Original ArticlePerindopril and Indapamide versus Losartan in the Treatment of Acta Hypertension Cardiol Sin 2005;21:199-206 Hypertension Low-Dose Perindopril and Indapamide Combination Compared with Losartan in the Treatment of Systemic Hypertension: A Randomized, Double-Blind Study Chien-Hsun Hsia1 and Yu-Deh Su2 Background and Purpose: We compared the efficacy and safety of a low-dose combination of perindopril and indapamide (P/I, 2/0.625 mg) with losartan (50 mg) in Taiwanese patients with mild to moderate essential hypertension. Methods: Fifty patients with mild to moderate essential hypertension were randomized to receive either P/I or losartan once daily for a period of 12 weeks after a 2-week run-in phase. After 8 weeks treatment, if the office blood pressure (BP) was 140/90 mmHg or greater, the dose was doubled. Response and normalization rates (systolic blood pressure [SBP] less than 140 mmHg and diastolic blood pressure [DBP] less than 90 mmHg), extent of BP reduction, and proportion of patients necessitating increase of dose were compared both in full set and per protocol set analyses. Results: The baseline characteristics were comparable between the two patient groups. Normalization rate was significantly higher in the P/I group than in the losartan group (69.2% vs 41.7%) (p < 0.05); so was the response rate (80.8% vs 54.2%) (p < 0.05). Mean sitting SBP and sitting DBP fell by 15.2 ± 10.0 and 9.5 ± 4.7 mmHg, respectively, in the P/I group (p < 0.001) and by 11.6 ± 12.3 and 6.7 ± 7.4 mmHg, respectively, in the losartan group (p < 0.001). The falls were greater with P/I than those with losartan; however, these differences did not reach statistical significance. Both treatments were well tolerated, and laboratory examinations did not show any significant difference between two groups. Conclusions: A low-dose combination of P/I is more effective than losartan in the treatment of mild to moderate essential hypertension, with similar safety profiles. The results suggest that low-dose combination of P/I can be considered as an alternative for the first-line antihypertensive treatment. Key Words: Hypertension · Low-dose combination therapy · Perindopril · Indapamide · Losartan INTRODUCTION end-organ damage.1,2 A case control study in northwest England3 suggested that the quality of hypertension con- Treating hypertension is of benefit for preventing trol correlated strongly with risk of stroke. Compared with non-hypertensive subjects, hypertensive patients re- ceiving treatment whose average pre-event systolic blood pressure (SBP) was controlled to 140 mmHg or Received: October 4, 2005 Accepted: October 26, 2005 1Department of Cardiology, 2Department of Family Medicine, less had an adjusted odds ratio for stroke of 1.3 (95% Changhua Christian Hospital, Changhua, Taiwan. confidence interval [95% CI], 0.6-2.7). Those with fairly Address correspondence and reprint requests to: Dr. Chien-Hsun well controlled (SBP, 140-149 mmHg), moderately con- Hsia, Department of Cardiology, Changhua Christian Hospital, No. 135 Nanhsiao Street, Changhua 500, Taiwan. Tel: 886-2-2568-1380 trolled (SBP, 150-159 mmHg), or poorly controlled ext. 323; Fax: 886-2-2568-1390; E-mail: [email protected] (SBP, ³ 160 mmHg) hypertension, or those untreated 199 Acta Cardiol Sin 2005;21:199-206 Chien-Hsun Hsia et al. had progressively increasing risks of stroke: 1.6, 2.2, 3.2 consent. and 3.5, respectively. Moreover, 21% of the cases of The active treatment phase consisted of a fixed-dose stroke were attributable to inadequate control with an- period for 8 weeks (W0 to W8) and titration period for 4 tihypertensive treatment.3 Despite the evidence of the weeks (W8 to W12). Patients in the P/I group received 1 need to treat hypertension, blood pressure (BP) is still capsule of P/I plus a placebo daily, while those in the poorly controlled in 27% and 6% of patients in USA4 losartan group received 1 capsule of losartan 50 mg plus and England,5 respectively. The reasons for failure to a placebo daily in the morning at breakfast with a glass achieve satisfactory BP control are multifactorial, and of water. The dose was doubled during the first 8 weeks poor compliance with the antihypertensive therapy and of treatment if the patient’s sitting SBP (sSBP) was 140 adverse effects resulting from the treatment may be con- mmHg or greater or sitting diastolic BP (sDBP) was 90 tributory. mmHg or greater. The study was approved by the Insti- Fixed low-dose combination of two antihypertensive tutional Review Board (IRB) of Changhua Christian drugs is a new approach to the treatment of hyperten- Hospital (CHCH). sion. The combination of two antihypertensive drugs used each at infra-therapeutic levels but acting synergis- tically offers many advantages. If different patients METHODS respond differently to different groups of antihyper- tensive agents, then a combination of antihypertensive To be enrolled, patients had to be 18 to 75 years of agents acting together would have a greater chance of age and non-obese (body mass index (BMI) < 30 kg/m2), success in achieving satisfactory BP control.6 Because and were required to have essential uncomplicated, mild many, and probably most, side effects are dose-related, to moderate hypertension, defined as the mean sSBP of and because side effects differ between drug groups, it three consecutive measurements at W0 of 140-180 follows that when an equivalent antihypertensive effect mmHg and sDBP of 90-105 mmHg. Exclusion criteria is obtained by combination of two drugs at a low dose included: pregnancy; breast feeding; participation in a from two different drug groups, the side effect profiles previous drug trial over the past one month; currently can be expected to be lower.6 taking more than two antihypertensive agents; secondary In this randomized, double-blind, active-control hypertension; complicated hypertension with target or- study, we aimed to compare the efficacy and safety of a gan damage, which included retinopathy, macroalbu- low-dose combination, perindopril and indapamide, (P/I, minuria, or renal failure (serum creatinine > 2.0 mg/dL); 2/0.625 mg) with losartan (50 mg) as the first-line treat- history of myocardial infarction; Class III and IV ment for mild to moderate hypertension in Taiwanese chronic heart failure; abdominal aneurysm or peripheral patients. artery disease; history of strokes; history of allergy to perindopril, indapamide, losartan, or sulfonamides; re- cent history of unstable angina or undergoing percu- PATIENTS AND METHODS taneous coronary angioplasty, coronary bypass surgery or arterial surgery within the previous 3 months; deep Study Design vein thrombosis or pulmonary embolism within the pre- This was a prospective, randomized, double-blind, vious 6 months; acute infection which would preclude parallel-group study to compare the efficacy and safety end-point evaluation or the progress in the study; anemia between perindopril/indapamine (P/I, 2/0.625 mg) com- (hemoglobin < 10 gm/dL); cancer; AIDS; requirement of bination therapy and losartan (50 mg) once daily for 12 transfusion or hemodialysis; current bleeding; history of weeks (W0 to W12) in Taiwanese patients with mild or Quincke edema in relationship with angiotensin- moderate hypertension. Following a 2-week single-blind converting enzyme inhibitor (ACEI); hepatic disease placebo run-in period (W-2 to W0), enrolled patients with or without complications, defined as abnormal liver were randomized to receive either P/I (2/0.625 mg) or function tests > 3-fold of upper limit of normal or biliru- losartan (50 mg) treatment after giving their informed bin total > 2-fold of upper limit of normal; alcoholism; Acta Cardiol Sin 2005;21:199-206 200 Perindopril and Indapamide versus Losartan in the Treatment of Hypertension drug abuse; hypokalemia (< 3.5 mmol/L) or hyper- mmHg or greater, or reduction of sSBP by 20 mmHg or kalemia (> 5.5 mmol/L); electrocardiogram (ECG) at the greater; the variation in sSBP and sDBP between W0 selection visit showing a bradycardia (< 50 beat per and W12; the between-group comparisons in terms of re- minute), torsades de pointe, ventricular tachycardia, ven- sponse rate and reduction of sDBP; and proportion of tricular extrasystoles (except isolated), or significant patients requiring dose adjustment at visit W8. increase in the QT interval. The heart rate was measured at each visit in sitting Oral potassium supplements were given immedi- position. A 12-lead ECG was carried out before and after ately to any patient whose potassium level measured at treatment. Hematological and biochemical analysis, W8 was 3.5 mmol/L or less. All concomitant medi- which included sodium, potassium, chloride, uric acid, cations specified as contraindicated, and all other anti- urea nitrogen, creatinine, hemoglobin and white blood hypertensive treatments or any treatment having an cell count with differentials, platelets, fasting blood glu- effect (direct or not) on the BP were not allowed during cose, total protein, lipids profiles (total cholesterol, the study. Other concomitant treatments required during triglycerides, high-density lipoprotein (HDL) chole- the study because of the patient’s condition and modifi- sterol, low-density lipoprotein (LDL) cholesterol), ami- cation of these concomitant treatments were recorded. notransaminases, and alkaline phosphatase, were mea- Concomitant treatment contraindicated in patients sured before and after 12 weeks of therapy. receiving perindopril included: lithium, while those con- Any symptoms or signs presented or reported by the traindicated in patients receiving indapamide included lit- participant and any abnormal values of biological sam- hium, baclofen; iodine-containing preparation (risk of renal ples considered to be clinically relevant were recorded as failure); treatments at risk of causing torsades de pointe “adverse event” at each visit. (amiodarone, astemizole, disopyramide, sotalol, sultopride, vincamine); and class 1 antiarrhythmic agents. Concomi- Statistical Analysis tant treatments contraindicated in patients receiving The study data management and statistical analysis losartan were spironolactone, triamterene, lithium, and were performed by iStat.