The management of hypertension has become

AJH 1997;10:743 749 Additive Effects of Diltiazem and Lisinopril in the Treatment of Elderly Patients With Mild-to-Moderate Hypertension Paul Chan, Chun-Nan Lin, Brian Tomlinson, Tz-Hsin Lin, and Ying-Shiung Lee A multicenter, double-blind, placebo-controlled trial with multifactorial design was conducted to evaluate the safety and efficacy of the calciumchannel blocker diltiazem, in a sustained release preparation, and the angiotensin converting enzyme inhibitor, lisinopril, in the treatment of elderly Chinese patients with mild-to-moderate hypertension. In addition to the hypotensive effects of combinations of both drugs compared with monotherapy, all given once daily, the effect on quality of life was also evaluated. This study consisted of a 3 2 multifactorial design in which 156 women and men with a sitting diastolic pressure of between 95 mm Hg and 114 mm Hg, after a 4-week placebo washout phase, were randomized to one of six treatment groups for 12 weeks of active treatment. Monotherapy with diltiazem 120 or 240 mg produced increasing reductions of systolic and diastolic blood pressure. Compared with placebo, lisinopril 10 mg had an effect intermediate between the diltiazem doses. The combinations of diltiazem 240 mg lisinopril 10 mg and diltiazem 120 mg lisinopril 10 mg showed increased efficacy in reducing systolic and diastolic blood pressure compared to these drug doses used in monotherapy, but the effect of the combinations was less than predicted by an additive model. Although the total number of other adverse events reported was similar for all active treatment groups compared to placebo, lisinopril-induced cough was common with an incidence of 31% after rechallenge. Premature drug withdrawal was necessary in four of 78 patients receiving lisinopril, due to intractable cough. The combination of diltiazem 240 mg and lisinopril 10 mg was significantly more effective at reducing blood pressure than either drug alone; this additive effect did not result in a higher rate of adverse effects or impairment of quality of life. Thus, combination therapy with these agents was well tolerated and resulted in increased efficacy in these elderly patients. Am J Hypertens 1997; 10:743 749 1997 American Journal of Hypertension, Ltd. KEY WORDS: Combination therapy, diltiazem, elderly hypertension, lisinopril, multifactorial design. Received January 1, 1996. Accepted December 17, 1996. From the Division of Cardiology and Clinical Pharmacology (PC, CNL, THL), Taipei Municipal Wan-Fang Hospital, Wen Shan, Taipei, Taiwan; Institute of Clinical Medicine (PC), National Yang-Ming University, Nan Kang, Taipei, Taiwan; Department of Cardiovascular Medicine (YSL), Chang-Gung Memorial Hospital and Chang-Gung Medical College, Taipei, Taiwan; Department of Clinical Pharmacology (BT), The Chinese University of Hong Kong, Shatin, Hong Kong. Address correspondence and reprint requests to Paul Chan, MD, PhD, Division of Cardiology and Clinical Pharmacology, Taipei Municipal Wan-Fang Hospital, No. 111, Hsin Lung Road, Wen Shan, Taipei, Taiwan 115. The management of hypertension has become more effective with the development of new classes of antihypertensive agents. However, there are still many patients who are not adequately controlled with monotherapy despite the multiple pharmacologic options available. Approximately half of all hypertensive patients require combination therapy in order to attain adequate blood pressure control. 1 The conventional concept of combi- 1997 by the American Journal of Hypertension, Ltd. 0895-7061/97/$17.00 Published by Elsevier Science, Inc. PII S0895-7061(96)00060-5

744 CHAN ET AL AJH JULY 1997 VOL. 10, NO. 7, PART 1 nation therapy is for the enhancement of the hypotensive effect by each component, 2 but not all studies have shown additive effects with combinations of different kinds of antihypertensive drugs. 3 5 The traditional method for evaluation of combination therapy is to compare the effect of a single drug with the response obtained after adding another agent. However, the existence of an interaction between individual drugs should be demonstrated with a more sophisticated design. That can be attained by a randomized, multifactorial design combining different doses of two drugs and placebo in a multicelled array. This design should be an appropriate method for the evaluation of the contribution of each component of the combination in order to find the most effective regimen. Although the Fifth Report of the Joint National Committee (JNC V) recommends diuretics and -blockers as first-line agents for hypertension treatment, 6 calcium antagonists are frequently used as first line agents, 7 9 especially in elderly hypertensive patients, who usually have a much higher incidence of low-renin hypertension. 10 However, the efficacy of angiotensin converting enzyme inhibitors (ACEI) has also been demonstrated in patients with low-renin essential hypertension, including the elderly. 11,12 The combination of ACEI and calcium antagonists is now widely used in effective regimens. 8,13,14 This study was undertaken to assess combinations of the calcium antagonist, diltiazem, and the ACEI/ lisinopril, and to investigate the potential additive effects of these agents, especially at the end of the 24-h dosing interval. A randomized 3 2 multifactorial design was chosen to quantify the hypotensive effects of each drug, separately and in combination, and thus to determine objectively the additive effects of each component. Side effects and quality of life assessments were included in these determinations. 15 PATIENTS AND METHODS This was a multicenter, randomized, double-blind, multifactorial study. The study protocol conformed to the ethical guidelines of the 1989 Declaration of Helsinski and was approved by the investigational review board of each participating center. All patients gave written informed consent. Patient Population Patients of both sexes (65 years or older) with a previous diagnosis of mild to moderate hypertension were enrolled for study. The patients had to be apparently healthy and free of secondary hypertension, other cardiac disease, malignancies, significant renal impairment (serum creatinine 2.0 mg/ dl), or hepatic dysfunction. Study Conduct After providing informed consent, and the withdrawal of any previous antihypertensive treatment, eligible patients entered a 4-week, singleblind, placebo wash-out phase. Those whose sitting diastolic blood pressure was between 95 mm Hg and 114 mm Hg (average of three readings) at the last two visits of the placebo period were eligible for randomization into one of six double-blind treatment regimens: a) 120 mg sustained release preparation of diltiazem placebo; b) 120 mg diltiazem 10 mg lisinopril; c) 10 mg lisinopril placebo; d) 240 mg diltiazem 10 mg lisinopril; e) 240 mg diltiazem placebo; f) placebo placebo. Diltiazem was used in a sustained release formulation with identical capsules for the 120 and 240 mg doses. The study drugs were taken once daily (between 8 am and 10 am) over a 12-week period. Patients were requested to attend for follow-up every 2 weeks during placebo wash-out and active treatment phases to assess side effects, and they also underwent complete physical examination (including fundoscopy), chest radiograph, and 12-lead electrocardiogram and laboratory tests (biochemistry, hematology, and urinalysis). Compliance was evaluated by tablet counting. Blood pressure was measured by trained personnel who were experienced in measuring blood pressure for epidemiological surveys. Blood pressure was measured to the nearest 2 mm Hg, using a standard mercury sphygmomanometer, after the subject had been sitting for 10 minutes at rest. Korotkoff phases I and V were taken as the systolic and diastolic blood pressures, respectively. The blood pressure was measured consecutively three times at 5 minute intervals and a 30 second pulse recording made at each measurement. The mean of the three measurements was used for the analysis. Efficacy assessment was based on the mean change from baseline in the sitting systolic and diastolic blood pressures at the end of 12 weeks of double-blind treatment. The modified Vital Signs Quality of Life Questionnaire was used to assess the impact of treatment on quality of life. 15 The questionnaire was administered before double-blind treatment was commenced and at each subsequent visit. This questionnaire contains a 25-question survey that assesses overall satisfaction with study drug treatment, as well as the frequency and intensity of problems associated with general health, relationships with others, mental functioning, and emotional state. Any patient who reported cough during the study period discontinued any ACEI treatment after completing the study and was then rechallenged with 10 mg lisinopril after a 4-week wash-out period. Statistics This 3 2 multifactorial design included all possible combinations of lisinopril 10 mg, diltiazem 120 mg or 240 mg, and placebo. This design has been found to be sensitive for studying dose response relationships as well as additivite effects of

AJH JULY 1997 VOL. 10, NO. 7, PART 1 ADDITIVE EFFECTS OF DILTIAZEM AND LISINOPRIL 745 TABLE 1. BASELINE DEMOGRAPHIC CHARACTERISTICS FOR ALL PATIENTS Variable D120 P (n 25) D120 L10 L10 P D240 L10 D240 P P P (n 27) Gender (M/F) 16/9 14/12 18/8 15/11 16/10 15/12 Heart rate (beats/min) 60.7 (52 84) 61.6 (45 85) 62.5 (46 86) 63.8 (46 84) 64.8 (48 85) 61.9 (49 89) Age (years) 70.9 (65 85) 72.3 (67 87) 70.5 (65 83) 72.8 (66 86) 73.1 (65 88) 73.4 (66 87) Body weight (kg) 67.1 (48 88) 65.8 (51 92) 64.7 (51 86) 68.4 (50 95) 68.8 (49 95) 69.4 (53 96) BMI (kg/m 2 ) 25.1 (22.4 29.5) 24.4 (22.6 28.8) 23.8 (22.8 27.8) 23.6 (22.9 28.4) 23.5 (23.0 27.2) 24.8 (22.6 30.1) Abbreviations: D120, 120 mg diltiazem; D240, 240 mg diltiazem; L10, 10 mg lisinopril; P, placebo; BMI, body mass index. Figures are mean (range) values and ratio of male/female for gender. combinations. 16,17 All study patients were included in the safety analysis. An intention-to-treat analysis was performed to assess efficacy and included all the randomized patients who had baseline blood pressure and follow-up blood pressure readings. Analysis of variance (ANOVA) was used for analysis of the primary variables comparing the different treatment regimens. An additive model was used to compare the expected effects of the combinations of diltiazem and lisinopril with the observed effects when the drugs were given together. 18 The dose response relationship of the two dose levels of diltiazem was examined by fitting the data to polynomial response curves. To confirm the results of primary analysis, additional analyses were performed adjusting for baseline and study site. No treatment-by-site interactions were found. Fischer s exact test was used to analyze side effects and quality of life. RESULTS Of 186 patients initially recruited, 156 (62 female, 94 male) met the entry criteria and were randomized to treatment. Eight patients were withdrawn before the last scheduled study visit for the following reasons: comcomitant illness (2 patients), lost to follow-up (2 patients), and side effects (4 patients). The efficacy and safety analysis included all 156 randomized patients. Premature withdrawal of treatment in four patients taking lisinopril was due to intractable cough. The baseline demographic characteristics of the treatment groups are shown in Table 1. The majority of patients were male (72%) and the average age of all patients was 72 years. There were no significant differences between treatment groups in any baseline demographic parameters. Efficacy The baseline and endpoint (last valid blood pressure measurement) sitting systolic blood pressure (SBP) results are summarized in Table 2. All active drug regimens were significantly different from placebo. The reduction in SBP achieved with lisinopril 10 mg was in between the reductions achieved with the two doses of diltiazem. The greatest reduction in sitting SBP (mean 19.4 mm Hg) was found with the 240 mg diltiazem 10 mg lisinopril, which was significantly greater than either 240 mg diltiazem (mean TABLE 2. MEAN SEATED SYSTOLIC BLOOD PRESSURE (SBP) MEASURED 24 H AFTER THE LAST DOSE AT BASELINE AND END OF TREATMENT Treatment Group Lisinopril Diltiazem Baseline Endpoint Change P value* 0 0 (n 27) 167.9 14.8 166.9 14.8 1.08 2.2 0 120 (n 25) 167.9 15.4 156.6 12.5 11.2 4.5.05 0 240 (n 26) 170.0 13.2 154.8 10.5 14.9 4.2.05 10 0 (n 26) 163.8 13.0 150.5 11.2 13.3 4.0.05 10 120 (n 26) 168.9 15.1 152.5 13.0 16.4 4.4.05 10 240 (n 26) 168.4 13.3 149 11.2 19.4 5.0.05 Values are given as mean SD in mm Hg. SBP, systolic blood pressure; SD, standard deviation; NS, not significant. * Compared with placebo placebo. The effect of the combination of: (1)D120 L10 D120 (P.05), but not L10 or D240 (NS); (2) D240 L10 D240, L10 and D120 L10; (3) D240 D120 (P.05).

746 CHAN ET AL AJH JULY 1997 VOL. 10, NO. 7, PART 1 TABLE 3. MEAN CHANGES FROM BASELINE TO END OF TREATMENT, MEASURED 24 H AFTER LAST DOSE, IN DIASTOLIC BLOOD PRESSURE FOR ALL TREATMENT GROUPS Treatment Group Lisinopril Diltiazem Baseline Endpoint Change P value* 0 0 (n 27) 105.5 5.4 104.1 4.8 1.4 2.7 0 120 (n 25) 104.5 5.4 96.3 4.5 8.2 2.5.05 0 240 (n 26) 105.9 5.7 95.0 5.1 10.9 2.9.05 10 0 (n 26) 104.9 5.0 95.4 4.6 9.5 2.8.05 10 120 (n 26) 104.7 5.3 93.1 4.2 11.6 3.3.05 10 240 (n 26) 106.2 6.0 92.9 4.8 13.3 3.0.05 Values are given as mean SD. DBP, diastolic blood pressure; SD, standard deviation; NS, not significant. * Compared with placebo placebo. The effect of the combination of: (1) D120 L10 D120 (P.05), but not L10 or D240 (NS); (2) D240 L10 D240, D120, L10 and D120 L10; (3) D240 D120, (P.05). 14.9 mm Hg) or 10 mg lisinopril (mean 13.3 mm Hg) alone and greater than 120 mg diltiazem 10 mg lisinopril. The second largest reduction in SBP (mean 16.4 mm Hg) was achieved with 120 mg diltiazem 10 mg lisinopril, which was greater than the effect of diltiazem 120 mg but not than that of lisinopril 10 mg or diltiazem 240 mg. The effects of the combinations of 120 mg diltiazem and 10 mg lisinopril or 240 mg diltiazem and 10 mg lisinopril were less than the effects of the combinations predicted from the sums of the components using the additive model (P.05). The baseline and endpoint sitting diastolic blood pressure (DBP) results are summarized in Table 3. All active drug regimens were significantly different from placebo. When diltiazem 240 mg or lisinopril 10 mg was administered as monotherapy, the hypotensive effect on DBP was almost equivalent (mean 10.9 mm Hg, 9.5 mm Hg respectively). The combination of 240 mg diltiazem 10 mg lisinopril resulted in a greater (P.05) reduction in sitting DBP (mean 13.3 mm Hg) when compared with 240 mg diltiazem (mean 10.9 mmhg) or 10 mg lisinopril (mean 9.5 mmhg) alone or with the combination of 120 mg diltiazem 10 mg lisinopril. The 120 mg diltiazem 10 mg lisinopril combination therapy was also more effective in reducing DBP (mean 11.6 mm Hg) than 120 mg diltiazem alone (mean 8.2 mm Hg, P.05) and tended to have a greater effect than lisinopril monotherapy (mean 9.5 mm Hg, P.05). The effect of the combination of 120 mg diltiazem and 10 mg lisinopril or 240 mg diltiazem and 10 mg lisinopril was less than the predicted effect from the two drugs given separately (P.05). The dose response relationship for the two doses of diltiazem showed a significant (P.05) quadratic component for SBP and DBP when diltiazem was used alone, but when used in combination with lisinopril, the dose response relationship showed a significant linear relationship for SBP and DBP (P.05). Safety and Compliance Similar to Materson et al s report, 19 the tolerability of diltiazem was found to be good and no significant adverse effects warranted drug discontinuation in these elderly subjects. Contrary to previous reports from studies in whites, lisinopril-induced cough was frequent, and four patients had severe cough that resulted in premature drug withdrawal in the groups receiving lisinopril, one patient from the group on lisinopril alone, one from the combination with 120 mg diltiazem, and two from the combination with 240 mg diltiazem. Cough induced by lisinopril usually appeared between the second and the fourth week after starting the drug. The average incidence of cough after rechallenge with 10 mg lisinopril was 31% of all those receiving lisinopril originally, whereas the average incidence of cough during the initial period of lisinopril treatment was 45% (Table 4). The timing of the appearance of cough after rechallenge was similar to the first intake. The incidence of patients reporting at least one adverse experience (regardless of drug relationship) varied between treatment groups largely due to the high incidence of cough in the lisinopril groups and ranged from 42% in the 240 mg diltiazem 10 mg lisinopril group to 22% in the 240 mg diltiazem group (compared with 36% in the placebo group). The most frequently reported side effects are summarized in Table 4. The mean compliance of the six study groups as assessed by tablet counting was 92 4% and there was no significant difference between groups. Few of these untoward effects, except for cough, were considered to be drug-related by the investigators. Dizziness was the most common event in the

AJH JULY 1997 VOL. 10, NO. 7, PART 1 ADDITIVE EFFECTS OF DILTIAZEM AND LISINOPRIL 747 TABLE 4. MOST FREQUENTLY REPORTED ADVERSE EXPERIENCES Adverse Experience D120 P (n 25) D120 L10 L10 P D240 L10 D240 P P P (n 27) Dizziness 2 2 1 2 2 2 Fatigue 2 2 1 2 2 3 Headache 2 1 1 3 2 2 Asthenia 1 1 0 1 1 1 Peripheral edema 1 1 1 1 1 1 Skin rash 1 2 2 2 1 2 Constipation 1 1 0 2 2 2 Cough 1 12(8*) 11(9*) 12(9*) 1 2 Number in brackets indicate persistent cough after rechallenge with lisinopril 10 mg. * Patient withdrawal: D120 L10 (1); L10 P (1); D240 L10 (2). diltiazem treatment groups (8% in all the groups receiving diltiazem) and this occurred with a similar incidence in the placebo groups (8%). No patients complained of symptoms suggestive of first dose hypotension, and no patients developed cardiac failure or rhythm disturbance. There were no clinically significant changes between pre- and posttreatment results of physical examination, electrocardiogram or laboratory values including the plasma lipid levels and renal function tests. Quality of Life Quality of life scores were maintained during the weeks of double-blind treatment. No statistically significant differences were found between pre- and posttreatment scores for any of the treatments when analyzing the results of the quality of life questionnaire, nor were there differences between treatment groups. The percentage of patients reporting improvement in quality of life was also evaluated comparing pre- and posttreatment. Again, no significant differences were found between groups (Table 5), although all the active treatment groups tended to improve more than the placebo group. DISCUSSION The management of elderly patients with hypertension requires individualization of treatment and special consideration of safety and quality of life, 20 as well as efficacy and cost. With advancing years a number of anatomical, biochemical, and physiological alterations may interact with the pathophysiology and treatment of hypertension. Despite an age-related decline in the activity of the circulating renin-angiotensin system, previous studies have shown that elderly patients are generally responsive to ACEI and these should be considered as effective alternative agents. 11,12 The rationale to choose lisinopril and diltiazem for the treatment of these elderly hypertensive subjects was based on previous studies, which showed that small doses of lisinopril were effective in elderly hypertensive subjects 21 and that diltiazem had the highest rate of successful therapy and lowest rate of side effects in the Veterans Affairs Cooperative Study. 19 Our data also show that diltiazem up to 240 mg and lisinopril 10 mg either alone or in combination have a good safety profile and effective hypotensive action. Despite the availability of numerous single agents, combination therapy is required in many patients to attain satisfactory control. Because the dose response curve for many antihypertensive agents tends to plateau at higer doses, titration toward maximum dose of a single agent often leads to only a small increase in efficacy at the expense of an undesirable increase in side effects. 22 In this study in elderly hypertensives, we have used a multifactorial design to characterize incremental hypotensive effects, although the effective combination of calcium-channel blockers and ACEIs has been previously described. 8,13,14,23 Previous reports have suggested that a multifactorial design provides a more rigorous approach to yield information regarding TABLE 5. PERCENT OF SUBJECTS SHOWING IMPROVEMENT IN QUALITY OF LIFE D120 L (n 25) D120 L10 L10 P D240 L10 D240 P P P (n 27) Percent improved 52 58 50 58 54 30

748 CHAN ET AL AJH JULY 1997 VOL. 10, NO. 7, PART 1 group responses to various doses of monotherapy and combinations, and helps to determine whether the combination is superior to either drug used alone. Individual responses, however, are more clearly evaluated by using a cross-over desgin. The present data show that diltiazem 240 mg and lisinopril 10 mg in combination provide better blood pressure control than either agent alone, with maintenance of quality of life and a good safety profile, but the blood pressure lowering effect is less than would be predicted from an additive model of the two drugs given separately. The combination of diltiazem 120 mg with lisinopril 10 mg also showed a greater effect than either drug dose alone, which was again slightly less than additive in lowering both systolic and diastolic blood pressure. The effect of diltiazem 120 mg with lisinopril 10 mg was less than that of diltiazem 240 mg plus lisinopril 10 mg. The dose response relationship for these diltiazem doses when used in monotherapy was quadratic rather than linear, suggesting these may be reaching the plateau part of the dose response curve. However, in combination with lisinopril, the relationship between diltiazem dose and additional hypotensive effect became linear. The effects of the drug combinations may have been less than additive because they were both in the higher part of the effective dose range for this patient group. Both lisinopril and diltiazem were well tolerated and drug related side effects were rare, except for cough in the groups receiving lisinopril. Lisinopril induced cough had a much higher incidence (mean 31% confirmed by rechallenge) in these Chinese patients than has been reported in previous studies in whites. 24,25 This high incidence of cough induced by lisinopril was convincing because it was confirmed by rechallenge with 10 mg lisinopril and this study was conducted in the summer when upper airway symptoms in these elderly patients would be less frequent. This higher incidence of cough induced by ACEI in Chinese compared with whites has been reported previously, 26 and may be explained by a racial or environmental difference. Fortunately, this ACEI-related cough was usually not annoying enough to warrant drug withdrawal. As for the results of the quality of life questionnaire, this showed no impact on quality of life scores for any of the treatment regimens. Our data provide further information that in elderly hypertensive subjects, presumably with low plasma renin activity, diltiazem, and ACEI used in combination have increased hypotensive effects than each drug alone. This greater efficacy did not result in a higher rate of adverse events in this study, suggesting that combining a calcium antagonist and an ACEI may be preferably to increasing the dosage of a single agent. Combinations of lower doses of either agent may show a more definite additive effect in this patient group who appeared very responsive to the doses used. This combination therapy can provide effective blood pressure control while minimizing dose-related adverse events. In conclusion, single drug therapy with either diltiazem 240 mg or 10 mg lisinopril reduced systolic and diastolic blood pressure to a comparable extent and significantly more than placebo. 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