Download Effects of Verapamil and Trandolapril in the Treatment of Hypertension

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
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
AJH–MARCH 1998 –VOL. 11, NO. 3, PART 1
MESSERLI ET AL
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
AJH–MARCH 1998 –VOL. 11, NO. 3, PART 1
EFFICACY OF TRANDOLAPRIL/VERAPAMIL COMBINATION
325
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.
326
AJH–MARCH 1998 –VOL. 11, NO. 3, PART 1
MESSERLI ET AL
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.