Original article 813 Efficacy of manidipine/delapril versus losartan/ hydrochlorothiazide fixed combinations in patients with hypertension and diabetes Alejandro Roca-Cusachsa, Roland E. Schmiederb, Filippos Triposkiadisc, Rene´ R. Wenzeld, Ste´phane Laurente, Osvaldo Kohlmann Jrf and Roberto Fogarig, on behalf of the MORE Study Group Background Hypertension markedly increases the already versus S9.3 mmHg) blood pressure were also not high risk for cardiovascular complications in patients with significantly different between treatments. Compliance and diabetes mellitus. Less than one in eight patients with adverse events were comparable for both groups. hypertension and type 2 diabetes have adequately controlled blood pressure. As a result, antihypertensive Conclusion The study demonstrated that the combination combinations are now widely used in management of of manidipine and delapril is as effective as losartan and hypertension associated with diabetes. hydrochlorothiazide in treatment of hypertension in type 2 diabetes. J Hypertens 26:813–818 Q 2008 Wolters Kluwer Methods This double-blind study investigated efficacy of a Health | Lippincott Williams & Wilkins. new fixed dose combination of a calcium antagonist, manidipine 10 mg, and an angiotensin-converting enzyme inhibitor, delapril 30 mg, compared with a combination of an Journal of Hypertension 2008, 26:813–818 angiotensin receptor blocker, losartan 50 mg, and a diuretic, hydrochlorothiazide 12.5 mg. Patients with hypertension Keywords: delapril, fixed dose combination, hypertension, manidipine, type 2 diabetes (blood pressure >– 130/80 mmHg) with controlled type 2 diabetes (HbA1c —< 7.5%) were randomized to manidipine/ Abbreviations: ABPM, ambulatory blood pressure monitor; ACE, U U angiotensin converting enzyme inhibitor; ANCOVA, analysis of covariance; delapril (n 153) or losartan/hydrochlorothiazide (n 161), ANOVA, analysis of variance; ARB, angiotensin receptor blocker; CI, administered once daily for 12 weeks. Patients underwent confidence interval; CVD, cardiovascular disease; DBP, diastolic blood ambulatory blood pressure monitor evaluation at baseline pressure; HCTZ, hydrochlorothiazide; HOT, Hypertension Optimal Treatment study; SBP, systolic blood pressure; SI, smoothness index; and end of treatment. UKPDS, United Kingdom Prospective Diabetes Study aSanta Creu I Sant Pau Hospital, Barcelona, Spain, bUniversity Hospital, Results Mean decreases in 24-h systolic blood pressure Erlangen, Germany, cLarissa University Hospital, Larissa, Greece, dA.O¨ . Hospital e were seen with both manidipine/delapril (S9.3 mmHg) and Zell am See, Zell am See, Austria, Georges Pompidou European Hospital, Paris, France, fFederal University of Sao Paulo, Sao Paulo, Brazil and gIRCCS Policlinic losartan/hydrochlorothiazide (S10.7 mmHg) combinations. San Matteo, Pavia, Italy The mean (95% confidence interval) treatment difference Correspondence to Dr A. Roca-Cusachs, Hypertension Unit, Internal Medicine was S1.4 (S4.5/1.8) mmHg, demonstrating noninferiority of Department, Hospital de la Santa Creu I Sant Pau, Universitat Autonoma de the manidipine/delapril combination. Reduction in 24-h Barcelona, Sant Antoni Maria Claret 167, 08025 Barcelona, Spain Tel: +34 9 35565609; e-mail: [email protected] diastolic blood pressure (S4.6 versus S4.5 mmHg) and daytime (systolic blood pressure S10.5 versus Received 6 July 2007 Revised 23 September 2007 S11.1 mmHg) and night-time (systolic blood pressure S7.1 Accepted 24 October 2007 Introduction but no risk decrease was seen in hypertensive patients Type 2 diabetes is associated with an increased risk of without diabetes [5]. Therefore, more aggressive blood death from cardiovascular disease (CVD) and stroke, as pressure targets (BP < 130/80 mmHg) are recommended well as microvascular diseases [1]. Hypertension affects for patients with diabetes [6]. Despite the availability of 50–80% of patients with type 2 diabetes and markedly a range of antihypertensive treatments, target blood pres- increases the risk of CVD compared with nondiabetic sure values are generally not attained and recent studies subjects [1–3]. The UK Prospective Diabetes Study demonstrated that hypertension was controlled in only (UKPDS) data demonstrated that hyperglycaemia 12% of patients with diabetes [7,8]. and hypertension are independently and additively associ- ated with risk of complications in type 2 diabetes, implying Blood pressure is difficult to control with monotherapy, that both must be minimized [4]. In the hypertension especially in patients with diabetes, highlighting the optimal treatment (HOT) study, a 4 mmHg reduction in requirement of drug combinations [9,10]. The advent diastolic blood pressure (DBP) resulted in a 50% decrease of low-dose, fixed dose combination therapy permits in risk for cardiovascular events in patients with diabetes, physicians to prescribe two drugs in one pill, which 0263-6352 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 814 Journal of Hypertension 2008, Vol 26 No 4 may be able to minimize side effects and improve patient in duplicate, using a sphygmomanometer, prior to admin- compliance. Fixed combinations for treatment of istration of the daily dose of study drug. At 1 day prior hypertension are now recommended by guidelines as a to first and last study drug administrations, patients first-line treatment option [10]. attended the clinic to have an ambulatory blood pres- sure monitor (ABPM) attached and ambulatory blood Manidipine (10 mg)/delapril (30 mg) is a new fixed dose pressure was measured for a 24-h period; for each indi- combination consisting of a calcium antagonist and an vidual patient the same device was used at start and angiotensin-converting enzyme (ACE) inhibitor, both of end of treatment. ABPMs were programmed to measure which are available as single components for hypertension blood pressure every 15 min throughout the 24-h period. management. Calcium antagonists and ACE inhibitors Safety was assessed from blood glucose, body weight, have complementary modes of action and combinations heart rate and adverse events recorded at each study induce additive antihypertensive effects [11]. Both visit. manidipine and delapril have antihypertensive actions maintained for up to 24 h, allowing once daily adminis- The primary efficacy endpoint was the change from tration [12]. This trial was designed to evaluate anti- baseline to final visit in 24-h SBP. Secondary efficacy hypertensive efficacy and safety of the combination of parameters included changes from baseline to final visit manidipine and delapril in patients with type 2 diabetes in mean 24-h DBP, mean daytime (0700 to 2300 h) SBP and hypertension, compared with a combination of and DBP, mean night-time (2300 to 0700 h) SBP and losartan and (HCTZ). DBP and office sitting SBP and sitting DBP at trough, as well as trough-to-peak ratio for SBP and smoothness Materials and methods index for SBP. This was an international, double-blind, randomized, parallel group study designed to demonstrate that the The primary efficacy analysis used an analysis of covari- reduction in mean 24-h systolic blood pressure (SBP) with ance (ANCOVA) on the change from baseline to end of a fixed manidipine/delapril combination was noninferior to treatment in 24-h mean SBP, with baseline as a covariate a fixed combination of losartan/HCTZ in patients and treatment and study centre as fixed factors. In order for with type 2 diabetes and hypertension. The study was the ABPM evaluations to be valid, at least 23 h of recording performed in 28 centres in Spain (nine), Italy (nine), was required, with at least one measurement per hour and Greece (four), Germany (three), France (two) and Brazil over 70% of expected readings. The primary analysis was (one). The protocol was approved by national independent carried out on the per protocol population, defined as ethics committees and the study was conducted in accord- patients completing the study with valid ABPM measure- ance with Good Clinical Practice and the Declaration ments and no protocol violations. The difference between of Helsinki. Written consent was obtained from all parti- adjusted means obtained in the two treatment groups was cipating patients prior to study commencement. calculated and the lower bound (difference losartan/ HCTZ minus manidipine/delapril) of its two-sided 95% All patients had type 2 diabetes controlled by diet and confidence interval (CI) was compared with the prespe- oral agents, with HbA1c 7.5%, and mild to moderate cified noninferiority margin of 5 mmHg; this approach is hypertension, with 24-h ambulatory SBP 130 mmHg equivalent to a 2.5% one-sided test. The same analyses and office sitting DBP 85 and 105 mmHg and used for assessment of primary efficacy variables were used SBP < 160 mmHg. Patients were excluded if they had for secondary variables involving change from baseline. secondary, complicated or severe hypertension (SBP Treatment difference of trough-to-peak ratios was 180 mmHg or DBP 110 mmHg), orthostatic hypoten- assessed by a nonparametric Mann–Whitney test and sion, evidence of CVD other than hypertension, or dia- difference of smoothness indices used analysis of variance betes that was uncontrolled or required insulin treatment. (ANOVA), with treatment as the main effect. For all tests, Concomitant antihypertensives other than study drugs the minimum level of statistical significance was set at were not permitted.