- Email: [email protected]
Effects of Verapamil and Trandolapril in the Treatment of Hypertension 1
AJH
1998;11:322–327
Effects of Verapamil and Trandolapril in the Treatment of Hypertension Franz Messerli, William H. Frishman, and William J. Elliott, for the Trandolapril Study Group*
The combination of an angiotensin converting enzyme inhibitor with a calcium antagonist has become a common way of treating patients with essential hypertension who respond insufficiently to monotherapy. This double-blind, randomized, parallel, placebo-controlled, multicenter, outpatient study evaluated the antihypertensive efficacy and safety of a calcium antagonist (verapamil SR) and an angiotensin converting enzyme inhibitor (trandolapril) in patients with mild-to-moderate (stages I and II) essential hypertension. Six hundred thirty-one patients were enrolled in this 10-week study. After a 4-week single-blind placebo phase, patients received one of the following daily dosage regimens in a double-blind fashion for 6 weeks: placebo, 4 mg of trandolapril, 240 mg of verapamil SR, or a combination of 4 mg of trandolapril and 240 mg of verapamil SR. Trough sitting diastolic blood pressure was lowered by 4.5 mm Hg, 4.3 mm Hg, and 8.1 mm Hg more than placebo in the trandolapril, verapamil SR, and combination groups,
A
respectively. In the combination group, sitting diastolic blood pressure was significantly lowered (P < .01) by 3.6 mm Hg more than in the trandolapril group and by 3.8 mm Hg more than in the verapamil SR group. An analysis of the troughto-peak ratio for sitting diastolic blood pressure revealed values of 0.75 and 0.67, for the 4-mg trandolapril and the combination groups, respectively, at end point. The overall incidence of adverse reactions was similar for all treatment groups. In this study the combination of an angiotensin converting enzyme inhibitor and calcium antagonist was well tolerated and more effective than either agent administered alone for the treatment of mild-to-moderate essential hypertension. Am J Hypertens 1998;11:322–327 © 1998 American Journal of Hypertension, Ltd. KEY WORDS:
Calcium antagonists, angiotensin converting enzyme inhibitors, combination therapy, drug effects, side effects.
s many as 50% of patients with uncomplicated mild-to-moderate (stages I and II)1 essential hypertension require two or more drugs for adequate blood pressure control.2 The need for combination therapy is based on increasing antihypertensive efficacy and the possibility of diminishing the adverse events associated with
high dose monotherapy. The Joint National Committee has stated that ‘‘combining antihypertensive drugs with different modes of action will often allow smaller doses of drugs to be used to achieve control, thereby minimizing the potential for dose-dependent side effects.’’1 Thus, combining two antihypertensive agents may enhance antihypertensive efficacy and may re-
Received September 18, 1996. Accepted September 29, 1997. From the Division of Hypertension, Ochsner Medical Institutions (FM), New Orleans, Louisiana; Department of Medicine, Division of Cardiology, Hospital of the Albert Einstein College of Medicine (WHF), Bronx, New York; and Department of Preventive Medicine, Rush Presbyterian-St Luke’s Medical Center (WJE), Chicago, Illinois.
This study was supported in part by a Research Grant from Knoll Pharmaceutical Company, Mt. Olive, New Jersey. * A list of principal investigators appears in the Appendix. Address correspondence and reprint requests to Franz Messerli, MD, Division of Hypertension, Ochsner Medical Institutions, 1514 Jefferson Highway, New Orleans, LA 70155.
© 1998 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
0895-7061/98/$19.00 PII S0895-7061(97)00466-4
AJH–MARCH 1998 –VOL. 11, NO. 3, PART 1
EFFICACY OF TRANDOLAPRIL/VERAPAMIL COMBINATION
FIGURE 1. Diagram of study protocol.
duce the incidence of adverse reactions because it is possible to use lower doses of each individual drug to achieve blood pressure control.3 The combination of a calcium antagonist with an angiotensin converting enzyme (ACE) inhibitor has become an important antihypertensive treatment option. Recent investigations have shown a greater reduction in blood pressure when ACE inhibitors are combined with a calcium antagonist.4 –7 In addition, both of these drug classes are well tolerated, have few side effects,4 –7 and do not adversely affect concomitant metabolic abnormalities.8 The multicenter study described here was designed to assess efficacy and safety of the combination of a heart rate-lowering calcium antagonist (verapamil SR) and a long-acting ACE inhibitor (trandolapril). METHODS Study Design After a 4-week single-blind placebo phase, patients were randomly assigned in a doubleblind fashion to one of four treatment groups: placebo once daily, trandolapril 4 mg once daily, verapamil SR 240 mg once daily, or a combination of 4 mg of trandolapril and 240 mg of verapamil SR once daily for 6 weeks (Figure 1). Patients randomized to the combination group received 120 mg and 180 mg of verapamil daily (in addition to 4 mg of trandolapril) during the first and second weeks of double-blind therapy, respectively, then 240 mg daily for the remaining 4 weeks. Patients were instructed to take study medications with food each morning for the duration of the study. All unused medication was returned at each visit for compliance monitoring. Study Population A total of 631 patients, aged 21 years or older, were enrolled in this multicenter investigation. All patients had mild-to-moderate essential hypertension, defined as diastolic blood pressure (DBP) of 95 to 114 mm Hg, after 4 weeks of singleblind treatment with placebo. The study protocol was approved by all Institutional Review Committees and
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informed consent forms were signed by all participants. Women were excluded from the study if they were pregnant, lactating, or sexually active and of childbearing potential and not using an adequate method of contraception. Also excluded were patients who had any of the following: any form of hypertension other than mild-to-moderate essential hypertension, or history or evidence of malignant, accelerated, or severe hypertension; cerebrovascular accident, convulsive disorder or episode of hypertensive encephalopathy within the previous year; history of myocardial infarction within the previous 3 months; clinically significant congestive heart failure or suspicion or evidence of serious cardiac decompensation; severe bradycardia, clinically significant cardiac dysrhythmia, evidence of sinus node dysfunction, abnormal sinoatrial, atrioventricular (AV) or intraventricular conduction abnormalities; first, second, or third degree AV block; clinically significant medical conditions that may have interfered with study drug absorption, metabolism, or excretion (eg, renal or hepatic failure); known allergy or hypersensitivity to ACE inhibitors or calcium channel blockers; a history of chronic substance abuse or dependence within 2 years preceding study entry; or donated blood within 1 month preceding study entry. Patients were not enrolled if they needed concomitant medications such as diuretics and other antihypertensive agents, antiarrhythmic drugs, digitalis glycosides, monoamine oxidase inhibitors, psychotropic drugs, nonsteroidal antiinflammatory drugs or analgesics, or any medications known to affect blood pressure. Other reasons for exclusion were participation in a clinical trial involving another investigational drug within 30 days preceding study entry; use of any antihypertensive medications within 4 weeks or spironolactone within 6 weeks of projected entry into the double-blind period of the study or previous treatment with trandolapril. Assessments Blood pressure was measured before the morning dose with a standard mercury sphygmomanometer and an appropriately sized cuff. Measurements were taken every week during the 4-week placebo run-in phase and at the end of weeks 5, 6, 8, and 10 of the double-blind phase. Measurements taken at week 4 of the placebo phase were considered baseline for the rest of the study. During the double-blind phase, both peak and trough blood pressure and heart rate measurements were recorded. During the doubleblind period, blood pressures were measured at ‘‘trough,’’ just before dosing, and approximately 4 to 6 hours after administration, which coincides with peak plasma trandolapril concentrations and peak effect.9 Sitting blood pressure and heart rate were calculated as the mean of three consecutive measurements that
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TABLE 1. PATIENT DEMOGRAPHICS AND BASELINE BLOOD PRESSURE DATA Treatment Patient Demographics/Characteristics Sex Male Female Race Black Oriental White Age (yr) Weight (lb) Duration of hypertension (yr) Sitting SBP (mm Hg) Sitting DBP (mm Hg)
Placebo (n 5 152)
4 mg Trandolapril (n 5 159)
103 49 15 3 134 53.8 192.8 9.7 153.6 6 13.4 100.5 6 4.5
106 53 18 3 138 54.3 188.9 8.7 151.8 6 14.8 101.3 6 5.0
240 mg Verapamil SR (n 5 157)
4/240 Combination (n 5 163)
96 61
96 67
23 1 133 53.8 191.0 9.1 151.1 6 14.6 100.8 6 4.7
15 2 146 56.1 193.3 9.6 152.3 6 14.5 101.4 6 5.3
The mean 6 SD is provided as appropriate. DBP, diastolic blood pressure; SBP, systolic blood pressure.
had been obtained at 2-min intervals after the patient had rested in a sitting position for 5 min. The main efficacy measure was a reduction in sitting DBP observed immediately before the administration of the next dose (trough). Satisfactory therapeutic response was defined as a reduction from baseline in average sitting DBP to ,90 mm Hg or a $10 mm Hg decrease from baseline at end point. End point was defined as the end of the double-blind phase or the last visit during which the patient received doubleblind medication. Adverse experiences, as well as pre- versus posttreatment results of physical examinations and laboratory tests, were included in the safety evaluation.
study sites (401 men, 230 women; 551 white, 71 black, and 9 oriental). There were no significant differences between the treatment groups for any baseline characteristic (Table 1). Of the 631 patients enrolled, 581 completed the 6-week double-blind treatment phase. Thirteen (9%) patients receiving placebo, 19 (12%) patients receiving trandolapril, 9 (6%) patients receiving verapamil, and 9 (6%) patients receiving the combination discontinued before completion of the study. For the patients who discontinued, adverse reactions (40%) and unsatisfactory therapeutic response (24%) represent the main reasons for discontinuation across all treatment groups.
Statistical and Analytical Methods Analyses of efficacy were performed on an intention-to-treat basis. Comparisons of mean blood pressures at end point were carried out between the treatment groups and placebo and between the combination group and its monotherapies using a general linear model approach. The model included the baseline values as a covariate and terms for investigator, treatment, and baseline by treatment interaction. Comparisons between the treatment groups and placebo were performed on the adjusted means; comparisons between the combination and its monotherapies were performed using Snappin’s T5 test. The proportion of responders was calculated and compared between treatment groups using the x2 test for proportions. All statistical tests were two-sided and P # .05 was considered statistically significant. Means 6 SD are reported.
Efficacy The end point analysis of efficacy included the 581 patients who completed the 6-week doubleblind treatment phase, plus 44 patients who discontinued treatment at an earlier double-blind week. All active treatment groups significantly lowered mean sitting DBP at trough as compared with placebo (Table 2). Trandolapril (4 mg/day) reduced mean sitting DBP by 4.5 mm Hg (P , .01). Verapamil SR (240 mg/day) decreased mean sitting DBP by 4.3 mm Hg (P , .01). The combination therapy reduced mean sitting DBP by 8.1 mm Hg (P , .01). In the combination group, an additional significant (P , .01) reduction in sitting DBP was realized: 3.6 mm Hg more than trandolapril alone and 3.8 mm Hg more than verapamil alone. During the titration weeks that preceded the full dose combination, the addition of 120 and 180 mg of verapamil to 4 mg of trandolapril also resulted in statistically significant (P , .001) decreases in mean sitting DBP of 6.8 mm Hg and 8.5 mm Hg, respectively. Significant decreases (P , .01) in mean sitting systolic blood pressure (SBP) were also observed for
RESULTS Study Population A total of 631 patients, 54.5 6 11.5 years of age (range, 21 to 88 years) were enrolled at 38
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TABLE 2. BETWEEN-TREATMENT COMPARISONS OF MEAN TROUGH SITTING SYSTOLIC/DIASTOLIC BLOOD PRESSURE AT END POINT
Treatment Placebo 4 mg Trandolapril 240 mg Verapamil SR 4/240 combination
Number of Patients
End Point Difference 6 SD* (treatment v double-blind placebo) (mm Hg)
P (treatment v placebo)
P (combination v monotherapy)
152 155 155 163
— 29.0 6 2.0/24.5 6 0.8 28.0 6 1.9/24.3 6 0.8 212.9 6 1.9/28.1 6 0.8
— ,.01 ,.01 ,.01
— — — ,.01
* Based on adjusted mean.
the three active treatment groups compared with placebo. The decrease in sitting SBP for the combination group was greater than the decreases observed for either monotherapy. A subgroup analysis of blood pressure effect by race was not performed because the number of black patients (71 patients, 11%) was too small to draw meaningful conclusions. Heart rate, as determined by supine pulse measurements, was not affected by the addition of verapamil SR to trandolapril. At end point, the overall responder rate was significantly greater for all active treatment groups compared with placebo (P , .01) (Figure 2). The combination therapy had a significantly greater percentage of responders compared with either trandolapril or verapamil administered as monotherapy. Trough-to-peak sitting DBP ratios for the 4 mg of trandolapril and 4/240 combination groups were greater than 0.5 (0.75 and 0.67, respectively) at end point. The trough-to-peak ratio for the 240 mg of verapamil SR group was 0.47. Adverse Events All 631 enrolled patients were included in the evaluation of safety. There were no
statistically significant differences between the treatment groups with respect to the proportion of patients having adverse events during the double-blind phase of the study: placebo 44%, trandolapril 45%, verapamil 50%, and combination therapy 46%. All adverse events reported by .3% of the patients during the double-blind phase are shown in Table 3. Adverse events common to ACE inhibitors (eg, cough and rash) and calcium channel antagonists (eg, constipation and headache)1,10 were reduced, although not significantly, with combination therapy. DISCUSSION Up to 50% of hypertensive patients do not achieve goal blood pressure with monotherapy and may require combination therapy to achieve adequate hypertensive control.2 If combination therapy is warranted, it is recommended that the antihypertensive agents have different modes of action so an additive, and possibly synergistic, effect can be obtained.3 However, not all studies have shown additive results with combination therapy.11–13 ACE inhibitors and calcium channel blockers are recognized as initial therapies for
FIGURE 2. Percentage of responders (sitting DBP ,90 mm Hg or a decrease in sitting DBP of $10 mm Hg at end point compared with baseline). *Statistically significant difference v placebo, P , .01; † Statistically significant difference v monotherapies (based on either respondent criteria), P , .01.
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TABLE 3. ALL ADVERSE EVENTS REPORTED BY >3% OF PATIENTS DURING DOUBLE-BLIND TREATMENT PHASE Percentage of Patients Adverse Event
Placebo (n 5 152)
4 mg Trandolapril (n 5 159)
240 mg Verapamil SR (n 5 157)
Any Dose Combination (n 5 163)
Headache URT infection Cough Dizziness Fatigue Chest pain Joint pain Constipation Diarrhea URT congestion Nausea Abdominal pain/cramps Edema Rash
10.5% 7.9% 2.6% 2.6% 2.6% 0.7% 0.7% 1.3% 1.3% 3.3% 0.7% 1.3% 3.3% 1.3%
10.7% 5.7% 7.5% 2.5% 3.1% 0.6% 1.3% 0.6% 3.1% 2.5% 3.1% 3.1% 1.3% 3.1%
12.1% 8.9% 0.6% 3.8% 1.3% 2.5% 0 3.8% 0.6% 0.6% 1.3% 0 1.3% 1.3%
6.7% 6.1% 5.5% 4.3% 3.7% 3.7% 3.7% 2.5% 2.5% 1.8% 1.2% 0.6% 0.6% 0
URT, upper respiratory tract.
essential hypertension.1,10 These two classes have differing mechanisms of action and when used in combination they have an additive antihypertensive effect.3,4 This present study confirms the effectiveness of trandolapril and verapamil SR, administered alone and in combination, for the treatment of essential mild-to-moderate hypertension. Either monotherapy was statistically superior to placebo in reducing sitting DBP and SBP. Combination therapy was significantly more effective in lowering blood pressure than either trandolapril or verapamil SR administered alone; this decrease in blood pressure in the combination group was additive. There was also a significantly greater proportion of responders in the combination group than in either of the monotherapy groups. Antihypertensive therapy should lower arterial blood pressure throughout a 24-h period. The US Food and Drug Administration has mandated that an antihypertensive drug should retain at least 50% of its antihypertensive efficacy at peak and at the end of the dosing interval (at trough).14 Consequently, the trough-to-peak ratio can be considered a means of measuring how effective an antihypertensive agent is in maintaining adequate blood pressure control over a 24-h period. Given the sustained duration of action of both trandolapril and verapamil SR in monotherapy, it is not surprising that their combination resulted in a high trough-to-peak ratio in the present study. The sitting DBP trough-to-peak ratio for the trandolapril monotherapy and the combination groups was .50%, satisfying the trough-to-peak ratio recommended by the US Food and Drug Administration and supporting once a day dosing.
All treatments were safe and well tolerated. In general, the incidence of adverse events was similar on trandolapril/verapamil combination therapy to that with the individual monotherapies. When the incidence of adverse events is corrected (adverse events divided by DBP) for the reductions in DBP observed (trandolapril, 24.5 mm Hg; verapamil SR, 24.3 mm Hg; combination of verapamil SR and trandolapril, 28.1 mm Hg), the benefit of combination therapy is even more pronounced. Thus, for a given decrease in DBP, combinations of drugs with different modes of action, as suggested in the fifth report of the Joint National Committee,1 do minimize the adverse events of individual components. In summary, the data presented here showed that the combination of verapamil SR and trandolapril has an additive effect on lowering blood pressure compared with either agent administered alone. The combination was well tolerated and maintained adequate blood pressure control throughout a 24-h time period. These features make the combination of verapamil SR and trandolapril useful for the treatment of mild-tomoderate essential hypertension. ACKNOWLEDGMENTS We thank Beverly A. Novrit and Edward B. Kirsten, PhD (Knoll Pharmaceutical Company), for their assistance with the manuscript.
REFERENCES 1.
Joint National Committee: The fifth report of the Joint National Committee on detection, evaluation, and treatment of high blood pressure (JNC V). Arch Intern Med 1993;153:154 –183.
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2.
Chobanian AV: Antihypertensive therapy in evolution. N Engl J Med 1986;314:1701–1702.
3.
Messerli FH: Combination antihypertensive therapy, in Messerli FH (ed): The ABC’s of Antihypertensive Therapy. New York, Raven Press, 1994, pp 247–260.
4.
Frishman WH, Ram CVS, McMahon FG, et al: Comparison of amlodipine and benazepril monotherapy to amlodipine plus benazepril in patients with systemic hypertension: a randomized, double-blind, placebocontrolled, parallel-group study. The Benazepril/ Amlodipine Study Groups. J Clin Pharmacol 1995;35: 1060 –1066.
5.
Salvetti A, Innocenti PF, Iardella M, et al: Captopril and nifedipine interactions in the treatment of essential hypertensives: a crossover study. J Hypertens 1987; 5(suppl 4):S139 –S142.
6.
Singer DR, Markandu ND, Shore AC, MacGregor GA: Captopril and nifedipine in combination for moderate to severe essential hypertension. Hypertension 1987;9: 629 – 633.
7.
Steiner G, Pauly NC, for the Investigator Study Group: Comparison of the efficacy and safety of trandolapril and nifedipine SR in mild-to-moderate hypertension. J Cardiovasc Pharmacol 1994;23:S81–S85.
8.
Kaplan NM: Antihypertensive therapy to maximally reduce coronary risk. Am Heart J 1993;125:1487–1493.
9.
Lenfant B, Mouren M, Bryce T, et al: Trandolapril: pharmacokinetics of single oral doses in healthy male volunteers. J Cardiovasc Pharmacol 1994;23(suppl 4): S38 –S43.
10.
Guidelines for the management of mild hypertension: memorandum from a WHO/ISH meeting. J Hypertens 1989;7:689 – 693.
11.
MacGregor GA, Markandu ND, Smith SJ, Sagnella GA: Captopril: contrasting effects of adding hydrochlorothiazide, propranolol, or nifedipine. J Cardiovasc Pharmacol 1985;7:S82–S87.
12.
Frishman WH, Landau A, Cretkovic A: Combination drug therapy with calcium-channel blockers in the treatment of systemic hypertension. J Clin Pharmacol 1993;33:752–755.
13.
Helgeland A, Strommen R, Hagelund CH, Tretli S: Enalapril, atenolol, and hydrochlorothiazide in mild to moderate hypertension. A comparative multicentre
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study in general practice in Norway. Lancet 1986;872– 875. 14.
Division of Cardio-Renal Drugs Products, Food and Drug Administration: Proposed Guidelines for the Clinical Evaluation of Antihypertensive Drugs. US Department of Health and Human Services, Rockville, MD, 1988.
APPENDIX Principal Investigators of the Trandolapril/Verapamil Study Group: Wombolt D, MD, Norfolk, VA; Nash D, MD, Syracuse, NY; Allen J, MD, White Memorial Medical Center, Los Angeles, CA; Lonigro A, MD, St. Louis University Medical Center, St. Louis, MO; Gradman A, MD, West Penn Hospital, Pittsburgh, PA; Cornette G, MD, University Clinical Research, Kansas City, MO; Adelglass J, MD, Carrollton, TX; Ginsberg D, MD, Harleysville, PA; O’Reilly T, MD, Puget Sound Medical Investigators, Olympia, WA; Gray J, Houston, TX; Cutler N, MD, California Clinical Trials, Beverly Hills, CA; Littlejohn T, MD, Piedmont Research Associates, Winston-Salem, NC; Ryan M, MD, Internal Medical Research, Portland, OR; Yellen L, MD, Cardiology Associates Medical Group of East San Diego, Inc, San Diego, CA; Benz J, MD, Cedar Rapids, IA; Bittar N, MD, University of Wisconsin-Madison Center for Health Sciences, Madison, WI; Jain A, MD, G McMahon Clinical Research Center, New Orleans, LA; Papedemetriou V, MD, VA Medical Center, Washington, DC; Gilderman L, MD, Pembroke Pines, FL; Boyden T, MD, Department of Veterans Affairs Medical Center, Tucson, AZ; Felicetta J, MD, Carl T Hayden VA Medical Center, Phoenix, AZ; Glasser S, MD, University of Southern Florida, Tampa, FL; Goldstein R, MD, Tampa, FL; Mitchell W, MD, New Mexico Medical Group, Albuquerque, NM; Rosen J, MD, Coral Gables, FL; Snyder F, MD, Lovelace Scientific Resources, Albuquerque, NM; DeQuattro V, MD, USC School of Medicine, Los Angeles, CA; Weber M, MD, Research Medical Center, Long Beach, CA; Applegate W, MD, University of Tennessee, Memphis, TN; Guthrie R, MD, UHC, Columbus, OH; Sorenson J, MD, Southwest Medical Associates, Las Vegas, NV; Shook M, MD, Health and Science Research, Inc, Delray Beach, FL; Adolphe A, MD, Georgia Professional Gardens, Albuquerque, NM; Angelo J, MD, New Orleans, LA; Jaffe C, MD, Vista, CA; Messerli F, Ochsner Medical Institutions, New Orleans, LA; Frishman W, MD, Albert Einstein Hospital, Bronx, NY; Stafford J, MD, Lincoln Medical Center, St Joseph, MI.
1998;11:322–327
Effects of Verapamil and Trandolapril in the Treatment of Hypertension Franz Messerli, William H. Frishman, and William J. Elliott, for the Trandolapril Study Group*
The combination of an angiotensin converting enzyme inhibitor with a calcium antagonist has become a common way of treating patients with essential hypertension who respond insufficiently to monotherapy. This double-blind, randomized, parallel, placebo-controlled, multicenter, outpatient study evaluated the antihypertensive efficacy and safety of a calcium antagonist (verapamil SR) and an angiotensin converting enzyme inhibitor (trandolapril) in patients with mild-to-moderate (stages I and II) essential hypertension. Six hundred thirty-one patients were enrolled in this 10-week study. After a 4-week single-blind placebo phase, patients received one of the following daily dosage regimens in a double-blind fashion for 6 weeks: placebo, 4 mg of trandolapril, 240 mg of verapamil SR, or a combination of 4 mg of trandolapril and 240 mg of verapamil SR. Trough sitting diastolic blood pressure was lowered by 4.5 mm Hg, 4.3 mm Hg, and 8.1 mm Hg more than placebo in the trandolapril, verapamil SR, and combination groups,
A
respectively. In the combination group, sitting diastolic blood pressure was significantly lowered (P < .01) by 3.6 mm Hg more than in the trandolapril group and by 3.8 mm Hg more than in the verapamil SR group. An analysis of the troughto-peak ratio for sitting diastolic blood pressure revealed values of 0.75 and 0.67, for the 4-mg trandolapril and the combination groups, respectively, at end point. The overall incidence of adverse reactions was similar for all treatment groups. In this study the combination of an angiotensin converting enzyme inhibitor and calcium antagonist was well tolerated and more effective than either agent administered alone for the treatment of mild-to-moderate essential hypertension. Am J Hypertens 1998;11:322–327 © 1998 American Journal of Hypertension, Ltd. KEY WORDS:
Calcium antagonists, angiotensin converting enzyme inhibitors, combination therapy, drug effects, side effects.
s many as 50% of patients with uncomplicated mild-to-moderate (stages I and II)1 essential hypertension require two or more drugs for adequate blood pressure control.2 The need for combination therapy is based on increasing antihypertensive efficacy and the possibility of diminishing the adverse events associated with
high dose monotherapy. The Joint National Committee has stated that ‘‘combining antihypertensive drugs with different modes of action will often allow smaller doses of drugs to be used to achieve control, thereby minimizing the potential for dose-dependent side effects.’’1 Thus, combining two antihypertensive agents may enhance antihypertensive efficacy and may re-
Received September 18, 1996. Accepted September 29, 1997. From the Division of Hypertension, Ochsner Medical Institutions (FM), New Orleans, Louisiana; Department of Medicine, Division of Cardiology, Hospital of the Albert Einstein College of Medicine (WHF), Bronx, New York; and Department of Preventive Medicine, Rush Presbyterian-St Luke’s Medical Center (WJE), Chicago, Illinois.
This study was supported in part by a Research Grant from Knoll Pharmaceutical Company, Mt. Olive, New Jersey. * A list of principal investigators appears in the Appendix. Address correspondence and reprint requests to Franz Messerli, MD, Division of Hypertension, Ochsner Medical Institutions, 1514 Jefferson Highway, New Orleans, LA 70155.
© 1998 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
0895-7061/98/$19.00 PII S0895-7061(97)00466-4
AJH–MARCH 1998 –VOL. 11, NO. 3, PART 1
EFFICACY OF TRANDOLAPRIL/VERAPAMIL COMBINATION
FIGURE 1. Diagram of study protocol.
duce the incidence of adverse reactions because it is possible to use lower doses of each individual drug to achieve blood pressure control.3 The combination of a calcium antagonist with an angiotensin converting enzyme (ACE) inhibitor has become an important antihypertensive treatment option. Recent investigations have shown a greater reduction in blood pressure when ACE inhibitors are combined with a calcium antagonist.4 –7 In addition, both of these drug classes are well tolerated, have few side effects,4 –7 and do not adversely affect concomitant metabolic abnormalities.8 The multicenter study described here was designed to assess efficacy and safety of the combination of a heart rate-lowering calcium antagonist (verapamil SR) and a long-acting ACE inhibitor (trandolapril). METHODS Study Design After a 4-week single-blind placebo phase, patients were randomly assigned in a doubleblind fashion to one of four treatment groups: placebo once daily, trandolapril 4 mg once daily, verapamil SR 240 mg once daily, or a combination of 4 mg of trandolapril and 240 mg of verapamil SR once daily for 6 weeks (Figure 1). Patients randomized to the combination group received 120 mg and 180 mg of verapamil daily (in addition to 4 mg of trandolapril) during the first and second weeks of double-blind therapy, respectively, then 240 mg daily for the remaining 4 weeks. Patients were instructed to take study medications with food each morning for the duration of the study. All unused medication was returned at each visit for compliance monitoring. Study Population A total of 631 patients, aged 21 years or older, were enrolled in this multicenter investigation. All patients had mild-to-moderate essential hypertension, defined as diastolic blood pressure (DBP) of 95 to 114 mm Hg, after 4 weeks of singleblind treatment with placebo. The study protocol was approved by all Institutional Review Committees and
323
informed consent forms were signed by all participants. Women were excluded from the study if they were pregnant, lactating, or sexually active and of childbearing potential and not using an adequate method of contraception. Also excluded were patients who had any of the following: any form of hypertension other than mild-to-moderate essential hypertension, or history or evidence of malignant, accelerated, or severe hypertension; cerebrovascular accident, convulsive disorder or episode of hypertensive encephalopathy within the previous year; history of myocardial infarction within the previous 3 months; clinically significant congestive heart failure or suspicion or evidence of serious cardiac decompensation; severe bradycardia, clinically significant cardiac dysrhythmia, evidence of sinus node dysfunction, abnormal sinoatrial, atrioventricular (AV) or intraventricular conduction abnormalities; first, second, or third degree AV block; clinically significant medical conditions that may have interfered with study drug absorption, metabolism, or excretion (eg, renal or hepatic failure); known allergy or hypersensitivity to ACE inhibitors or calcium channel blockers; a history of chronic substance abuse or dependence within 2 years preceding study entry; or donated blood within 1 month preceding study entry. Patients were not enrolled if they needed concomitant medications such as diuretics and other antihypertensive agents, antiarrhythmic drugs, digitalis glycosides, monoamine oxidase inhibitors, psychotropic drugs, nonsteroidal antiinflammatory drugs or analgesics, or any medications known to affect blood pressure. Other reasons for exclusion were participation in a clinical trial involving another investigational drug within 30 days preceding study entry; use of any antihypertensive medications within 4 weeks or spironolactone within 6 weeks of projected entry into the double-blind period of the study or previous treatment with trandolapril. Assessments Blood pressure was measured before the morning dose with a standard mercury sphygmomanometer and an appropriately sized cuff. Measurements were taken every week during the 4-week placebo run-in phase and at the end of weeks 5, 6, 8, and 10 of the double-blind phase. Measurements taken at week 4 of the placebo phase were considered baseline for the rest of the study. During the double-blind phase, both peak and trough blood pressure and heart rate measurements were recorded. During the doubleblind period, blood pressures were measured at ‘‘trough,’’ just before dosing, and approximately 4 to 6 hours after administration, which coincides with peak plasma trandolapril concentrations and peak effect.9 Sitting blood pressure and heart rate were calculated as the mean of three consecutive measurements that
324
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TABLE 1. PATIENT DEMOGRAPHICS AND BASELINE BLOOD PRESSURE DATA Treatment Patient Demographics/Characteristics Sex Male Female Race Black Oriental White Age (yr) Weight (lb) Duration of hypertension (yr) Sitting SBP (mm Hg) Sitting DBP (mm Hg)
Placebo (n 5 152)
4 mg Trandolapril (n 5 159)
103 49 15 3 134 53.8 192.8 9.7 153.6 6 13.4 100.5 6 4.5
106 53 18 3 138 54.3 188.9 8.7 151.8 6 14.8 101.3 6 5.0
240 mg Verapamil SR (n 5 157)
4/240 Combination (n 5 163)
96 61
96 67
23 1 133 53.8 191.0 9.1 151.1 6 14.6 100.8 6 4.7
15 2 146 56.1 193.3 9.6 152.3 6 14.5 101.4 6 5.3
The mean 6 SD is provided as appropriate. DBP, diastolic blood pressure; SBP, systolic blood pressure.
had been obtained at 2-min intervals after the patient had rested in a sitting position for 5 min. The main efficacy measure was a reduction in sitting DBP observed immediately before the administration of the next dose (trough). Satisfactory therapeutic response was defined as a reduction from baseline in average sitting DBP to ,90 mm Hg or a $10 mm Hg decrease from baseline at end point. End point was defined as the end of the double-blind phase or the last visit during which the patient received doubleblind medication. Adverse experiences, as well as pre- versus posttreatment results of physical examinations and laboratory tests, were included in the safety evaluation.
study sites (401 men, 230 women; 551 white, 71 black, and 9 oriental). There were no significant differences between the treatment groups for any baseline characteristic (Table 1). Of the 631 patients enrolled, 581 completed the 6-week double-blind treatment phase. Thirteen (9%) patients receiving placebo, 19 (12%) patients receiving trandolapril, 9 (6%) patients receiving verapamil, and 9 (6%) patients receiving the combination discontinued before completion of the study. For the patients who discontinued, adverse reactions (40%) and unsatisfactory therapeutic response (24%) represent the main reasons for discontinuation across all treatment groups.
Statistical and Analytical Methods Analyses of efficacy were performed on an intention-to-treat basis. Comparisons of mean blood pressures at end point were carried out between the treatment groups and placebo and between the combination group and its monotherapies using a general linear model approach. The model included the baseline values as a covariate and terms for investigator, treatment, and baseline by treatment interaction. Comparisons between the treatment groups and placebo were performed on the adjusted means; comparisons between the combination and its monotherapies were performed using Snappin’s T5 test. The proportion of responders was calculated and compared between treatment groups using the x2 test for proportions. All statistical tests were two-sided and P # .05 was considered statistically significant. Means 6 SD are reported.
Efficacy The end point analysis of efficacy included the 581 patients who completed the 6-week doubleblind treatment phase, plus 44 patients who discontinued treatment at an earlier double-blind week. All active treatment groups significantly lowered mean sitting DBP at trough as compared with placebo (Table 2). Trandolapril (4 mg/day) reduced mean sitting DBP by 4.5 mm Hg (P , .01). Verapamil SR (240 mg/day) decreased mean sitting DBP by 4.3 mm Hg (P , .01). The combination therapy reduced mean sitting DBP by 8.1 mm Hg (P , .01). In the combination group, an additional significant (P , .01) reduction in sitting DBP was realized: 3.6 mm Hg more than trandolapril alone and 3.8 mm Hg more than verapamil alone. During the titration weeks that preceded the full dose combination, the addition of 120 and 180 mg of verapamil to 4 mg of trandolapril also resulted in statistically significant (P , .001) decreases in mean sitting DBP of 6.8 mm Hg and 8.5 mm Hg, respectively. Significant decreases (P , .01) in mean sitting systolic blood pressure (SBP) were also observed for
RESULTS Study Population A total of 631 patients, 54.5 6 11.5 years of age (range, 21 to 88 years) were enrolled at 38
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TABLE 2. BETWEEN-TREATMENT COMPARISONS OF MEAN TROUGH SITTING SYSTOLIC/DIASTOLIC BLOOD PRESSURE AT END POINT
Treatment Placebo 4 mg Trandolapril 240 mg Verapamil SR 4/240 combination
Number of Patients
End Point Difference 6 SD* (treatment v double-blind placebo) (mm Hg)
P (treatment v placebo)
P (combination v monotherapy)
152 155 155 163
— 29.0 6 2.0/24.5 6 0.8 28.0 6 1.9/24.3 6 0.8 212.9 6 1.9/28.1 6 0.8
— ,.01 ,.01 ,.01
— — — ,.01
* Based on adjusted mean.
the three active treatment groups compared with placebo. The decrease in sitting SBP for the combination group was greater than the decreases observed for either monotherapy. A subgroup analysis of blood pressure effect by race was not performed because the number of black patients (71 patients, 11%) was too small to draw meaningful conclusions. Heart rate, as determined by supine pulse measurements, was not affected by the addition of verapamil SR to trandolapril. At end point, the overall responder rate was significantly greater for all active treatment groups compared with placebo (P , .01) (Figure 2). The combination therapy had a significantly greater percentage of responders compared with either trandolapril or verapamil administered as monotherapy. Trough-to-peak sitting DBP ratios for the 4 mg of trandolapril and 4/240 combination groups were greater than 0.5 (0.75 and 0.67, respectively) at end point. The trough-to-peak ratio for the 240 mg of verapamil SR group was 0.47. Adverse Events All 631 enrolled patients were included in the evaluation of safety. There were no
statistically significant differences between the treatment groups with respect to the proportion of patients having adverse events during the double-blind phase of the study: placebo 44%, trandolapril 45%, verapamil 50%, and combination therapy 46%. All adverse events reported by .3% of the patients during the double-blind phase are shown in Table 3. Adverse events common to ACE inhibitors (eg, cough and rash) and calcium channel antagonists (eg, constipation and headache)1,10 were reduced, although not significantly, with combination therapy. DISCUSSION Up to 50% of hypertensive patients do not achieve goal blood pressure with monotherapy and may require combination therapy to achieve adequate hypertensive control.2 If combination therapy is warranted, it is recommended that the antihypertensive agents have different modes of action so an additive, and possibly synergistic, effect can be obtained.3 However, not all studies have shown additive results with combination therapy.11–13 ACE inhibitors and calcium channel blockers are recognized as initial therapies for
FIGURE 2. Percentage of responders (sitting DBP ,90 mm Hg or a decrease in sitting DBP of $10 mm Hg at end point compared with baseline). *Statistically significant difference v placebo, P , .01; † Statistically significant difference v monotherapies (based on either respondent criteria), P , .01.
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TABLE 3. ALL ADVERSE EVENTS REPORTED BY >3% OF PATIENTS DURING DOUBLE-BLIND TREATMENT PHASE Percentage of Patients Adverse Event
Placebo (n 5 152)
4 mg Trandolapril (n 5 159)
240 mg Verapamil SR (n 5 157)
Any Dose Combination (n 5 163)
Headache URT infection Cough Dizziness Fatigue Chest pain Joint pain Constipation Diarrhea URT congestion Nausea Abdominal pain/cramps Edema Rash
10.5% 7.9% 2.6% 2.6% 2.6% 0.7% 0.7% 1.3% 1.3% 3.3% 0.7% 1.3% 3.3% 1.3%
10.7% 5.7% 7.5% 2.5% 3.1% 0.6% 1.3% 0.6% 3.1% 2.5% 3.1% 3.1% 1.3% 3.1%
12.1% 8.9% 0.6% 3.8% 1.3% 2.5% 0 3.8% 0.6% 0.6% 1.3% 0 1.3% 1.3%
6.7% 6.1% 5.5% 4.3% 3.7% 3.7% 3.7% 2.5% 2.5% 1.8% 1.2% 0.6% 0.6% 0
URT, upper respiratory tract.
essential hypertension.1,10 These two classes have differing mechanisms of action and when used in combination they have an additive antihypertensive effect.3,4 This present study confirms the effectiveness of trandolapril and verapamil SR, administered alone and in combination, for the treatment of essential mild-to-moderate hypertension. Either monotherapy was statistically superior to placebo in reducing sitting DBP and SBP. Combination therapy was significantly more effective in lowering blood pressure than either trandolapril or verapamil SR administered alone; this decrease in blood pressure in the combination group was additive. There was also a significantly greater proportion of responders in the combination group than in either of the monotherapy groups. Antihypertensive therapy should lower arterial blood pressure throughout a 24-h period. The US Food and Drug Administration has mandated that an antihypertensive drug should retain at least 50% of its antihypertensive efficacy at peak and at the end of the dosing interval (at trough).14 Consequently, the trough-to-peak ratio can be considered a means of measuring how effective an antihypertensive agent is in maintaining adequate blood pressure control over a 24-h period. Given the sustained duration of action of both trandolapril and verapamil SR in monotherapy, it is not surprising that their combination resulted in a high trough-to-peak ratio in the present study. The sitting DBP trough-to-peak ratio for the trandolapril monotherapy and the combination groups was .50%, satisfying the trough-to-peak ratio recommended by the US Food and Drug Administration and supporting once a day dosing.
All treatments were safe and well tolerated. In general, the incidence of adverse events was similar on trandolapril/verapamil combination therapy to that with the individual monotherapies. When the incidence of adverse events is corrected (adverse events divided by DBP) for the reductions in DBP observed (trandolapril, 24.5 mm Hg; verapamil SR, 24.3 mm Hg; combination of verapamil SR and trandolapril, 28.1 mm Hg), the benefit of combination therapy is even more pronounced. Thus, for a given decrease in DBP, combinations of drugs with different modes of action, as suggested in the fifth report of the Joint National Committee,1 do minimize the adverse events of individual components. In summary, the data presented here showed that the combination of verapamil SR and trandolapril has an additive effect on lowering blood pressure compared with either agent administered alone. The combination was well tolerated and maintained adequate blood pressure control throughout a 24-h time period. These features make the combination of verapamil SR and trandolapril useful for the treatment of mild-tomoderate essential hypertension. ACKNOWLEDGMENTS We thank Beverly A. Novrit and Edward B. Kirsten, PhD (Knoll Pharmaceutical Company), for their assistance with the manuscript.
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APPENDIX Principal Investigators of the Trandolapril/Verapamil Study Group: Wombolt D, MD, Norfolk, VA; Nash D, MD, Syracuse, NY; Allen J, MD, White Memorial Medical Center, Los Angeles, CA; Lonigro A, MD, St. Louis University Medical Center, St. Louis, MO; Gradman A, MD, West Penn Hospital, Pittsburgh, PA; Cornette G, MD, University Clinical Research, Kansas City, MO; Adelglass J, MD, Carrollton, TX; Ginsberg D, MD, Harleysville, PA; O’Reilly T, MD, Puget Sound Medical Investigators, Olympia, WA; Gray J, Houston, TX; Cutler N, MD, California Clinical Trials, Beverly Hills, CA; Littlejohn T, MD, Piedmont Research Associates, Winston-Salem, NC; Ryan M, MD, Internal Medical Research, Portland, OR; Yellen L, MD, Cardiology Associates Medical Group of East San Diego, Inc, San Diego, CA; Benz J, MD, Cedar Rapids, IA; Bittar N, MD, University of Wisconsin-Madison Center for Health Sciences, Madison, WI; Jain A, MD, G McMahon Clinical Research Center, New Orleans, LA; Papedemetriou V, MD, VA Medical Center, Washington, DC; Gilderman L, MD, Pembroke Pines, FL; Boyden T, MD, Department of Veterans Affairs Medical Center, Tucson, AZ; Felicetta J, MD, Carl T Hayden VA Medical Center, Phoenix, AZ; Glasser S, MD, University of Southern Florida, Tampa, FL; Goldstein R, MD, Tampa, FL; Mitchell W, MD, New Mexico Medical Group, Albuquerque, NM; Rosen J, MD, Coral Gables, FL; Snyder F, MD, Lovelace Scientific Resources, Albuquerque, NM; DeQuattro V, MD, USC School of Medicine, Los Angeles, CA; Weber M, MD, Research Medical Center, Long Beach, CA; Applegate W, MD, University of Tennessee, Memphis, TN; Guthrie R, MD, UHC, Columbus, OH; Sorenson J, MD, Southwest Medical Associates, Las Vegas, NV; Shook M, MD, Health and Science Research, Inc, Delray Beach, FL; Adolphe A, MD, Georgia Professional Gardens, Albuquerque, NM; Angelo J, MD, New Orleans, LA; Jaffe C, MD, Vista, CA; Messerli F, Ochsner Medical Institutions, New Orleans, LA; Frishman W, MD, Albert Einstein Hospital, Bronx, NY; Stafford J, MD, Lincoln Medical Center, St Joseph, MI.