influence of race, sex and weight on blood pressure behavior in young adults. Am J Cardiol. 1975;35:523-528. 2. Chiang BN, Perlman LV, Elpstein FH. Overweight lation. 1969;39:403-421.
and hypertension:
A review. Circu-
3. Stamler R, Stamler J, Riedlinger WF, et al. Weight and blood pressure: Findings hypertension screening of 1 million Americans. JAMA. 1978;240:1607-1612.
in
4. Modan M, Halkin H, Almog S, et al. Hyperinsulinaemia: A link between hypertension, obesity and glucose intolerance. J Clin Invest. 1995;75:809-817. 5. Landsberg L. Pathophysiology of obesity-related hypertension: Role of insulin and the sympathetic nervous system. J Cardiovasc Ph.u~mucol. 1994;23(Suppl ll:Sl-S8. 6. James IM. Which antihypertensives?
Br J Clin Pratt.
996
1990;44:102-105.
1. NALBANTGIL
ET AL.
7. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fraction. NEJM. 1992;327:685-691. 8. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement Trial. NEJM. 1992;327:669-677. 9. Yusuf S, Held P, Furberg C. Update of effects of calcium antagonists in myocardial infarction or angina in light of the Second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol. 1991;67:1295-1297. 10. Bakris GL, Bamhill BW, Sadler R. Treatment of arterial hypertension in diabetic humans: Importance of therapeutic selection. Kidney Znt. 1992;41:912-919. 11. Aursnes I, Litleskare I, Freland H, Abdelnoor M. Association between various drugs used for hypertension and risk of acute myocardial infarction. Blood Press. 1995;4:157-163. 12. Guidelines Subcommittee. 1993 Guidelines for the management of mild hypertension: Memorandum from a World Health Organization/International Society of Hypertension meeting. J Hypertens. 1993;11:905-918. 13. Wiseman LR, McTavish D. Trandolapril: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in essential hypertension. Drugs. 1994;48:7190. 14. Snedecor GW, Cochran WG, eds. Statistical University Press; 1980:91-116, 135-170.
Method. 7th ed. Ames, Iowa: Iowa State
,
15. Nalbantgil I, Onder R, Kiliccioglu B, Turkoglu C. Combination therapy with verapamil and nitrendipine in patients with hypertension. J Hum Hypertens. 1993;7:305-308. 16. Zanchetti A. A re-examination of stepped-care. A retrospective and prospective study. J Cardiouasc Pharmncol. 1985;7(Suppl l):S127-S131. 17. Gaillard CA, de Leeuw PW. Clinical experiences with trandolapril. Am Heart J. 1993; 125:1542-1546. 18. Weichenhain B, van Kooten HJ, Stand1 E. Hypertension and insulin resistance. Drugs. 1993;46(Suppl 2):183-188. 19. Zannad F. Trandolapril. How does it differ from other angiotensin converting enzyme inhibitors? Drugs. 1993;46(Suppl 2):172-182. 20. Pledger G. The role of a placebo-treated control group in combination drug trials. Control Clin Trials. 1989;10:97-107. 21. Weidmann P, de Courten M, Boehlen L, Shaw S. The pathogenesis of hypertension in obese subjects. Drugs. 1993;46(Suppl 2):197-209.
997
1996
SUSTAINED-RELEASE VERAPAMIL AND TRANDOLAPRIL, ALONE AND IN COMBINATION, IN THE TREATMENT OF OBESE HYPERTENSIVE PATIENTS: A DOUBLE-BLIND PILOT STUDY Is~Eiw
NALBANTGIL,
Cardiology Department,
REMZI
BINDER,
AND
SANEM
NALBANTGIL
Ege University Medical School, Izmir, Turkey
ABSTRACT
The purpose of this pilot study was to compare the ability of sustainedrelease verapamil (verapamil SR) and trandolapril, both alone and combined in half doses, to reduce blood pressure in obese patients with mild-to-moderate essential hypertension. Twenty patients (13 men and 7 women) took part in the study. Ten (group A) received verapamil SR 240 mg/d, and 10 (group B) received trandolapril 2 mg/d for 6 weeks. All patients were then given both drugs in half-doses for 6 weeks. After combination therapy, group B received verapamil SR 240 mg/d, and group A received trandolapril2 mg/d for 6 weeks. When verapamil and trandolapril were used alone, systolic and diastolic blood pressures decreased significantly in each group. However, systolic and diastolic blood pressures fell further when combination therapy was used and rose slightly when the treatment was changed again to single-drug therapy. Side effects were fewer during the combination therapy. Thus the combination of half doses of verapamil SR and trandolapril was more effective in reducing blood pressure in obese patients with mildto-moderate essential hypertension than a full dose of either drug given alone. INTRODUCTION
The association between high blood pressure and obesity is well documented.’ Evidence for this association is based on two observations: (1) hypertensive patients tend to become obese as the disease progresses2; and (2) obese patients are at higher risk of hypertension than nonobese patients. Therefore, weight gain may indicate whether borderline hypertension has evolved into established hypertension.3 Furthermore, there is a close association among hypertension, obesity, glucose intolerance, and dyslipidemia. In one study,4 more than 80% of identified hypertensive patients were obese, glucose intolerant, or both. Hence, pharmacologic agents that improve-or at least do not worsen-the metabolic abnormalities associated with obesity-related hypertension should be used.5 The internationally accepted recommendation for the treatment of Address correspondence to: Dr. Istemi Nalbantgil, Mithat pasa cad. 75015, 35280, Izmir, Turkey Received forpublication OR September 19, 1996. Printed in the U.S.A. Reproduction in whole or part is not permitted.
990
OOll-393x/96/$3.50
I. NALBANTGIL ET AL
hypertension is to start with a single agent. However, in more than 50% of patients, as demonstrated in all intervention trials,6 combination therapy is necessary. Combinations of two or more drugs can reduce blood pressure via several mechanisms and produce additive or potentiated effects. By using low doses of drugs, side effects are minimized, and this may improve patient compliance. Among the many groups of effective antihypertensive agents that are currently available, angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers present several advantages in terms of favorable hemodynamic and biochemical profiles, as well as patient convenience and quality of life. Both classes of antihypertensives have shown cardioprotective’-’ and nephroprotective effects,” as well as a relative lack of adverse metabolic effects.” Hence, a combination of these drugs could offer benefits over other combined regimens. The efficacy of the calcium channel blocker verapamil in sustainedrelease form (verapamil SR) is well established in hypertension managemen&l2 as is that of trandolapril, a long-acting lipophilic ACE inhibitor.13 We undertook a pilot study to compare the ability of trandolapril and verapamil SR, both alone and combined in half doses, to reduce blood pressure in obese patients with mild-to-moderate essential hypertension. PATIENTS
AND METHODS
Twenty patients (13 men and 7 women), aged between 41 and 64 years, were included in the study. All were overweight (body mass index 227 kg/m2), and had mild-to-moderate essential hypertension (sitting diastolic blood pressure [DBPI between 90 and 99 mm Hg [mild] and 100 and 109 mm Hg [moderate], respectively). Causes of secondary hypertension were excluded by clinical examination; measurement of plasma electrolytes, creatinine, and catecholamine excretion; and intravenous pyelography. Patients with clinical evidence of severe hepatic or renal impairment or any of the known contraindications to the individual study drugs were excluded. Seventeen patients had had previous treatment with several other drugs, but their hypertension remained uncontrolled. No concomitant antihypertensive agents were allowed. The study was approved by each local ethics committee and was conducted in accordance with the Declaration of Helsinki (Hong Kong Revision, 1989). All patients gave written informed consent before study entry. After a washout period of 2 weeks, patients were randomized into two groups of 10; the study was double blind. For 6 weeks, the first group of patients (group A) received verapamil SR 240 mg/d, and the second group (group B) received trandolapri12 mg/d as the standard doses of these drugs. At the end of the 6-week period, all patients were given half doses of both verapamil SR and trandolapril, and this combination was continued for 991
VERAPAMIL
AND TRANDOLAPRIL
IN THE TREATMENT
OF OBESE
HYPERTENSIVE
PATIENTS
another 6 weeks. For the last 6 weeks, the treatment groups were crossed over tie, group A patients received trandolapril 2 mgld and group B patients received verapamil SR 240 mg/d). All drugs, whether used alone or in combination, were given in a single capsule. Patients took the capsule in the morning, and clinical examinations were carried out between 3 and 5 PM. At entry into the study, a medical history was taken, and patients underwent a physical examination. During the M-week treatment period, systolic blood pressure @BP) and DBP and heart rate were recorded each week. Blood pressure and radial pulse rate were measured after the patient had been in the physician’s office for at least 15 minutes and resting for at least 10 minutes. For each patient, SBP and DBP were recorded by the same investigator with a mercury sphygmomanometer at Korotkoff phases I and V, respectively, using the same cuff on the same arm. Each value recorded was the mean of three consecutive readings. Electrocardiographic and echocardiographic examinations were performed at the end of the washout period. Blood tests (hematocrit; hemoglobin; erythrocyte, leukocyte, and platelet counts; and determinations of levels of fasting blood glucose, triglyceride, high-density lipoprotein, low-density lipoprotein, total cholesterol, uric acid, creatinine, aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma-glutamyltransferase, and plasma sodium and potassium) and urinalysis were performed at the end of the washout period and at 6, 12, and 18 weeks after the start of therapy. Adverse events and tolerability were assessed by casual questioning during the scheduled visits. Statistical
Analysis
Changes in blood pressure, heart rate, and blood test results were compared by means of the paired Student’s t test. The results are presented as mean ? SD. A two-tailed P < 0.05 was considered indicative of statistical significance. ‘* RESULTS The demographic data for the 20 patients included in the study are given in Table I. Effects on Blood Pressure In group A, mean SBP was 170.4 & 3.1 mm Hg and mean DBP was 99.2 ? 2.9 mm Hg at the end of the washout period (Table II). After 6 weeks of treatment with verapamil SR 240 mg/d as monotherapy, mean SBP fell to 151.6 ? 4.7 mm Hg (P -=c0.0001) and mean DBP to 93.2 * 2.5 992
I. NALBANTGIL ET AL.
Table I. Demographic data.* Range
Mean %R#n of hypertension (y) Systolic blood pressure (mm Hg) Drastolic blood pressure (mm Hg) Heart rate (beatslmin) Body mass index (kg/m’) Left ventricular mass (g) Left ventricular mass index (g/m*) Previous treatment Unspecified: 10 patients Beta-blockers: 2 patients Diuretics + beta-blockers: 4 patients Beta-blockers + calcium channel blockers:
4.35 55.2 170.8 99.6 76.0 28.54 173.76 92.76
+2 t 2 2 ? -t 2
41-64
7.2 2.78 4.9 3.7 6.2 1.50 42.99 27.63
16k:80 tE 27.0-31.97 111.70-272.36 62.67-171.29
1 patient
* N = 20 (13 men, 7 women).
mm Hg (P < 0.0001). In group B, initial mean SBP was 171.2 +_ 5.1 mm Hg, and mean DBP was 99.8 5 4.8 mm Hg; these fell to 147.4 ‘-c 4.6 mm Hg (P < 0.0001) and 91.0 -+ 2.5 mm Hg (P = 0.0002), respectively, after 6 weeks of treatment with trandolapril. There was no statistical difference between the effects of the two drugs on SBP (P = 0.061 or DBP (P = 0.069). During the 6 weeks of combination therapy, mean SBP in the two groups fell to 140.4 5 4.3 mm Hg (P < 0.00011, and mean DBP fell to 88.1 f 2.4 mm Hg (P < 0.0001). On reverting to monotherapy, mean SBP and DBP in the verapamil
Table II. Systolic blood pressure (SBP, mm Hg), diastolic blood pressure (DBP, mm Hg), and heart rate (HR, beats/min) at the end of the washout period and at 6, 12, and 18 weeks after start of therapy (mean 2 SD). Group Period
Variable
Washout
SBP DBP
6 Weeks monotherapy
EP DBP
6 Weeks combination therapy (12 weeks after start)
!;P DBP
6 Weeks monotherapy $r;tq=.$pped; 18 weeks
Z!P DBP HR
Verapamil SR 170.4 99.2 78.8 151.6 93.2 65.2
r 2 k 5 2 t
3.1 2.9 4.9 4.7’ 2.5’ 4.9*
149.4 2 5.5f 92.6 59.0 -c * 4.7t 5.1t
P < 0.0001 versus end of washout period. t P < 0.05 versus end of combination therapy (12 weeks). l
993
Combination
140.4 2 4.3’ 88.1 2 2.4’ 67.8 -t 5.9’
Trandolapril 171.2 99.8 73.2 147.4 91.0 71.4
2 -+ * 2 4 +
5.1 4.8 7.6 4.6* 2.5* 5.5
143.2 ” 3.7 77.8 2” 3.4t 89.9 1.7
VERAPAMIL
AND TRANDOLAPRIL
IN THE TREATMENT
OF OBESE
HYPERTENSIVE
PATIENTS
SR group (group B) rose to 149.4 % 5.5 and 92.6 -+ 4.7 mm Hg (P = 0.0006 and P = 0.018, respectively). In the trandolapril group (group A), mean SBP rose to 143.2 ? 3.7 and mean DBP to 89.9 5 1.7 mm Hg (P= 0.18 and P = 0.11, respectively). Both SBP and DBP rose more rapidly in the verapamil SR group than in the trandolapril group. This difference was statistically significant for SBP (P = 0.18 for the second week, P = 0.032 for the fourth week, and P = 0.01 for the sixth week) but not for DBP. Effects on Heart Rate At the end of the washout period, mean heart rates were 78.8 + 4.9 beats/min in group A and 73.2 + 7.6 beats/min in group B. At the end of the first 6 weeks, mean heart rate fell to 65.2 ? 4.9 beats/min in the verapamil SR group (group A) (P< 0.0001) and was essentially unchanged in the trandolapril group (group B) (71.4 -C 5.5 beats/min; P = 0.55). After 6 weeks of combination therapy, mean heart rate was 67.8 + 5.9 beatslmin (P = 0.57). In the last 6-week period, mean heart rate fell to 59.0 ? 5.1 beats/min (P= 0.046) in the verapamil SR group (group B) and rose to 77.8 + 3.4 beats/min (P= 0.0003) in the trandolapril group (group A) (Table II). There were no clinically important changes in blood chemistry or hematology, except for a rise in serum potassium in trandolapril users from 4.92 & 0.32 mmol/L at baseline to 5.03 2 0.28 mmol/L (P< 0.05). Side effects (Table III) were less frequent during combination therapy than during monotherapy. Unwanted effects were mild, and all patients continued to take the drugs without need for further therapy to counteract side effects. DISCUSSION
During the first 6-week period, the effect of trandolapri12 mg/d on SBP and DBP was similar to that of verapamil SR 240 mg/d. However, verapamil SR had a heart rate-lowering effect not shown by trandolapril. In the second 6-week period, half-dose combination therapy produced greater decreases in both SBP and DBP than did monotherapy. During the third Table III. Number of patients reporting side effects during verapamil, trandolapril, bination therapy (N = 20).
Verapamil
Trandolapril
Constipation Headache Cough Palpitations Gastrointestinal disorders
994
and com-
Combination
I. NALBANTGIL
ET AL.
6-week period, when monotherapy was again given, the increase in SBP was significant with verapamil SR. With trandolapril alone, SBP and DBP rose progressively, but the changes after 6 weeks were not significant. The purpose of giving half doses of both drugs was to investigate whether the two drugs potentiated each other’s effect. This protocol has been used previously to estimate the combined effect of two different calcium channel blockers.15 If drugs had been combined at the starting doses, then results could have been due to an additive effect. On the other hand, if the half-dose combination produces better results than monotherapy, as it did here, this can be attributed to potentiation. Verapamil SR has been used successfully in the treatment of hypertension for more than 20 years, either as a first-line agent or in combination with other drugs.16 In our study the antihypertensive effect was observed during the first week of treatment and continued progressively throughout the treatment period. Trandolapril has been reported to be efficacious in hypertensive patients with renal dysfunction or insulin reIn this study the beneficial effect of sistance and in elderly patients. 13*17,18 both drugs in overweight hypertensive patients was demonstrated. Verapamil SR and trandolapril had no effect on blood counts or blood chemistry; only serum potassium levels increased significantly after trandolapril treatment. Combination therapy was well tolerated; no side effects other than those generally observed in studies involving verapamil SR or trandolapri113,1gwere reported, and none were severe enough to warrant discontinuation of therapy. Trandolapril was associated with an increased incidence of cough, gastrointestinal disorders, and headache, and verapamil SR was associated with constipation, headache, and palpitations. These side effects are known to occur occasionally with either drug. With combination therapy, these effects were two to three times less frequent, presumably because of the lower doses of each drug. Evaluation of combination therapy in patients with hypertension and comparison with monotherapy require a study design that minimizes variability (observer or patient) and order effects, eliminates bias, and includes sufficient numbers of patients to allow real differences in blood pressure between patient groups to be detected at conventional levels of statistical significance. Crossover study design requires successive examination of different treatments, which may result in a lengthy trial and an increase in the dropout rate. Therefore, the parallel-group design is usually used to compare several active drugs and placebo; this design avoids the potential problems of order and carryover effects and, when the study is of long duration, takes into account short-term and long-term responses to drugs. Crossover trials that incorporate limited periods of treatment for each phase can be carried out with fewer numbers of patients and are more economical with regard to patient resources. However, in this study we cannot exclude carryover effects. Furthermore, a design such as this usu-
VERAPAMIL
AND TRANDOLAPRIL
IN THE TREATMENT
OF OBESE
HYPERTENSIVE
PATIENTS
ally allows comment only on short-term blood pressure responses. Pledger2’ has discussed the primary comparisons of a two-component combination drug trial as AB versus A and AB versus B; if a placebo-treated group is added, this can provide a critical frame of reference for correct interpretation of study results. A placebo-treated group can show whether the individual treatment components provided the expected effects and can provide valuable information for the design of future trials. It can also identify drug interactions tie, antagonism or synergism). However, because of ethical constraints and the well-established antihypertensive effects of each treatment component, we did not include a placebo control; this would also have made the design unwieldy. In the past, we have used this same design effectively.15 With it, we were able to establish that combination therapy with verapamil SR and trandolapril, even in a lower dosage, is superior in effectiveness to monotherapy with either component. CONCLUSION
The combination of half doses of verapamil SR and trandolapril was more effective in reducing blood pressure in obese patients with mild-tomoderate essential hypertension than a full dose of either drug given alone. In the dosage used, the combination was better tolerated than either drug alone. Thus we believe that this combination offers a new option in antihypertensive therapy for obese patients. More studies are required, particularly to investigate the effect on the inappropriately elevated peripheral vascular resistance commonly observed21 in obese patients and the mechanism of connection between obesity and hypertension, because the clinical implications are very clear: Despite having disparate cardiovascular effects, the two conditions take a heavy toll on the heart, particularly when they occur together. Acknowledgment The study was sponsored by Knoll Alman Ltd, Istanbul, Turkey. References: 1. Johnson AL, Cornoni JC, Cassel JC, et al. Influence of race, sex and weight on blood pressure behavior in young adults. Am J Cardiol. 1975;35:523-528. 2. Chiang BN, Perlman LV, Elpstein FH. Overweight lation. 1969;39:403-421.
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A review. Circu-
3. Stamler R, Stamler J, Riedlinger WF, et al. Weight and blood pressure: Findings hypertension screening of 1 million Americans. JAMA. 1978;240:1607-1612.
in
4. Modan M, Halkin H, Almog S, et al. Hyperinsulinaemia: A link between hypertension, obesity and glucose intolerance. J Clin Invest. 1995;75:809-817. 5. Landsberg L. Pathophysiology of obesity-related hypertension: Role of insulin and the sympathetic nervous system. J Cardiovasc Ph.u~mucol. 1994;23(Suppl ll:Sl-S8. 6. James IM. Which antihypertensives?
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1990;44:102-105.
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7. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fraction. NEJM. 1992;327:685-691. 8. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement Trial. NEJM. 1992;327:669-677. 9. Yusuf S, Held P, Furberg C. Update of effects of calcium antagonists in myocardial infarction or angina in light of the Second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol. 1991;67:1295-1297. 10. Bakris GL, Bamhill BW, Sadler R. Treatment of arterial hypertension in diabetic humans: Importance of therapeutic selection. Kidney Znt. 1992;41:912-919. 11. Aursnes I, Litleskare I, Freland H, Abdelnoor M. Association between various drugs used for hypertension and risk of acute myocardial infarction. Blood Press. 1995;4:157-163. 12. Guidelines Subcommittee. 1993 Guidelines for the management of mild hypertension: Memorandum from a World Health Organization/International Society of Hypertension meeting. J Hypertens. 1993;11:905-918. 13. Wiseman LR, McTavish D. Trandolapril: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in essential hypertension. Drugs. 1994;48:7190. 14. Snedecor GW, Cochran WG, eds. Statistical University Press; 1980:91-116, 135-170.
Method. 7th ed. Ames, Iowa: Iowa State
,
15. Nalbantgil I, Onder R, Kiliccioglu B, Turkoglu C. Combination therapy with verapamil and nitrendipine in patients with hypertension. J Hum Hypertens. 1993;7:305-308. 16. Zanchetti A. A re-examination of stepped-care. A retrospective and prospective study. J Cardiouasc Pharmncol. 1985;7(Suppl l):S127-S131. 17. Gaillard CA, de Leeuw PW. Clinical experiences with trandolapril. Am Heart J. 1993; 125:1542-1546. 18. Weichenhain B, van Kooten HJ, Stand1 E. Hypertension and insulin resistance. Drugs. 1993;46(Suppl 2):183-188. 19. Zannad F. Trandolapril. How does it differ from other angiotensin converting enzyme inhibitors? Drugs. 1993;46(Suppl 2):172-182. 20. Pledger G. The role of a placebo-treated control group in combination drug trials. Control Clin Trials. 1989;10:97-107. 21. Weidmann P, de Courten M, Boehlen L, Shaw S. The pathogenesis of hypertension in obese subjects. Drugs. 1993;46(Suppl 2):197-209.
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