Efficacy, tolerability, and quality of life of losartan, alone or with hydrochlorothiazide, versus nifedipine GITS in patients with essential hypertension

CLINICAL THERAPEUTICSVVOL. 18, NO. 3, 1996

Efficacy, Tolerability, and Quality of Life of Losartan, Alone or with Hydrochlorothiazide, Versus Nifedipine GITS in Patients with Essential Hypertension Matthew R. Weir, MD,’ Michelle Elkins, RN,2 Charles Liss, MS,3 Arthur J. Vrecenak, PhD,2 Eliuv Barr, MD,2 and Jonathan M. Edelmun, MD2 ‘Division of Ne p hrology and Clinical Research Unit, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, and 2Clinical Development Department, US Human Health, and 3BARDS, Merck Research Labs, Merck & Co., Inc., West Point, Pennsylvania

ABSTRACT A randomized, double-masked, parallelgroup, multicenter clinical trial was conducted to compare the efficacy, tolerability, and effects on quality of life associated with the angiotensin II receptor antagonist losartan, alone or with hydrochlorothiazide (HCTZ), and the dihydropyridine calcium channel blocker nifedipine gastrointestinal therapeutic system (GITS) in patients whose sitting diastolic blood pressure measurements were between 95 and 115 mm Hg, inclusive, while receiving placebo. Patients were randomized to receive either losartan or nifedipine GITS in a double-masked, double-dummy fashion. A 4-week placebo washout period established baseline untreated blood pressure measurements and was followed by

0149-2918/'96/$3.50

a 12-week active treatment period. Patients receiving losartan (n = 110) were initially given 50 mg once a day (QD) and could be titrated to losartan/I-ICTZ 50 mg/12.5 mg QD after 4 weeks followed by losartan/I-ICTZ 50 mg/25 mg QD after 8 weeks, as necessary. Patients in the nifedipine GITS group (n = 113) received 30 mg QD, which could be titrated to 60 mg QD after 4 weeks followed by 90 mg QD after 8 weeks. Medication was titrated upward as necessary to achieve a sitting trough diastolic blood pressure ~90 mm Hg. Efficacy, tolerability, and quality-oflife scores were assessed after 12 weeks of each therapy. Trough sitting diastolic blood pressure reductions after 4, 8, and 12 weeks of therapy were clinically comparable: losartan, -8.9, -11.6, and -12.7 mm Hg, respectively, and nifedipine

411

CLINICAL THERAPEUTICS@

GITS, -9.3, -11.0, and -11.1 mm Hg, respectively, with the mean reduction in sitting diastolic blood pressure at 12 weeks in the losartan group 1.6 mm Hg lower (95% confidence interval, 3.4 mm Hg lower to 0.3 mm Hg higher) than the mean reduction in sitting diastolic blood pressure in the nifedipine GITS group. Similarly, reductions in systolic blood pressure between the two treatment groups were comparable at all time points. The percentage of patients reaching the goal trough sitting diastolic blood pressure was comparable for the two treatment groups, with 74% of patients in the losartan regimen and 68% of patients in the nifedipine GITS regimen reaching the goal. Of patients reporting adverse events in the two groups (75 patients receiving losartan and 69 receiving nifedipine GITS), there was significantly more edema in the nifedipine GITS group (15% vs 4%; P = 0.005). Fourteen (12%) patients in the nifedipine GITS group were withdrawn due to an adverse event (eight of these were for edema). Six patients (5%) in the losartan group were withdrawn due to an adverse event (none of these patients had edema). There were significant differences in the patient-reported quality-of-life symptom bother inventory with respect to edema, with nifedipine GITS therapy causing significantly more bother due to edema in patients, regardless of whether that symptom was present at baseline (27% vs 9%; P = 0.0004). No statistically significant differences for bother due to the other symptoms in the inventory were noted. Of note, while the incidence of patientreported symptom bother due to edema in the nifedipine GITS group was 27%, the incidence of physician-reported drugrelated edema was 12%. This difference points to the need for improved physi-

412

cian-patient communication regarding adverse effects and their impact on patients’ quality of life. In conclusion, a regimen of losartan, when compared with a regimen of nifedipine GITS, provides comparable efficacy, and with respect to edema, superior tolerability, less bother to patients, and fewer therapy dropouts.

INTRODUCTION Because hypertension is an asymptomatic disease, the development of antihypertensive pharmacotherapy is accompanied by two significant challenges: drugs must be both highly efficacious and well tolerated, as patients must undergo therapy for many years. Several classes of antihypertensive drugs have been developed with varying mechanisms of action and consequently varying efficacy and tolerability profiles. An important target for antihypertensive therapy has been the renin-angiotensin-aldosterone system. This system plays a major role in influencing systemic arterial pressure through its effects on vascular tone and structure,’ renal sodium and water homeostasis, and sympathetic activating mechanisms.2 Because angiotensin II represents the major active component of this system, pharmacologic blockade of the effects of this hormone represents an ideal target for antihypertensive therapy. All known clinical effects of angiotensin II, including vasoconstriction, aldosterone release, renal tubular sodium reabsorption, increased thirst, and augmented catecholamine release,2 are mediated through the ATl-type angiotensin II receptor.3 Recently, losartan, the first of a new class of AT1 angiotensin II receptor antagonists, has been cleared for clinical use in the treatment of hypertension. Extensive clinical trials us-

M.R. WEIR ET AL.

ing losartan have verified its efficacy and tolerability.ti The dihydropyridine calcium channel blockers represent another class of antihypertensive agent that has been demonstrated to have important clinical efficacy in the treatment of hypertension. These agents reduce systemic arterial pressure, in part, through their ability to induce vasodilation and to facilitate natriuresis.‘~’ Since the usefulness of an antihypertensive medication depends on both the efficacy and tolerability of the agent, evaluation of various therapeutic regimens should consist of measurements of both of these variables. Whereas determination of the clinical efficacy of antihypertensive medications is relatively straightforward, assessment of tolerability or patient perception of a change in quality of life in response to administration of these agents is more complicated. Efforts have been made to design instruments that are able to measure the effects of antihypertensive therapy on patient quality of life and to detect differences in these measures between classes of antihypertensive agents.s9 Because many patients do not always fully respond to the initial level of administration of an antihypertensive medication, they may require dose escalation of that drug. Alternatively, physicians may elect to add a low dose of a second agent to achieve blood pressure-lowering goals. A recent clinical studylo has suggested that starting doses of two antihypertensive agents may provide similar efficacy with fewer adverse events than higher dose therapy with a single agent. The purpose of this study was to compare the efficacy of losartan, alone and with low doses of hydrochlorothiazide (HCTZ), with the dihydropyridine calcium channel blocker nifedipine gastrointestinal

therapeutic system (GITS) in the treatment of patients with stage I and II hypertension. For the purposes of the study, the two therapeutic regimens were hypothesized to be comparable. In addition, this study was designed to compare the impact of these two differing drug regimens on clinical adverse-event rates and patientreported quality-of-life assessments.

PATIENTS

AND METHODS

Study Design This was a randomized, doublemasked, parallel-group, multicenter clinical trial comparing the antihypertensive efficacy, tolerability, and quality-of-life effects of therapy with losartan 50 mg alone or with HCTZ 12.5 or 25 mg versus nifedipine GITS 30, 60, or 90 mg in patients with essential hypertension. The study included a 4-week placebo baseline period followed by a 1Zweek active treatment period.

Patient eligibility was established by a complete medical history, physical examination, and laboratory studies, including a complete blood count with serum electrolytes, blood urea nitrogen, creatinine, transaminases, alkaline phosphatase, urinalysis, and electrocardiogram. Men and women aged 21 years and older were eligible as long as there was no known drug hypersensitivity to the study medications. Other exclusionary criteria were significant cardiovascular, cerebrovascular, renal, or hepatic disease; recent myocardial infarction; or secondary hypertension. Also excluded were patients with clinically significant laboratory abnormalities

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CLINICAL TI-IJZRAPEUTICS”

above the established normal ranges. Women of childbearing potential were excluded unless they were using approved methods of contraception.

Study Procedures Before the placebo baseline period, patients were required to provide written informed consent, as approved by the institutional review board at each of the participating sites. In addition, patients completed a quality-of-life questionnaire and discontinued all antihypertensive medication. During the 4-week placebo baseline period, all patients received one tablet each of placebo matching losartan and nifedipine GITS daily. The patients were monitored every 2 weeks for vital signs and adverse experiences. Laboratory assessment was obtained after the 4week placebo period. No antihypertensive drugs, other than the study drugs, were allowed during the study. All blood pressure measurements were taken at trough (ie, 22 to 26 hours after the prior dose of medication). Blood pressures were measured in the sitting position after at least 5 minutes of rest. Three individual readings were obtained at lminute intervals and averaged to provide a mean trough value. Before beginning the study, clinic personnel responsible for obtaining blood pressure measurements were certified through a standardized training program according to the American Heart Association guidelines for the measurement of blood pressure.” Those patients with two mean trough sitting diastolic blood pressure measurements between 95 and 115 mm Hg, inclusive, at weeks 2 and 4 of the placebo baseline period that did not differ by more than 7 mm Hg, and with no exclusion cri-

414

teria, were considered eligible for entry into the active treatment period. At the end of the baseline period, patients were stratified by diastolic blood pressure (stratum I: sitting diastolic blood pressure, 95 to 105 mm Hg; stratum II: sitting diastolic blood pressure, 106 to 115 mm Hg). Patients were then randomized to receive either losartan or nifedipine GITS in a double-masked, double-dummy fashion. During the active treatment period, patients returned every 4 weeks for measurement of vital signs, safety monitoring, and qualityof-life determination. Controlled blood pressure was defined as mean trough sitting diastolic blood pressure <90 mm Hg. In patients whose blood pressures were not adequately controlled (ie, if the mean trough sitting diastolic blood pressure remained 290 mm Hg), their medication was titrated as follows: in the losartan group, patients initially received 50 mg once a day (QD), which could be titrated to losartan 50 mg plus HCTZ 12.5 mg QD after 4 weeks, followed by losartan 50 mg and HCTZ 25 mg QD after 8 weeks. Patients in the nifedipine GITS group initially received 30 mg QD, and treatment could be titrated to 60 mg QD after 4 weeks and 90 mg QD after 8 weeks. Regardless of regimen, for the first two steps of the titration, patients received two tablets (Cozaar@,* Hyzaar’s’,* Procardia XL@‘+30 mg or 60 mg, or their matched placebos). For patients receiving the highest doses in both regimens, the patients received three tablets (Cozaar, HCTZ 25 mg, Procardia XL 90 mg, or their matched placebos). All medication and matching

*Trademark: Merck & Co., Inc., West Point, Pennsylvania. +Trademark: Pratt Pharmaceuticals Division, Pfizer Inc., New York, New York.

M.R. WEIR ET AL.

placebo were taken at the same time of day, usually in the morning. At the conclusion of the active treatment period, a follow-up clinical examination, electrocardiogram, and laboratory safety assessment profile were obtained. Those patients with mean sitting diastolic blood pressure of 110 mm Hg or greater after 2 weeks of placebo were eligible for early randomization, provided that a repeat blood pressure measurement within 3 days confirmed the elevation. Patients with similarly elevated mean sitting diastolic blood pressure after 6 weeks of active therapy were eligible for accelerated titration, provided the elevation was confirmed 1 week later.

Statistical Analysis Baseline comparability of the two treatment groups with respect to demographic and clinical characteristics was assessed using Student’s r test and Fisher’s exact test. Changes in blood pressure and pulse were analyzed using the paired t test for within-group differences and analysis of variance (ANOVA) for between-group differences. The ANOVA model included terms for an overall mean, treatments, center, level of pretreatment diastolic blood pressure (stratum I: sitting diastolic blood pressure, 95 to 105 mm Hg; stratum II: sitting diastolic blood pressure, 106 to 115 mm Hg), and the interaction of treatments with centers and strata. The primary end point of the study was the change in mean trough sitting diastolic blood pressure from baseline to the end of the study. Comparisons were also made between treatment groups with respect to the number of patients who reached goal sitting diastolic blood pressure at study end. This goal was a sitting diastolic blood pressure

c90 mm Hg or a sitting diastolic blood pressure SO mm Hg and a reduction in sitting diastolic blood pressure of at least 10 mm Hg from baseline. The MantelHaenszel test was used in this comparison. A battery-of-scales questionnaire, composed of questions from previously validated questionnaires, was used to evaluate differences in quality of life.‘* Seven domains of health-related quality of life were included: symptom bother, overall health perceptions, psychologic well-being, social functioning, sleep disturbance, cognitive functioning, and sexual functioning. The symptom bother inventory, containing responses of “not at all,” “little,” “moderately,” “quite a bit,” or “extremely,” was used to assess changes in disease and in treatment-related complaints between baseline and weeks 4, 8, and 12. Items from the symptom inventory were analyzed individually. The percentage of patients who responded “not at all” or “little” to the first 31 items and “no” to the final item as opposed to the percentage of those who responded “moderately, ” “quite a bit,” or “extremely” to the first 31 items and “yes” to the final item was determined in each time period. Differences between treatment groups were compared using the chi-square test and within-group changes were analyzed via McNemar’s test. The symptoms included dry mouth, headaches, weakness in limbs, blurred vision, shortness of breath, swollen ankles, constipation, bad taste in mouth, feeling of burnt mouth, blocked or runny nose, nausea, rash on body, itching, cramps in legs, pain in joints or hands, shaky hands, racing heart, stomach pain, heartburn, sore throat, dry cough, sweating, wheezing, dry eyes, mouth ulcers, light sensitivity, cold hands or feet, noc-

415

CLINICAL THERAPEUTICS’

turia, diarrhea, flushing of face, heart pounding, and faintness. The symptoms of swollen ankles, headache, and flushing were emphasized. A Bonferroni correction for multiplicity was employed (alpha 50.02 for significance). For all other symptoms, treatment differences were considered significant at alpha 10.01. In addition, the domains of general health and sexual function were emphasized. A Bonferroni correction for multiplicity was used (alpha = 0.03) for comparing treatments with regard to these two domains. For four of the other six quality-of-life scales, differences between treatment groups were considered significant at an alpha level of 0.05. Quality-of-life indices were compared between treatment groups using an ANOVA model including treatment, studies, and their interaction. Likewise, within-group changes were analyzed using a paired t test. The incidences of adverse experiences, abnormal laboratory findings, clinically significant changes in physical examinations and electrocardiograms were all considered in the evaluation of the safety and tolerability of the two regimens. Differences in the overall incidence of adverse events were compared using Fisher’s exact test.

RESULTS Patients A total of 223 patients-110 treated with losartan alone and/or with HCTZ and 113 with nifedipine GITS-from 26 centers were entered into the study. The demographic and clinical characteristics of the patients are summarized in Table I. There were no significant differences with regard to the characteristics examined between the treatment groups at baseline.

416

Eighty-four percent of the patients were receiving some antihypertensive therapy the month before study entry; the most commonly used antihypertensive drugs were lisinopril (16%), HCTZ (13%), nifedipine (12%), and verapamil (10%). Nineteen (9%) of the 223 patients entered the active treatment phase before completing 4 weeks of baseline. Fifteen of these patients were randomized to the losartan group and 4 to the nifedipine GITS group resulting in a statistically significant difference (P = 0.008). Of the 223 patients who entered the treatment phase, 93% (102/110) of the losartan group and 81% (92/l 13) of the nifedipine GITS group completed all 12 weeks of therapy. More patients withdrew from the study in the nifedipine GITS treatment group (n = 21 [ 19%]) than from the losartan group (n = 8 [7%]) (P = 0.012). The most common reason for withdrawal overall was adverse clinical experience (Table II).

Reductions in mean trough sitting diastolic blood pressure are illustrated in Table III and Figure 1. The data in Table III are divided into stratum I, stratum II, and all patients. The data in Figure 1 are for all patients. Almost identical blood pressure reductions occurred at all time periods, with the mean reduction in sitting diastolic blood pressure at 12 weeks in the losartan group 1.6 mm Hg lower (95% confidence interval, 3.4 mm Hg lower to 0.3 mm Hg higher) than the mean reduction in sitting diastolic blood pressure in the nifedipine GITS group. The number of patients requiring titration of their medication was similar in each group. In the losartan group, 41 patients

M.R. WEIR ET AL.

Table I. Patient demographic

and clinical characteristics.* Losartan f HCTZ+ (n = 110)

Nifedipine GITS (n = 113)

Age (y) (average f SD)

Male Female All Sex (%) Male Female Race (%) Black White Hispanic Previous treatment (%) Yes No Duration of hypertension (y) (average f SD)

54k 11 52* 11 53* 11

54 f 12 54 f 9 54* 11

63 (57) 47 (43)

71 (63) 42 (37)

21 (19) 86 (78) 3 (3)

17 (15) 91 (81) 5 (4)

107 (97)

109 (96) 4 (4) 11*9

3 (3) 9*9

HCTZ = hydrochlorothiazide; GITS = gastrointestinal therapeutic system. *There were no statistically significant differences between the two groups. +Losartan with or without HCTZ.

pine GITS group, 43 patients (38%) did not require titration and thus remained on 30 mg QD, 38 (34%) required titration to 60 mg QD, and 32 (28%) required titration to 90 mg QD (Figure 2).

(37%) did not require titration and remained on losartan 50 mg alone, 35 (32%) required titration to 50 mg and 12.5 mg HCTZ, and 34 (3 1%) required titration to 50 mg and 25 mg HCTZ. In the nifedi-

Table II. Reasons for patient withdrawal

from the study.

Losartan f HCTZ (n = 110)

Reason for withdrawal Adverse clinical experience Lost to follow-up Other Adverse laboratory findings Therapy ineffective Total patient withdrawals

Nifedipine GITS (n = 113)

All (N = 223)

No.

%

No.

%

No.

%

P

6 0 1 0 1 8

5 0 1 0 1 7

14 4 2 1 0 21

12 4 2 1 0 19

20 4 3 1 1 29

9.0 2 1
NS NS NS NS NS 0.012

HCTZ = hydrochlorothiazide; GITS = gastrointestinal therapeutic system.

417

12

8

4

12

8

4

12

8

4

Nifedipine Losartan Nifedipine Losartan Nifedipine Losartan Nifedipine

LOSartan

Nifedipine

LOSXkUl

Nifedipine Losartan Nifedipine Losartan Nifedipine Losartan Nifedipine

LOStilUl

Treatment* 81 91 81 91 81 91 29 22 29 22 29 22 110 113 110 113 110 113

n 98.0 f 2.6 98.1 f 2.3 98.0 + 2.6 98.1 * 2.3 98.0 f 2.6 98.1 zt 2.3 109.0 f 2.6 107.7 f 2.5 109.0 f 2.6 107.7 + 2.5 109.0 f 2.6 107.7 zt 2.5 100.9 f 5.5 100.0 f 4.5 100.9 + 5.5 100.0 f 4.5 100.9 f 5.5 100.0 f 4.5

Mean f SD 81 89 81 89 81 89 29 22 29 22 29 22 110 111 110 111 110 111

n 89.1 zt 8.3 89.4 f 6.4 87.2 + 7.9 87.7 zt 7.6 86.6 * 7.9 87.8 f 7.0 99.8 f 7.8 95.8 zt 8.7 95.3 + 7.7 94.3 + 8.7 92.8 * 7.5 93.4 f 6.3 92.0 f 9.4 90.7 f 7.3 89.3 * 8.6 89.0 f 8.2 88.2 + 8.2 88.9 zt 7.2

Mean f SD 81 89 81 89 81 89 29 22 29 22 29 22 110 111 110 111 110 111

n -8.9 -8.7 -10.8 -10.5 -11.4 -10.3 -9.2 -12.0 -13.6 -13.4 -16.2 -14.3 -8.9 -9.3 -11.6 -11.0 -12.7 -11.1

f 7.5 + 5.9 + 7.6 + 7.6 f 8.0 f 6.9 zt 7.7 + 8.1 f 7.2 f 8.4 f 7.1 f 7.1 zt 7.5 f 6.5 f 7.6 +: 7.8 f 8.0 f 7.1

Mean f SD

Difference

0.35

0.64

0.78

0.03

0.83

0.21

0.66

0.84

0.61

P

‘Losartan

50 mg alone at week 4, alone or withhydrochlorothiazide (HCTZ) 12.5 mg at week 8, alone or with HCTZ 12.5 or 25 mg at week 12. Nifedipine system mg mg, mg mg mg, mg 60 or 90 at week 12. at week 4; 30 or 60 at week 8; 30 trointestinal therapeutic 30

All patients

II (DBP 106-115 mm Hg)

Strata I (DBP 95-105 mm Hg)

Week

Treated DBP

(DBP). Values are given as absolute mean A SD.

Baseline DBP

Table III. Reductions in trough sitting diastolic blood pressure

gas-

Y

$

E

Fs

4

Ft z 8

M.R. WEIR ET AL.

Baseline

Week 4

Week 8

Week 12

-18 -) Figure

1. Changes in mean trough sitting diastolic blood pressure (DBP) at weeks 4, 8, and 12 in patients receiving losartan (50 mg alone at week 4, alone or with hydrochlorothiazide [HCTZ] 12.5 mg at week 8, alone or with HCTZ 12.5 mg or 25 mg at week 12) or nifedipine gastrointestinal therapeutic system (GITS) (30 mg at week 4; 30 mg or 60 mg at week 8; 30 mg, 60 mg, or 90 mg at week 12).

Table IV and Figure 3 illustrate the reduction of mean trough sitting systolic blood pressure in each treatment group. The data in Table IV are also divided into stratum I, stratum II, and all patients; the data in Figure 3 are for all patients. There were no significant differences between the two treatment regimens in systolic blood pressure reduction. When response was evaluated based on the percentage of patients who achieved a sitting diastolic blood pressure ~90 mm Hg, 65 patients (59%) were successful in the losartan group compared with 60 patients (54%) in the nifedipine GITS group (P = NS). Additional patients who did not achieve goal of sitting diastolic blood pressure c90 mm Hg but who had achieved a reduction in sitting diastolic blood pressure 210 mm Hg from baseline included 17 patients in the losartan group (15%) and 15 patients in the nifedipine GITS group (13%) (P = NS). These overall response rates were comparable in several

subgroups of patients, including (1) patients whose pretreatment diastolic blood pressure was between 105 and 115 mm Hg (losartan group, 83% [24/29 total] vs nifedipine GITS group, 73% [ 16/22 total]; P = NS); (2) women (losartan group, 77% [36/47 total] vs nifedipine GITS group, 71% [29/41 total]; P = NS); and (3) blacks (losartan group, 81% [ 17/21 total] vs nifedipine GITS group, 76% [ 13/17 total]; P = NS). Overall, 74% of patients in the losartan group reached goal, as did 68% of patients in the nifedipine GITS group (P = NS) (Figure 4). The average sitting pulse in the two treatment groups at week 12 was not significantly different from baseline (data not shown).

Adverse Experiences Of’ the 223 patients entered into the active treatment period, 38% (85 patients) had adverse experiences during the placebo washout

419

R

0

12

8

4

12

8

4

Losartan Nifedipine Losartan Nifedipine Losartan Nifedipine Losartan Nifedipine Losartan Nifedipine Losartan Nifedipine Losartan Nifedipine Losartiln Nifedipine Losartan Nifedipine

Treatment* 81 91 81 91 81 91 29 22 29 22 29 22 110 113 110 113 110 113

n 147.7 + 14.1 148.4 + 13.4 147.7 f 14.1 148.4 f 13.4 147.7 & 14.1 148.4 f 13.4 163.4 zt 15.0 166.0 f 14.1 163.4 & 15.0 166.0 f 14.1 163.4 zt 15.0 166.0 f 14.1 151.8 * 15.9 151.8 + 15.2 151.8 f 15.9 151.8 + 15.2 151.8 zt 15.9 151.8 f 15.2

Mean&SD 81 89 81 89 81 89 29 22 29 22 29 22 110 111 110 111 110 111

n

n 81 89 81 89 81 89 29 22 29 22 29 22 110 111 110 111 110 111

Mean f SD 139.1 + 14.8 137.6 + 11.0 135.5 f 14.6 135.0 zt 13.5 135.2 + 15.5 135.7 + 12.8 150.9 f 17.9 150.7 f 13.0 143.6 -r-17.5 147.2 f 10.8 141.5 f 17.1 146.7 f 12.0 142.2 + 16.5 140.2 f 12.5 137.6 ? 15.7 137.4 + 13.8 136.9 -+ 16.1 137.9 f 13.4

Treated SBP

f 12.1 f 11.7 f 12.5 f 12.9 f 13.2 f 11.8 2 15.0 + 15.1 f 13.5 zt 13.0 EIC 11.9 +I 13.2 +- 13.0 zt 12.5 f 13.1 -14.5 f 13.1 -15.0 f 13.5 -14.0 zt 12.3

-8.6 -10.8 -12.2 -13.4 -12.5 -12.7 -12.4 -15.2 -19.8 -18.7 -21.9 -19.3 -9.6 -11.7 -14.2

Mean+SD

Difference

0.65

0.84

0.41

0.63

0.94

0.34

0.57

0.59

0.46

P

DBP = diastolic blood pressure. ‘Losartan 50 mg alone at week 4, alone or with hydrochlorothiazide (HCTZ) 12.5 mg at week 8, alone or with HCTZ 12.5 mg or 25 mg at week 12. Nifedipine gastrointestinal therapeutic system 30 mg at week 4; 30 mg or 60 mg at week 8; 30 mg, 60 mg, or 90 mg at week 12.

All patients

II (DBP 106-115 mm Hg)

12

8

4

Week

Baseline SBP

in trough sitting systolic blood pressure @BP). Values are given as absolute mean f SD.

Strata I (DBP 95-105 mm Hg)

Table IV. Reductions

F F 3

M.R. WEIR ET AL.

2 .P, z 3

n Losartan 50 mg

40 35 30 25 20 15

q Losartan 50 mg/HCTZ 12.5 mg n Lcsartan 50 mS/HCTZ 25 nICI q Nifedipine GITS 30 mg q Niiedipine GITS SO mg

$! 10 5 0

Nifedipine GITS 90 mg

Losartan

Nifedipine GITS

Figure 2. Distribution of treatments at the end of 12 weeks of therapy. GITS = gastrointestinal therapeutic system; HCTZ = hydrochlorothiazide.

Baseline

Week 4

Figure 3. Changes in mean trough sitting systolic blood pressure (SBP) at weeks 4, 8, and 12 in patients receiving losartan (50 mg alone at week 4, alone or with hydrochlorothiazide [HCTZ] 12.5 mg at week 8, alone or with HCTZ 12.5 mg or 25 mg at week 12) or nifedipine gastrointestinal therapeutic system (GITS) (30 mg at week 4; 30 mg or 60 mg at week 8; 30 mg, 60 mg, or 90 mg at week 12).

period. These events were evenly divided between the two treatment groups. The most common adverse experience during the placebo period was headache (11%). Approximately two thirds of the patients reported adverse events during active tmatment (Table V). Overall incidence of adverse events was similar in the two groups.

Headache, edema, and dizziness were the most commonly reported adverse events during this active treatment phase. Edema was signiticantly more common in the nifedipine GITS treatment group compared with the losartan group (15% vs 4%; P = 0.005). Drug-related edema was also significantly more common in the nifedipine GlTS tmat-

421

CLINICAL THERAPEUTICS’

bf’j @ , @$fzq Losartan (n = 110)

Nifedipine GITS (n = 113)

Figure 4. Percentage of patients reaching goal diastolic blood pressure (DBP) at week 12 in the losartan group (50 mg alone, with or without hydrochlorothiazide [HCTZ] 12.5 mg or 25 mg) and the nifedipine gastrointestinal therapeutic system (GITS) group (30 mg, 60 mg, or 90 mg). *Goal: Category I-DBP <90 mm Hg; Category II-DBP 290 mm Hg with 210 mm Hg decrease.

Table V. Summary

of adverse experiences

with an overall incidence Losartan (n = 110)

Drug-related adverse experience* Headache Edema Dizziness Asthenia/fatigue Patients with any adverse event Patients withdrawn due to an adverse event Patients with any drug-related adverse event* Patients withdrawn due to a drug-related adverse event*

of 2% or more. Nifedipine GITS (n = 113)

No.

%

No.

%

6 3 4 3 75 6 24 4

5 3 4 3 68 5 22 4

13 14 1 2 69 14 35 12

12 12+ 1 2 61 12 31 II

GITS = gastrointestinal

therapeutic system. *Considered possibly, probably, or definitely +P = 0.007.

drug related by tbe investigator.

ment group compared with the losartan group (12% vs 3%; P = 0.007). Twenty patients withdrew due to adverse experiences during the active treatment period, 14 (12%) in the nifedipine GITS group and 6 (5%) in the losartan group (P = NS). Of these, 12 (11%) were considered drug related in the nifedipine

422

GITS group and 4 (4%) drug related in the losartan group (P = NS). The most common overall reason for patient withdrawal was adverse experiences, and the most common adverse experience that led to withdrawal was edema (8 patients in the nifedipine GITS group and 0 patients in the losartan group; P = 0.007). A sta-

M.R. WEIR ET AL.

Table VI. Changes in symptom bother after 12 weeks of therapy (regardless the symptom was present at baseline). Losartau f HCTZ Symptom Edema Nocturia Runny nose Headache Faintness HCTZ = hydrochlorothiazide;

of whether

Nifedipine GITS

No.

%

No.

%

P

10 31 15 12 16

9 28 14 11 15

30 42 14 15 10

27 38 13 14 9

0.0004 0.116 1.000 0.545 0.296

GITS = gastrointestinal

tistically significantly higher incidence of upper respiratory tract infections was found in the losartan treatment group than in the nifedipine GITS group. However, none of the upper respiratory tract infections were considered by the investigators to be drug related. Eight percent of the study group had one or more adverse laboratory findings. These were evenly divided between the two treatment regimens, affecting nine patients in the losartan group and eight patients in the nifedipine GITS group. Quality of Life The battery-of-scales quality-of-life instrument was administered at baseline and after 4, 8, and 12 weeks of therapy. As outlined in Table VI, the five most commonly reported bothersome symptoms at week 12 for both treatments were: edema (40/219 patients [IS%]), nocturia (73/219 patients [33%]), runny nose (29/219 patients [ 13%]), headache (27/219 patients [12%]), and faintness (26/219 patients [12%]). Of these symptoms, there was a significantly higher incidence of patients

therapeutic

system.

who reported bother due to edema, regardless of whether the edema was present at baseline (27% vs 9%; P = 0.0004). No statistical differences for bother due to the other symptoms were detected. Likewise, no differences were detected in the other six scales of quality of life at the end of 12 weeks of therapy (Table VII), nor were there any significant changes in therapy comparing baseline with the end of 4 weeks or 8 weeks of therapy (data not shown). The lack of differences between treatments for these quality-of-life dimensions may be the result of inadequate sensitivity of the instrument to detect change if one existed, or the lack of a true difference between treatments for these domains of quality of life.

DISCUSSION

AND CONCLUSIONS

This clinical trial demonstrated that a regimen using a fixed dose of the angiotensin II receptor antagonist losartan alone or in combination with a low dose of HCTZ (12.5 or 25 mg) provided similar antihypertensive efficacy but improved tolerability with respect to edema compared

423

Nifedipine Losartan Nifeclipine Losartan Nifedipine Losartan

Nifedipine

(range, 742)

f 0.8 f 0.8 f 1.5 f 1.4 f 4.5 f 4.5 f 3.3 +- 3.5 f 13.8 f 14.5 zt 5.9

+ 0.8 f 0.7 f 1.5 * 1.5 zt 4.6 f 4.6 f 2.8 f 3.1 f 13.4 f 13.7 f 6.3 28.0 + 6.7

3.6 3.7 9.1 9.1 14.7 14.6 25.3 25.5 107.0 107.9 28.4

Mean f SD

106

110 109 110 109 109 109 110 109 110 109 108

n

f 0.7 f 0.6 f 1.3 f 1.4 zt 2.9 f 3.4 f 1.8 f 2.3 f 8.1 -t 9.5 f 3.9 0.7 f 3.9

0.1 0.1 -0.0 -0.1 -0.1 -0.4 0.6 0.5 1.4 1.2 0.0

Mean f SD

Difference

are given as mean + SD.

0.20

0.91

0.72

0.57

0.99

0.61

P

8 %

F

m

;

108

110 110 110 110 109 110 110 110 110 110 109

n

Final

Values

gastrointestinal therapeutic system 30 mg at week 4; 30 mg or 60 mg at week 8; 30 mg, 60 mg, or 90 mg at week 12.

27.3 f 6.5

3.6 3.6 9.2 9.3 14.8 15.1 24.7 25.0 105.6 106.8 28.4

Mean -c SD

of therapy.

‘Lcsartan 50 mg alone at week 4, alone or with hydrochlorothiazide (HCTZ) 12.5 mg at week 8, atone or with HC’lZ 12.5 mg or 25 mg at week 12. Nifedipine

108

110 112 110 112 110 112 110 112 110 112 108

n

Baseline

after 12 weeks

P 2 F;

LOSartCiIl

Nifedipine

LOSartan

Losartan Nifedipine

dimensions

Overall health perceptions (range, 1-5) Social functioning (range, 2-10) Sleep disturbance (range, O-20) Cognitive functioning (range, 7-28) Psychologic well-being total (range, 22-132) Sexual satisfaction

in quality-of-life

Treatment”

Changes

(worst-best)

Dimension

Table VII.

M.R. WBIR ET AL.

with a regimen that titrated the dihydropyridine calcium channel blocker nifedipine GITS. The number of losartan patients requiring titration (the addition of HCTZ) or nifedipine GITS patients requiring dose titration to achieve goal blood pressure was comparable. Both treatment regimens also provided excellent blood pressure reduction. Using the criterion of a reduction in sitting diastolic blood pressure to <90 mm Hg or to 290 mm Hg but 210 mm Hg from baseline, 74% of patients in the losartan group and 68% of patients in the nifedipine GITS group responded (P = NS). Importantly, these overall response rates were also comparable in patients whose pretreatment diastolic blood pressure was between 106 and 115 mm Hg (losartan group 83% vs nifedipine GITS group 73%; P = NS). The efficacy of these drugs in the treatment of middle-aged patients with hypertension, particularly those with more significant elevation in diastolic blood pressure, is not surprising, since both drugs are vasodilators and target the blood vessel for a major part of their antihypertensive activity. Losartan, the angiotensin II receptor antagonist, reduces peripheral vascular resistance by blocking the AT1 receptor, the critical binding site for the vasoconstrictor angiotensin II.3 Nifedipine GITS, the dihydropyridine calcium channel blocker, reduces vascular resistance by decreasing vascular sensitivity to circulating vasoconstrictors such as angiotensin II and norepinephrine by blockade of the L-type calcium channel.13 Both classes of drugs also possess intrinsic natriuretic properties that may facilitate better blood pressure contro1.2*7J4 Losartan attenuates angiotensin II-mediated stimulation of aldosterone production and inhibits renal tubular sodium reabsorp-

tion.2**4 Nifedipine’s natriuretic effect is poorly characterized and may consist of a direct action of the drug on the renal tubule.’ The HCTZ moiety, when added to losartan in low doses, is thought to provide blood pressure reduction through mild natriuresis and direct vasodilatory effects of the drug on the blood vessel.15*16 Whereas the efficacy of therapy with losartan, alone or in combination with low doses of HCTZ, and nifedipine GITS was comparable, there were differences in the tolerability profiles of these two treatment regimens. Although the overall incidence of clinical and laboratory adverse events was similar between therapies, significantly more patients in the nifedipine GITS group experienced drug-related edema and were withdrawn from the trial. The symptom bother inventory also illustrated the importance of edema as a side effect, in that there was a highly significant difference between the two treatment regimens for bother due to swollen ankles, regardless of whether the symptom was present at baseline. However, no statistically significant differences for bother due to the other symptoms in the inventory were noted. Increasing doses of nifedipine GITS were associated with increasing occurrences of edema. After 4 weeks of treatment, 7 patients not experiencing edema at baseline reported this phenomenon. The incidence of this symptom increased to 13 patients after 8 weeks and 20 patients after 12 weeks of therapy. When taking into account the number of patient-days at risk for each dosage strength, there was a clear dose dependency for the development of edema (Table VIII). The results of the study support the concept that antihypertensive therapy using usual starting doses of two drugs, as com-

425

CLINICAL THERAPEUTICS@

Table VIII. Dose dependency treatment group. Dose (mg) 30 60 90 GITS = gastrointestinal

therapeutic

of adverse experiences

Days at Risk

Case/1000 Patient-Days

5500 2400 850

1.09 2.50 5.88

GITS

system.

pared with a regimen that uses dose escalation of a single drug, may result in fewer dose-dependent adverse events. This paradigm may in part explain the cause of the increased incidence of study terminations observed in patients receiving nifedipine GITS. Other comparative, doublemasked, clinical studies have similarly demonstrated that a usual starting-dose strategy may be better tolerated than titration of other single agents.4 It is important to note that patient-reported symptom bother due to edema, regardless of whether the edema was present at baseline, in the nifedipine GITS group was 27% and physician-reported drug-related edema in this group was 12%. This difference in reporting of adverse experiences between patients and physician may point to the need for improved patientphysician communication regarding drugrelated adverse experiences and the effects of such symptoms on patients’ quality of life. In conclusion, both treatment regimens had equal efficacy, with excellent control rates for diastolic and systolic blood pressures, even for moderately hypertensive patients with untreated diastolic blood pressure at baseline between 106 and 115 mm Hg. However, treatment using the losartan regimen was better tolerated. Al-

426

due to edema in nifedipine

though there did not appear to be any significant differences between treatment regimens with regard to quality of life, therapy with nifedipine GITS was associated with significantly more dropouts and symptom bother due to edema compared with treatment using losartan alone or in combination with low doses of HCTZ. Finally, the results of this clinical trial provide evidence that regimens using usual starting doses of two drugs may provide similar efficacy as higher doses of an individual drug while at the same time avoiding undesirable side effects and higher discontinuation rates due to drugrelated adverse events.

ACKNOWLEDGMENTS We would like to acknowledge the following individuals who participated in this multicenter study: Steven Bowman, MD, Clearwater, Florida; Luis A. Campos, MD, Houston, Texas; William J. Carter, MD, Little Rock, Arkansas; Steven Chrysant, MD, PhD, Oklahoma City, Oklahoma; Stephen Daniels, DO, Houston, Texas; Michael S. Doyle, MD, Ferndale, Michigan; Carlos Ferrario, MD, WinstonSalem, North Carolina; David Ginsberg, DO, Kenhurst, Pennsylvania; Roy Kaplan, MD, Concord, California; Moti L.

M.R. WEIR ET AL

MD, Irvine, California; Lance Kirkegaard, MD, Tacoma, Washington; Kenneth Miller, MD, Park Ridge, Illinois; Sam S. Miller, MD, San Antonio, Texas; William S. Mullican, MD, Evansville, Indiana; John D. Norton, MD, Colorado Springs, Colorado; Vasilios Papademetriou, MD, Springfield, Virginia; James L. Pool, MD, Houston, Texas; Douglas Schumacher, MD, Cincinnati, Ohio; Jerry D. Schumacher, MD, Columbus, Ohio; Charles Shields, MD, Lubbock, Texas; Domenic A. Sica, MD, Richmond, Virginia; William B. Smith, MD, New Orleans, Louisiana; Kumjad Unnoppet, MD, Hollywood, Alabama; Keith VanZandt, MD, Winston-Salem, North Carolina; Matthew R. Weir, MD, Baltimore, Maryland; Bruce E. Wilson, MD, Las Vegas, Nevada; and Paul Wolfson, DO, Olympia Fields, Illinois. We would also like to acknowledge the excellent secretarial assistance of Jacqueline Brandenburg, and US Human Health, Merck & Co., Inc., West Point, Pennsylvania, for providing a grant to conduct this study. We would also like to thank Pfizer, Inc., Groton, Connecticut, for providing nifedipine GITS clinical supplies for the trial. Kashyap,

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