The Addition of Mibefradil to Chronic Hydrochlorothiazide Therapy in Hypertensive Patients Is Associated with a Signiﬁcant Antihypertensive Effect

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ORIGINAL ARTICLE The addition of mibefradil to chronic hydrochlorothiazide therapy in hypertensive patients is associated with a signiﬁcant antihypertensive effect

S Carney1, L Wing2, A Ribeiro3, R Kallwellis4, R Zimlichman5, RJ Viskoper6, D Mion Jr7 and I Kobrin8 1John Hunter Hospital, Medicine, Newcastle, Australia; 2Flinders Medical Centre, Adelaide, Australia; 3Excola Paulista de Medinica, Sao Paulo, Brazil; 4Aerztehaus, Greifswald, Germany; 5Edith Wolfson Hospital, Holon, Israel; 6Barzilai Medical Center, Ashkelon, Israel; 7Hospital das Clinica Medica, Sao Paulo, Brazil; 8Hoffmann-La Roche, Nutley, NJ, US

Objective: To evaluate the antihypertensive efﬁcacy, tol- cally relevant, dose-related reductions in sitting dias- erability, safety, and dose-response characteristics of tolic blood pressure (SDBP) and sitting systolic blood the novel calcium antagonist, mibefradil, in combination pressure (SSBP) at trough, which were signiﬁcantly with a diuretic regimen. greater in the 50 and 100 mg dose groups compared to Design: A multinational, double-blind, randomised, pla- the placebo group (P р 0.003). Placebo-corrected treat- cebo-controlled, parallel-design trial. ment effects on SDBP and SSBP at the end of the com- Methods: Three hundred and seven patients whose bined treatment period relative to baseline were, mild-to-moderate essential hypertension remained respectively, −4.1 and −8.0 mm Hg in the 50 mg mibefra- uncontrolled after 4 weeks of treatment with hydrochlor- dil group and −9.5 and −8.0 mm Hg in the 100 mg mibef- othiazide (HCTZ) 25 mg/day and placebo were random- radil group. Therapeutic response rates to combination ised to receive combined treatment with HCTZ and mibefradil and HCTZ therapy were high and dose once-daily doses of 12.5, 25, 50, or 100 mg of mibefradil related, reaching 82% for SDBP in the 100 mg group. or placebo. After 8 weeks of combined treatment, HCTZ Conclusions: The addition of once-daily doses of 50 or was withdrawn and the mibefradil groups continued on 100 mg of mibefradil to patients whose hypertension is their respective doses for an additional 6 weeks. not controlled by HCTZ alone is well tolerated and effec- Results: After 8 weeks, the addition of once-daily doses tive in improving BP control. of mibefradil to the initial HCTZ regimen resulted in clini-

Keywords: mibefradil; hydrochlorothiazide; antihypertensives; combination therapy

Introduction antihypertensive agent may be more effective than increasing the dose of diuretic. However, patients on Thiazide diuretics, including hydrochlorothiazide chronic diuretic therapy might be more sensitive to (HCTZ), are among the most frequently used drugs the addition of a second antihypertensive because for the treatment of hypertension because they are of volume depletion. Therefore, when evaluating inexpensive and effective in lowering blood press- any new antihypertensive drug, it is important to ure (BP). In addition, they have been documented characterise its efficacy, safety, and tolerability in large prospective trials to reduce cardiovascular when given in combination with a thiazide diuretic. morbidity and/or mortality with long-term treat- Calcium antagonists (CAs) are often added to a 1–5 ment. diuretic for patients whose BP remains uncon- Despite their usefulness, diuretics at increased trolled. Although numerous CAs are available, they doses are associated with numerous undesirable comprise an extremely heterogeneous class of drugs, side effects. In addition to impotence, fatigue, vol- and there is ongoing controversy as to which of ume depletion, and urinary frequency, metabolic these compounds have relevant additive antihyper- effects on serum potassium, glucose, and lipid levels tensive effects with diuretics.7–12 6 have also been observed. Consequently, for most Mibefradil (Ro 40-5967), a benzimidazolyl-substi- patients whose hypertension is unsatisfactorily con- tuted tetraline derivative,13 is a novel CA that com- trolled by a low-dose diuretic, prescribing a second bines the desirable properties of high bioavailability (approximately 90%), once-a-day dosing, absence of reflex tachycardia, and the ability to lower heart rate Correspondence: Dr Shane Carney, John Hunter Hospital, Medi- without decreasing myocardial contractility.14–18 cine, Newcastle, Australia 2300 Mibefradil differs from established CAs not only by Mibefradil and HCTZ in hypertension S Carney et al 460 its chemical structure but also by its mechanism of assessments. A complete physical examination was action. It binds to a unique receptor site19 and, performed at screening and at the last visit. A 12- unlike traditional CAs, selectively blocks T-type cal- lead electrocardiogram (ECG) was recorded at the cium channels.20 This combination of pharmaco- end of the run-in period, after 4 and 8 weeks of com- kinetic and pharmacodynamic features makes mib- bined treatment, and at the final visit. efradil particularly useful in the treatment of Laboratory evaluations (haematology, chemistry, hypertension and angina pectoris. Clinical studies lipid profile, and urinalysis) were performed using have confirmed that mibefradil as monotherapy is blood and urine samples obtained at trough follow- effective and well tolerated in the treatment of mild- ing an 8 h fast at screening, at Week 3 of the HCTZ to-moderate essential hypertension and stable run-in period, at Weeks 4 and 8 of the combined angina pectoris when administered once daily at treatment period, and at the final visit. Plasma doses of 50 and 100 mg.21,22 samples were analysed for mibefradil concen- The present study was designed to determine the trations using a high-pressure liquid chromatogra- dose-response characteristics and to evaluate the phy (HPLC) technique. efficacy and safety of mibefradil vs placebo during and after treatment with HCTZ in patients with Statistical analysis mild-to-moderate essential hypertension. The primary analysis of study parameters was con- Materials and methods ducted using the intent-to-treat (ITT) population. Patients who received one or more doses of random- Men and women between the ages of 20 and 70 ised trial medication and had a valid baseline SDBP years with a diagnosis of uncomplicated essential (procedurally correct and performed at 24 ± 3h hypertension participated in this multinational, postdose) and at least one valid post-randomisation double-blind, randomised, parallel-design, placebo- SDBP measurement, were included in the ITT effi- controlled trial. The study was conducted in 11 cacy analyses. In the ITT analyses, patients prema- countries in accordance with the principles of the turely withdrawn from the study had their last post- Declaration of Helsinki as amended in Tokyo, Ven- randomisation measurements carried forward for ice, and Hong Kong. Local ethics committee evaluation. approval was obtained at each of the 20 study sites. The primary efficacy parameter was the change in The trial consisted of three periods. During the SDBP from baseline (end of run-in period) to Week first period, eligible patients had all current antihy- 8 of the combined treatment period. The dose- pertensive medications withdrawn; they were then response relationship was evaluated using a trend given 4 weeks of single-blind treatment with 25 mg test applying the appropriate linear hypotheses in of HCTZ and placebo, administered once daily. an analysis of covariance (ANCOVA), with treat- Patients entered the second period if, after 4 weeks ment, centre, and treatment-by-centre interaction of HCTZ therapy, their predose sitting diastolic BP included as model effects, and baseline SDBP used (SDBP) remained between 90 and 110 mm Hg, their as a covariate. Pairwise comparisons of each dose compliance was at least 80% (capsule counting), group with placebo were performed using the appro- and they were tolerating diuretic therapy. Those priate contrast in the linear model. All statistical who qualified were randomised to receive once- tests were two-sided and were performed using an daily double-blind treatment with placebo or one of alpha level of 0.05. four mibefradil doses (12.5, 25, 50, or 100 mg) for 8 Secondary efficacy parameters included the weeks; patients continued to receive once-daily change from baseline to the end of the combined treatment with HCTZ 25 mg during this period. At treatment period (Week 8) in sitting systolic BP the end of the 8-week combined-therapy period, (SSBP) at trough, response rates after combined HCTZ treatment was discontinued and patients treatment, changes in BP at trough following 6 remained on their respective placebo or mibefradil weeks of monotherapy relative to values obtained at treatment for 6 additional weeks. the end of the combined treatment period, and nor- Excluded from the trial were patients with severe, malisation rates for SDBP (р90 mm Hg) at the end malignant, or secondary hypertension; major sys- of the combined treatment period as well as at the temic disease; body weight Ͼ150% of ideal; or a his- end of the trial. For patients with a baseline SDBP tory of alcohol or drug abuse. Concomitant use of between 90 and 94 mm Hg, response was defined as medications affecting BP or interfering with the a reduction from baseline in trough SDBP of у5 effects of a CA was not allowed during the trial. mm Hg. For patients with a baseline SDBP between After screening, patients returned to the clinic at 95 and 110 mm Hg, response was defined as a Weeks 3 and 4 of the HCTZ run-in period, after 1, decrease from baseline of у10 mm Hg or normalis- 4, and 8 weeks of combined HCTZ and placebo or ation of trough SDBP to р9 mm Hg. Data are mibefradil treatment, and after 1 and 6 weeks of pla- expressed as the mean ± standard deviation (s.d.) cebo or mibefradil monotherapy following HCTZ unless otherwise stated. withdrawal. At each visit, BP and heart rate were measured at trough (21–27 h after the previous dose Results and before the current day’s dose) in the sitting pos- ition, and adverse events (AEs); including intercur- A total of 360 patients entered the HCTZ run-in per- rent illnesses, were monitored by physical examin- iod; 53 failed to meet the eligibility criteria with ations and electrocardiographic and laboratory regard to SDBP or were unable to proceed for admin- Mibefradil and HCTZ in hypertension S Carney et al 461 Table 1 Patient demographics and baseline characteristics

Mibefradil dose

Placebo 12.5 mg 25 mg 50 mg 100 mg (n = 61) (n = 63) (n = 60) (n = 60) (n = 63)

Age (years) 56.1 ± 9.4 53.1 ± 10.6 55.5 ± 9.7 54.4 ± 7.6 57.2 ± 9.0 Sex (M:F) 27:34 39:24 28:32 28:32 24:39 Race (W:B:O) 55:6:0 57:6:0 55:3:2 55:3:2 57:4:2 Body weight (kg) 78.9 ± 14.9 81.8 ± 16.2 79.3 ± 12.8 78.7 ± 12.3 76.8 ± 13.2 Baseline SDBP 100.1 ± 4.3 98.8 ± 7.0 98.6 ± 6.0 99.6 ± 5.4 99.1 ± 5.8 (mm Hg)

M = male; F = female; W = white; B = black; O = other; SDBP = sitting diastolic blood pressure. Values are mean ± standard deviation or number of patients. istrative or personal reasons. Of the 307 patients who were randomised to receive trial medication, 273 completed the 14-week double-blind treatment period. The placebo and the four mibefradil dose groups were similar with respect to baseline characteristics (Table 1). The proportion of males and females was similar in all groups except in the mibefradil 12.5-mg group, where the proportion of males was higher than in the other groups. Twenty- two patients were terminated from the study because of adverse events, five because of inad- equate BP control, and seven for other reasons (Table 2). With the exception of one patient in the 100-mg mibefradil group who had no post-randomisation efficacy data, data from all randomised patients were included in the ITT efficacy analyses. All randomised patients were included in the safety analysis.

Effects of combined mibefradil and HCTZ therapy In patients whose BP was not normalised by daily treatment with 25 mg of HCTZ alone, the addition of once-daily doses of 50 or 100 mg mibefradil resulted in clinically meaningful reductions in Figure 1 Mean change in SDBP and SSBP from baseline (end of SDBP and SSBP at trough after 8 weeks. These 4-week HCTZ run-in period) to Week 8 of combined mibefradil reductions were statistically significantly greater and HCTZ 25 mg/day treatment. than those observed in the placebo plus HCTZ group (P р 0.003) (Figure 1). The addition of 12.5- and 25- for both SDBP and SSBP (P Ͻ 0.001). Most of the mg doses of mibefradil was not associated with sig- antihypertensive effects of the 50- and 100-mg doses nificant changes in SDBP or SSBP compared to pla- of mibefradil were achieved during the first week of cebo. The linear-trend test across the five treatment combined treatment, with only slight further groups for the change from the end of the HCTZ run- decreases in SDBP and SSBP observed during the in period to Week 8 of combined mibefradil and remaining 3 weeks of combined treatment HCTZ treatment was highly statistically significant (Figure 2).

Table 2 Patient disposition

Mibefradil dose

Placebo 12.5 mg 25 mg 50 mg 100 mg (n = 61) (n = 63) (n = 60) (n = 60) (n = 63)

Completed therapy 52 60 55 49 57 Prematurely withdrawn: Adverse events 6 3 3 7 3 Treatment failure 2 0 1 2 0 Administrative reasons 9 3 5 11 6 Mibefradil and HCTZ in hypertension S Carney et al 462 heart rate in the mibefradil 12.5-, 25-, 50-, and 100- mg dosage groups at the end of the combined treatment period were 0.0, 0.2, −2.2, and −4.8 bpm, respectively. While there would appear to be a clear dose response, the decrease is not statistically sig- niﬁcant.

Effects of mibefradil following HCTZ withdrawal Withdrawal of HCTZ was associated with a slight increase in SDBP in all groups (4.5, 4.0, 1.8, 3.2, and 1.5 mm Hg for placebo, mibefradil 12.5 mg, 25 mg, 50 mg, and 100 mg, respectively). A similar effect was noted for SSBP (Figure 4). At the end of the study, the normalisation rates of SDBP achieved in the 12.5-, 25-, 50-, and 100-mg mibefradil groups (26%, 35%, 43%, and 76%, respectively) were higher than that of the placebo group (18%). Cessation of HCTZ treatment had negligible effects on heart rate. Mean changes in sitting heart rate from the end of the combined treatment period to the end of the 6-week HCTZ withdrawal period Figure 2 Time course of SDBP and SSBP changes during com- were Ͻ2.0 bpm in all treatment groups. bined daily treatment with mibefradil and HCTZ (hydrochlorothiazide 25 mg) compared with placebo. (BL = baseline; Mib = mibefradil). Safety and tolerability Tolerability: The overall incidence of adverse The proportion of patients demonstrating a thera- events across the 14-week double-blind treatment peutic response to combined mibefradil and HCTZ period, as well as the incidence of AEs judged by therapy after 8 weeks was clearly dose related, the investigators to be at least remotely related to increasing from 32% in the placebo plus HCTZ trial medication (‘treatment-related AEs’), were very group, to 82% in the 100-mg mibefradil plus HCTZ similar in all treatment groups (Table 3). Leg oedema group (Figure 3). The response rates observed in the was the only AE that was more frequent in the mib- 50- and 100-mg mibefradil groups were signiﬁcantly efradil 100-mg dose group (6%) than in any other greater than those observed in the placebo group (P group (2% to 3%). In all mibefradil treatment Ͻ 0.01 for both groups). groups, the rate of premature withdrawal due to AEs The placebo-corrected treatment effects on sitting was either similar to or lower than that in the placebo group (Table 2). Worsening of hypertension

Figure 4 Time course of SDBP and SSBP changes during com- Figure 3 Therapeutic response rates following 8 weeks of combined treatment and after withdrawal of HCTZ. (BL = baseline; bined mibefradil and HCTZ 25 mg/day therapy. Mib = mibefradil). Mibefradil and HCTZ in hypertension S Carney et al 463 Table 3 Overview of treatment-related AEs and main ECG changes

Parameter Mibefradil dose (mg/day)

Placebo 12.5 25 50 100 (n = 61) (n =63) (n = 60) (n = 60) (n = 63)

Total no. of patients 13 (20.6) 12 (20.0) 8 (13.3) 15 (23.8) with у1 AE [No. (%)] 12 (19.7) Headache 3 (4.9) 6 (9.5) 7 (11.7) 2 (3.3) 2 (3.2) Leg oedema 1 (1.6) 2 (3.2) 1 (1.7) 1 (1.7) 4 (6.3) Angina pectoris 1 (1.6) 2 (3.2) 2 (3.3) 1 (1.7) — Dizziness 1 (1.6) 1 (1.6) 1 (1.7) 2 (3.3) 1 (1.6) Fatigue 1 (1.6) — 1 (1.7) 1 (1.7) 1 (1.6) Total no. of patients 11 (17.7) 6 (10.1) 13 (22) 13 (21.7) with у1 ECG change 4 (6.9) First-degree AV block 0 2 (3.2) 0 2 (3.4) 5 (8.3) Sinus bradycardia 1 (1.7) 3 (4.8) 3 (5.0) 8 (13.5) 9 (15.0) was the leading AE responsible for premature with- unchanged mibefradil during the combination treat- drawal; it was reported in three, two, one and one ment period were similar to those observed during patients receiving placebo, 12.5, 25, and 100 mg of the HCTZ withdrawal period (ie, mibefradil mibefradil, respectively. monotherapy) (Table 4).

ECG findings: At the end of the trial, mibefradil treatment was associated with a dose-dependent Discussion reduction in heart rate that ranged from −1.8 ± 14.6 bpm with the 12.5-mg dose to −8.9 ± 8.5 bpm with The results of this trial clearly demonstrate that the the 100-mg dose. A slight dose-related increase in addition of once-daily doses of 50 or 100 mg mibef- the PQ interval that averaged 10.6 ± 19.4 msec was radil to the diuretic regimen of patients whose BP observed in the 100-mg dosage group. Sinus brady- was not controlled by HCTZ 25 mg alone resulted in cardia (heart rate Ͻ55 bpm with a change from base- clinically relevant and statistically significant line of у10 bpm) and first-degree atrioventricular reductions in diastolic and systolic BP in compari- (AV) block (PQ interval Ͼ200 msec) were the most son with placebo. Doses of 12.5 and 25 mg of mibef- common treatment-emergent ECG changes in the radil combined with HCTZ 25 mg did not result in mibefradil groups (Table 3). The remaining ECG clinically relevant reductions in BP. The magnitude changes were sporadically distributed among the of the effects induced by the 50- and 100-mg doses dose groups, and none were judged to be of a serious of mibefradil in this study were similar to those nature. Only one patient in the 50-mg mibefradil observed in the dose-finding study reported by group was withdrawn because of sinus bradycardia Bernink et al21 in patients receiving mibefradil alone (heart rate of 50 bpm) associated with dizziness, and for the treatment of mild-to-moderate hypertension. one patient in the placebo group was discontinued Similarly, the present study also found that the because of atrial fibrillation. effect of the 25-mg dose of mibefradil was no differ- ent than that of placebo. Laboratory results, including plasma lipids: The Patients on diuretic therapy could be more sensi- addition of mibefradil 50 or 100 mg to HCTZ did not tive to the addition of a CA which acts to lower BP result in relevant changes in serum lipid profile, primarily through peripheral vasodilation. Never- including triglycerides, total cholesterol, low-den- theless, such sensitivity was not observed in this sity lipoprotein (LDL) cholesterol, high-density lipo- study and the ineffectiveness of the 25-mg dose indi- protein (HDL) cholesterol, and very-low-density cates that, in the population studied, the lowest lipoprotein (VLDL) cholesterol at Week 8 (Figure 5). effective dose of mibefradil is 50 mg. Therefore, There was no consistent pattern of mean changes or among patients whose BP was not controlled with individual abnormalities for the remaining haema- HCTZ 25 mg/day, there was no enhanced sensitivity tology, chemistry, or urinalysis parameters during to the BP lowering activity of mibefradil. No cases of this trial. One patient in the 50-mg mibefradil dos- postural hypotension or first-dose hypotension were age group was withdrawn 16 days after randomis- observed as might be the case when some drugs such ation because of elevations in serum levels of liver as an ACE inhibitor are added to chronic diuretic enzymes; these changes were already evident during therapy.23 the HCTZ run-in period and were thought to be a The statistically significant linear dose trend possible consequence of diuretic therapy, even observed for both SDBP and SSBP in this trial indi- though hepatic adverse drug reactions are rare cates that increased doses of mibefradil during with diuretics. HCTZ therapy are associated with improvements in the magnitude of BP control. After 8 weeks of combi- Plasma concentrations of mibefradil: Within each nation therapy, response rates were high, reaching dose group, mean trough concentrations of 82% for patients receiving daily treatment with Mibefradil and HCTZ in hypertension S Carney et al 464 Table 4 Trough plasma concentrations (ng/mL) of mibefradil

Mibefradil dose During combined After HCTZ (mg) treatment withdrawal (Week 8) (Week 14)

12.5 29.62 ± 92.46 18.51 ± 42.73 25 83.65 ± 58.88 82.82 ± 48.56 50 283.48 ± 132.26 265.41 ± 119.96 100 586.59 ± 285.99 564.54 ± 275.00

Values are mean ± s.d. HCTZ = hydrochlorothiazide.

No pharmacokinetic interaction was apparent between mibefradil and HCTZ. Plasma trough concentrations of unchanged mibefradil at steady state were comparable during combination therapy with HCTZ and during mibefradil monotherapy after withdrawal of HCTZ, and were also similar to those reported by Bernink et al21 and Bakx et al22 in patients receiving mibefradil monotherapy at similar doses. Cessation of HCTZ therapy resulted in a small but clear increase in SDBP and SSBP in all treatment groups, suggesting that the treatment with HCTZ 25 mg contributed to the antihypertensive efficacy of the mibefradil-HCTZ combination. The magnitude of the effect of HCTZ in the present population cannot be precisely evaluated because of the lack of baseline measurements prior to HCTZ treatment. Nevertheless, based on the slight increase in BP observed after HCTZ withdrawal and the continued high response rates after 6 weeks of mibefradil monotherapy (76% in the mibefradil 100-mg dose group); it appears that the contribution of HCTZ to the control of BP in these patients was modest. Previous studies have reported conflicting results for the additive potential of a thiazide diuretic and a calcium antagonist.7–12 The observations of the present trial cannot be extrapolated to the general hypertensive population because patients were selected for this study based on their insufficient response to therapy with HCTZ 25 mg. Therefore, further studies using more appropriate designs – such as a factorial design – will be required to evaluate the true contribution of each component to the mibefradil-HCTZ combination.24 When such a factorial design study was undertaken to examine the interaction between diltiazem and HCTZ, the additive antihypertensive effects of the drug combination were clearly demonstrated.12 Combination HCTZ plus mibefradil therapy cannot be rec- ommended as first-line treatment over mibefradil Figure 5 Effects of (a) mibefradil 50 mg and (b) 100 mg treatment on plasma lipids during combined treatment and after with- monotherapy on the basis of the current study alone. drawal of HCTZ. (HDL-C = HDL-cholesterol; LDL-C = LDL-choles- All previously discovered classes of calcium antag- terol; VLDL-C = VLDL-cholesterol). onists have been shown to produce diuresis and natriuresis25 without impairing renal function. This effect occurs independently of the hypotensive mibefradil 100 mg plus HCTZ 25 mg. Previous stud- response and appears to be long term and persistent. ies of mibefradil monotherapy have typically No studies have yet been published on mibefradil reported response rates somewhat lower than this. in this regard. For example, Bernink et al21 found that 43% of Plasma lipid profiles remained virtually patients treated with mibefradil 100 mg were nor- unchanged during the combination treatment per- malised to a SDBP р90 mm Hg and 60% had a iod. Only a marginal increase was observed in LDL reduction in SDBP у10 mm Hg. cholesterol in patients receiving mibefradil 100 mg Mibefradil and HCTZ in hypertension S Carney et al 465 plus HCTZ. However, in those patients who stopped Acknowledgements HCTZ and continued mibefradil 100 mg, treatment was associated with a decrease in LDL cholesterol Per-Olof Andersson, MD, Carlofelice Beretta-Piccoli, of a similar magnitude as the increase observed dur- MD; Jose Fidel, MD; Slobodan Gasic, MD; Roswitha ing the first 8 weeks. Therefore, it is likely that the Kallwellis, MD; Kjell Langaker, MD; John McNeil, slight increase observed from baseline to Week 8 MD; Sven Mehlsen, MD, Jan Meyer-Christensen, resulted from either the large variability of the MD; Joergen Munck, MD; Willie Oigman, MD; Hel- measurements (Figure 5) or from the effects of the mut Schneider, MD; Peder-Lars Stahnke, MD; Anno diuretic itself. Such effects have been reported pre- Wesler, MD. viously with chlorthalidone plus HCTZ.26,27 Thus, F Hoffmann-La Roche Ltd: Elisabet Lindberg, MD; this study does not suggest any effect of mibefradil Norbert Neumann, PhD; Maurizio Rainisio; Ian S. itself on plasma lipids. However, because of the Small; Catherine Ward; Horst A. Welker, PhD. potential confounding effects of diuretics on plasma This study was supported by a grant from F. lipids, long-term studies with mibefradil monother- Hoffmann-La Roche Ltd. apy will be needed to further characterise its effects in this regard. References During the entire 14-week double-blind treatment period, the reported incidence of AEs in each of the 1 Medical Research Council Working Party. Medical four mibefradil dosage groups was similar to that in Research Council trial of treatment of mild hyperten- the placebo group. Leg oedema was the only AE that sion: principal results. Br Med J 1985; 291: 104. 2 SHEP Cooperative Research Group. Prevention of appeared to be dose-related. Nevertheless, the inci- stroke by antihypertensive drug treatment in older per- dence was low (6% in the 100-mg dose group), and sons with isolated systolic hypertension: final results no patient discontinued mibefradil therapy for this of the Systolic Hypertension in the Elderly Program reason. There was no pattern or common reason for (SHEP). JAMA 1991; 265: 3255–3264. treatment-related premature discontinuation. Com- 3Da¨hlof B et al. Morbidity and mortality in the Swedish pared with the placebo group, a similar number of trial in old patients with hypertension (STOP- patients in the 50-mg group and fewer patients in hypertension). Lancet 1991; 338: 1281–1285. the 12.5-, 25-, 100-mg groups terminated treatment 4 Hypertension Detection and Follow-up Program Coop- due to AEs. erative Group. The effect of treatment on mortality in As has been reported in previous clinical stud- ‘mild’ hypertension: results of the Hypertension Detec- 21,22 tion and Follow-up program. N Engl J Med 1982; 307: ies, treatment with mibefradil was associated 976–980. with a modest decrease in mean heart rate of 2– 5 Cutter J, MacMahon S, Furberg C. Controlled clinical 5 bpm at the effective doses of 50 and 100 mg. This trials of drug treatment for hypertension: a review. Am decrease did not reach the level of statistical signifi- J Hypertens 1989; 13 (Suppl I): I36–I44. cance, but is worth noting because there seemed to 6 Pool P, Seagren S, Salel A. Metabolic consequences of be a clear dose effect and this decrease has been con- treating hypertension. Am J Hypertens 1991; 4 (suppl sistently reported in previous studies. The effect of 7): 494S–502S. mibefradil on heart rate is of particular importance, 7 Cappuccio F et al. A double-blind study of the blood as the observations of epidemiologic studies suggest pressure lowering effect of a thiazide diuretic in hyper- that a lower heart rate is associated with a reduction tensive patients already on nifedipine and a beta- blocker. J Hypertens 1987; 5: 733–738. in cardiovascular morbidity and mortality, 8 Cappuccio F et al. A double-blind crossover study of especially in patients with cardiovascular dis- the effect of concomitant diuretic therapy in hyperten- 28–32 eases. Since many individuals with hypertensive patients treated with amlodipine. Am J Hypertens sion have – or might develop – ischaemic heart dis- 1991; 4: 297–302. ease, the decrease in cardiac workload and oxygen 9 Nicholson J, Resnick L, Laragh J. Hydrochlorothiazide consumption secondary to lowered heart rate and is not additive to verapamil in treating essential hyper- BP associated with mibefradil therapy may prove tension. Arch Intern Med 1989; 149: 125–128. beneficial. This assumption, however, needs to be 10 Poulter N, Thompson A, Sever P. A double-blind, pla- evaluated in large, prospective studies. cebo-controlled, crossover trial to investigate the The decrease in heart rate observed with mibefra- additional hypotensive effect of a diuretic (mefruside) to that produced by nifedipine. J Cardiovasc Pharma- dil was reflected in a higher incidence of asymptom- col 1987; 10 (Suppl 10): 53–56. atic sinus bradycardia. The slight increase in PQ 11 Glasser S et al. Safety and efficacy of amlodipine interval observed with mibefradil was also reflected added to hydrochlorothiazide therapy in essential by a slightly higher incidence of first-degree AV hypertension. Am J Hypertens 1989; 2: 154–157. block. However, no mibefradil-treated patients 12 Burris J et al. An assessment of diltiazem and hydroch- developed higher degree AV block. lorothiazide in hypertension. JAMA 1990; 263: 1507– In conclusion, the addition of once-daily doses of 1512. 50 or 100 mg mibefradil to the regimen of patients 13 Osterrieder W, Holck M. In vitro pharmacologic profile + with hypertension uncontrolled by HCTZ alone is of Ro-40-5967, a novel Ca2 channel blocker with effective in improving BP control. Combination potent vasodilator but weak inotropic action. J Car- diovasc Pharmacol 1989; 13: 754–759. treatment with mibefradil and HCTZ was safe and 14 Welker H et al. Ro 40-5967: pharmacokinetics of a new well tolerated, and the anithypertensive response to calcium antagonist. Eur J Clin Pharmacol 1989; 36: mibefradil in these patients is comparable to that A304. seen in patients with mild-to-moderate essential 15 Portegies M et al. Lack of negative inotropic effects of hypertension receiving mibefradil monotherapy. the new calcium antagonist Ro 40-5967 in patients Mibefradil and HCTZ in hypertension S Carney et al 466 with stable angina pectoris. J Cardiovasc Pharmacol 24 Spilker B (ed). Combination medicine trials. In: Guide 1991; 18: 746–751. to clinical trials. Raven Press: New York, 1991, 16 Clozel J-P, Veniant M, Osterrieder W. The structurally pp 361–366. novel Ca2+ channel blocker Ro 40-5967, which binds 25 Epstein M, DeMicheli A, Forster H. Natriuretic effects to the [3H] desmethoxyverapamil receptor, is devoid of calcium antagonists in humans: a review of experi- of the negative inotropic effects of verapamil in normal mental evidence and clinical data. Cardiovasc Drug and failing rat hearts. Cardiovascular Drugs Ther 1990; Rev 1992; 9: 399–413. 4: 731–736. 26 Grimm R Jr et al. Long term effects on plasma lipids 17 Clozel J-P et al. Ro 40-5967: a new non-dihydropyrid- of diet and drugs to treat hypertension. JAMA 1996; ine calcium antagonist. Cardiovasc Drug Rev 1991; 9: 275: 1549–1556. 4–17. 27 Weinberger M. Antihypertensive therapy and lipids. 18 Schmitt R et al. Hemodynamic and humoral effects of Evidence, mechanisms and implications. Arch Intern the novel calcium antagonist Ro 40-5967 in patients Med 1985; 145: 1102–1105. with hypertension. Clin Pharmacol Ther 1992; 52: 28 Gillum R, Makuc D, Feldman J. Pulse rate, coronary 314–323. heart disease, and death: the NHANES I epidemiologic 19 Rutledge A, Triggle D. The binding interactions of Ro + follow-up study. Am Heart J 1991; 121: 172–177. 40-5967 at the L-type Ca2 channel in cardiac tissue. 29 Perski A et al. Minimum heart rate and coronary Eur J Pharmacol 1995, 290: 155–158. atherosclerosis: independent relations to global sever- 20 Mishra S, Hermsmeyer K. Selective inhibition of T- + ity and rate of progression of angiographic lesions in type Ca2 channels by Ro 40-5967. Circ Res 1994; 75: 144–148. men with myocardial infarction at a young age. Am 21 Bernink P, Prager G, Schelling A, Kobrin I. Antihyper- Heart J 1992; 123: 609–616. tensive properties of the novel calcium antagonist mib- 30 Kannel W, Kannel C, Paffenbarger R, Cupples A. Heart efradil (Ro 40-5967): a new generation of calcium rate and cardiovascular mortality: The Framingham antagonists? Hypertension 1996; 27: 426–432. Study. Am Heart J 1987; 113: 1489–1494. 22 Bakx A et al. Effects of the new calcium antagonist 31 Thaulow E, Erikssen J. How important is heart rate? J mibefradil (Ro 40-5967) on exercise duration in Hypertens 1991; 9: 527–530. patients with chronic stable angina pectoris: a multi- 32 Dyer A et al. Heart rate as a prognostic factor for con- center, placebo-controlled study. Am Heart J 1995; onary heart disease and mortality: findings in three 130: 748–757. Chicago epidemiologic studies. Am J Epidemiol 1980; 23 Cleland J et al. Severe hypotension after the first dose 112: 736–749. of enalapril in heart failure. Br Med J 1985; 291: 1309–1312.