Abstract. INTRODUCTION Hypertension is a highly prevalent condition and has. Lekha Pathak*, MS Hiremath**, PG Kerkar***, VG Manade+ Original Article

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1 Original Article Multicentric, Clinical Trial of S-Amlodipine 2.5 mg Versus Amlodipine 5 mg in the Treatment of Mild to Moderate Hypertension - A Randomized, Doubleblind Clinical Trial Lekha Pathak*, MS Hiremath**, PG Kerkar***, VG Manade+ Abstract Objective : To compare the efficacy and tolerability of 2.5 mg of S-Amlodipine with 5 mg of Amlodipine in the treatment of mild to moderate hypertension in a double blind, double dummy, randomized, comparative clinical trial. Method and Materials : Two hundred OPD patients (97 women and 103 men) with mean age 53.4 ± 5.58 years, with stage 1 and stage 2 hypertension were enrolled for the study after obtaining informed written consent. Twelve patients were dropped out as lost to follow up. Ninety seven patients in the S-Amlodipine 2.5 mg treatment group and ninety one patients in the Amlodipine 5 mg treatment group completed the study. Those with a history of angina pectoris, myocardial infarction or recent cerebrovascular accident in the past six months and those with stage 3 and stage 4 hypertension were excluded from the study. Those showing a history of secondary hypertension were also excluded from the study. For the first two weeks all patients received dummy tablets of both S-Amlodipine and Amlodipine, as a wash out therapy and to get the actual blood pressure reading. After two weeks, enrolled patients received a preparation containing either S-Amlodipine (containing 2.5 mg of S- Amlodipine) and dummy tablets of Amlodipine or Amlodipine besylate (containing 5 mg of racemic Amlodipine) and dummy tablets of S-Amlodipine once daily for a period of six weeks. Results : The results were analyzed by Student s t test. The reduction in the average systolic and diastolic blood pressure, in the standing, supine and sitting postures in the S-Amlodipine group as well as in the Amlodipine group after six weeks of treatment was highly significant (P ). The baseline values for average systolic blood pressure in standing, supine and sitting positions in the S-Amlodipine 2.5 mg treatment group were found to be ± 10.28, ± and ± mm of Hg respectively, which after treatment of six weeks changed to ± 7.4, ± 8.56 and ± 8.32 mm of Hg. The baseline values for average systolic blood pressure in standing, supine and sitting positions in the Amlodipine 5 mg treatment group were found to be ± 10.36, ± and ± mm of Hg respectively, which after treatment of six weeks changed to ± 6.33, ± 7.11 and ± 7.54 mm of Hg. The baseline values for average diastolic blood pressure in standing, supine and sitting positions in the S-Amlodipine 2.5 mg treatment group were found to be ± 6.22, ± 7.18 and ± 6.6 mm of Hg respectively, which after treatment of six weeks changed to 86.0 ± 4.70, ± 5.20 and ± 5.68 mm of Hg. While the baseline values for average diastolic blood pressure in standing, supine and sitting positions in the Amlodipine 5 mg treatment group were found to be ± 5.54, ± 6.71 and ± 6.38 mm of Hg respectively, which after treatment of six weeks changed to ± 4.77, ± 5.44 and ± 5.98 mm of Hg. However the difference in the average reduction in systolic and diastolic blood pressures, in the two treatment groups, in the sitting, supine and the standing positions was not found to be statistically significant (p > 0.1) (CI = 0.95). There was no statistically significant change in the levels of serum creatinine, SGOT, SGPT, HDL, LDL, triglyceride and total cholesterol in patients receiving Amlodipine 5 mg. The reduction in total cholesterol as well as triglyceride level in the S-Amlodipine 2.5 mg treatment group was found to be greater but it failed to show any statistically significant difference. Conclusion : S-Amlodipine 2.5 mg is found to be equivalent in its efficacy and tolerability when compared to Amlodipine 5 mg in the treatment of mild to moderate hypertension. INTRODUCTION Hypertension is a highly prevalent condition and has become a major cause of concern due to it s insidious *Director - Professor and Head (Ex), Department of Cardiology, Sir JJ Group of Hospitals, Mumbai. **Consulting Cardiologist & Head, Ruby Hall Clinic, Pune. ***Professor and Head, Department of Cardiology, GS Medical College and KEM Hospital, Mumbai. +Consulting Physician and Cardiologist, Kolhapur. Received : ; Accepted : nature of onset and also due to the high rates of mortality and morbidity associated with the condition. Amlodipine belongs to the dihydropyridine group of calcium channel blockers. The dihydropyridine group is an important group of drugs which can be used alone in the treatment of mild to moderate hypertension and is equally effective especially in the elderly subjects. 1 Due to it s prolonged half-life, a missed dose is of little significance. It is considered safer than other drugs of the JAPI VOL. 52 MARCH

2 same class. 2 At a dose range of mg daily, amlodipine produces a significant reduction in blood pressure. 3 It has also been found to be useful in reducing both symptomatic and asymptomatic ischemic events in patients with chronic stable angina when used in combination with other antihypertensive treatment. 4 Like other drugs of the same class, it does not alter the plasma concentration of lipids, uric acid or electrolytes. 1 The common side effects associated with Amlodipine are palpitation, hypotension, nausea and edema. 5 Chirality of a drug is an upcoming area and has several benefits to offer. Amlodipine is available as a racemic mixture of (R) and (S) isomers. Various studies of the racemic mixture of (R) and (S) isomers show that the S (-) isomer of amlodipine has a grater pharmacological effect. 7 Studies on amlodipine as a displace of (3H) (-) PN binding showed that displacement was stereoselective with the S (-) isomer being 1000 times more potent than the R (+) isomer. 7 It is porposed that the observed enantioselectivity of oral amlodipine is due to differences in the systemic blood clearance of the enantiomers. 8 Use of isolated S-Amlodipine, the pharmacologically active isomer of amlodipine instead of the racemic mixture could be of immense benefit as the required dose and systemic toxicity can be reduced. Hence, the present study has been conducted to compare the efficacy and tolerability of S-amlodipine with racemic amlodipine in patients of mild to moderate hypertension. ThePrimary objective was to compare the efficacy of S-Amlodipine 2.5 mg with Amlodipine 5 mg in the treatment of mild of moderate hypertension and Secondary objective was to compare the tolerability of the two treatments. MATERIAL AND METHODS Setting : Patients attending the OPD at the study centres. The study was completely sponsored by Emcure Pharmaceuticals Ltd., Pune. Ethical Committee approval : Ethical committee approval was sought from all the concerned Institutional ethics committee. Study Population Patients attending the OPD at the centers were enrolled. Two hundred patients of both sexes, with clinically confirmed stage 1 and stage 2 hypertension were enrolled for the study, after obtaining informed written consent. Patients with a previous history of myocardial infarction, angina pectoris or cerebrovascular accidents in the last six months were excluded from the study. Those with a history of secondary and malignant hypertension were also excluded from the study. A washout period of two weeks was given to patients who were on prior antihypertensive therapy. Interventions Based on the standard dose, patients were randomized and given either of the following preparations- 1) Tab. S-amlodipine containing 2.5 mg of S-Amlodipine and dummy tablets of Amlodipine. 2. Tab. Amlodipine containing 5 mg of Amlodipine and dummy tablets of S-Amlodipine. All the medications were provided by Emcure Pharmaceuticals Limited, Dapodi, Pune. Thus, One hundred patients received S-Amloidpine and one hundred received Amlodipine. Both medications were administered once daily, per orally, for a period of six weeks, after a washout period of two weeks. Thus for the first two weeks all patients received dummy tablets of both S- Amlodipine and Amlodipine. Out of the two hundred enrolled patients, one hundred and eighty-eight (ninety seven on S- Amlodipine and ninety-one on Amlodipine) completed the study. Randomization and Blinding method Prior to commencement of treatment randomization was done in blocks of ten with the help of computer-based programme (True Epistat Standard version 1999). The patients were enrolled in a chronological order. The study medications for both groups were dispensed in tamper proof, opaque, plastic bottles that were similar in appearance. Labels on the bottles contained study code, patient serial number, manufacturing date and expiry date and space for date of dispensing. The dosage instructions to the patient were enclosed in the bottles. The active medication and the dummy tablets of both the medications were made identical in size, shape and colour. Amlodipine active and dummy tablets were blue in colour, while S-Amlodipine active and dummy tablets were white in colour. Hence, neither the paient nor the investigator was aware of the medication received by the patients. The investigator monitored the patient for clinical signs and symptoms and evaluated the laboratory investigations. All the patients were sent to a single laboratory for conducting the investigations, to ensure uniformity of the procedure and methodology used. Variables All patients were subjected to a clinical examination and measurement of blood pressure to diagnose the type of hypertension. The average systolic and diastolic blood pressure at baseline, for both the treatment groups was comparable. The systolic and diastolic blood pressure of each patient was recorded every week in standing, supine and sitting positions. Incidence of adverse events reported by the patients was used for tolerability assessment. Patients were asked to record in the patient diary card as soon as they take the medication and drug accountability was done by the investigator to cross check. They were asked to report any of the adverse effects, to be reported on a prescribed adverse drug reaction form. Any adverse event observed during the study period was recorded in the case report form. The biochemical variables, diagnosed were serum creatinine, SGOT, SGPT, total cholesterol, LDL, HDL and triglycerides. Statistical analysis The demographic data of the two groups was compared by paired Student s t-test JAPI VOL. 52 MARCH

3 Student s t-test was used to test the difference between reduction in the average systolic and diastolic blood pressure. Efficacy was estimated by measuring the average systolic and diastolic blood pressure before and after treatment. The difference in the reduction in the average systolic and diastolic blood pressure in standing, supine and sitting postures in the two treatment groups was measured by paired Student s t test. Tolerability was estimated by measuring the proportion of patients reporting adverse-events. RESULTS Blood pressure changes In the S-Amlodipine (2.5 mg) treated group : The average systolic blood pressure (in mm of Hg) in the standing position was ± pressure after treatment (at the end of six weeks) was ± The reduction in the average systolic blood pressure was found to be statistically significant. (P ) (Table 1, Fig. 1). The average diastolic blood pressure prior to the treatment, in the standing position was found to be ± 6.22 as compared to ± 4.70 mm of Hg after six weeks. The reduction in the average diastolic blood pressure was found to statistically significant (p ). The average systolic blood pressure (in mm of Hg) in the supine position was ± prior to treatment. The corresponding average systolic blood pressure after treatment (at the end of six weeks) was found to be ± The reduction in the average systolic blood pressure in the supine position was found to be statistically significant. (p ) (Table 1, Fig. 2). The average diastolic blood pressure prior to the treatment, in the supine position was found to be ± 7.18 as compared to ± 5.20 mm of Hg after six weeks. The reduction in the average diastolic blood pressure was found to be statistically significant (p ). The average systolic blood pressure (in mm of Hg) in the sitting position was ± prior to treatment. The corresponding average systolic blood pressure after treatment (at the end of six weeks) was ± The reduction in the average systolic blood pressure in the sitting position was found to be statistically significant. (P ) (Table 1, Fig. 3). The average diastolic blood pressure prior to the treatment, in the sitting position was found to be ± as compared to ± 9.36 mm of Hg after six weeks. The reduction in the average diastolic blood pressure was found to be statistically significant (p ). In the Amlodipine (5 mg) treated group : The average systolic blood pressure (in mm of Hg) in the standing position was ± prior to treatment. The corresponding mean blood pressure after treatment (at the end of six weeks) was ± The reduction in the average systolic blood pressure in the standing position was found to be statistically significant. (p ) (Table 1, Fig. 1). The average diastolic blood pressure in the standing position prior to the treatment was found to be ± 5.54 as compared to ± 4.77 mm of Hg after six weeks of treatment. The reduction in the diastolic blood pressure in the standing position was found to be statistically significant. In the group treated with Amlodipine (5 mg), the average systolic blood pressure (in mm of Hg) in the supine position was ± prior to treatment. The corresponding Table : Reduction in average systolic and diastolic blood pressure in the standing, supine and sitting positions Mean blood pressure Drugs with Dosage Standing Supine Sitting Prior After Prior After Prior After mean ± SD mean ± SD mean ± SD mean ± SD mean ± SD mean ± SD (n=97) S-Amlodipine (2.5 mg) Systolic blood pressure ± ± 7.40 ± ± 8.56 ± ± 8.32 Reduction in BP (mm of Hg) ± ± ± 2.34 S-Amlodipine (2.5 mg) Diastolic blood pressure ± 6.22 ± 4.70 ± 7.18 ± 5.20 ± 6.60 ± 5.68 Reduction in BP (mm of Hg) ± ± ± 0.98 (n=91) Amlodipine (5 mg) Systolic blood pressure ± ± 6.33 ± ± 7.11 ± ± 7.54 Reduction in BP (mm of Hg) ± ± ± 3.0 Amlodipine (5 mg) Diastolic blood pressure ± 5.54 ± 4.77 ± 6.71 ± 5.54 ± 6.38 ± 5.98 Reduction in BP (mm of Hg) ± ± ± 0.40 Between S Amlodipine 2.5 mg and Amlodipine 5 mg p value (systolic BP) p value (diastolic BP) = > As p > 0.1, the difference between groups treated with Amlodipine (5 mg) and S-Amlodipine (2.5 mg) is not significant. JAPI VOL. 52 MARCH

4 Fig. 1 : Reduction in the standing systolic and diastolic blood pressure. Fig. 3 : Reduction in the sitting systolic and diastolic blood pressure. Fig. 2 : Reduction in the supine systolic and diastolic blood pressure. average systolic blood pressure after treatment (at the end of six weeks) was ± The reduction in the average systolic blood pressure in the supine position was found to be statistically significant (p ) (Table 1, Fig. 2). The average diastolic blood pressure in the supine position was found to be ± 6.71 as compared to ± 5.54 mm of Hg after six weeks of treatment. The reduction in the average diastolic blood pressure in supine position was found to be statistically significant (p < ). The average systolic blood pressure (in mm of Hg) in the sitting position was ± prior to treatment. The corresponding average systolic blood pressure after treatment (at the end of six weeks) was ± The reduction in the average systolic blood pressure was found to be statistically significant (p ) (Table 1, Fig. 3). The average diastolic blood pressure in the sitting position before treatment was found to be ± 6.38 mm of Hg, as compared to ± 5.98 after six weeks of treatment. The reduction in the average diastolic blood pressure was found to be statistically significant (p < ). Although both the treatment groups showed significant reduction in the average systolic and diastolic blood pressure, the reduction was not found to be statistically significant between the two treatment groups. None of the patients in either drug group reported any adverse drug effects. Other laboratory investigations : In the group treated with S-Amlodipine (2.5 mg) the mean serum creatinine prior to treatment was 0.83 ± After treatment, the mean values were found to be 0.83 ± 0.13 (p = 1.00). In the Amlodipine treated group, the corresponding values were 0.83 ± 0.17 before treatment which reduced t 0.81 ± 0.14 after treatment (p = 0.63). Table 2 : Different parameters before and after treatment with S-Amlodipine and Amlodipine S-Amlodipine (2.5 mg) (n=97) Amlodipine (5 mg) (n=91) Parameter Before After Reduction p value Before After Reduction p value treatment treatment (R1) treatment treatment (R2) Serum creatinine ± 0.17 ± 0.13 ± 0.17 ± 0.14 SGOT ± 6.69 ± 5.17 ± 6.67 ± 4.95 SGPT ± 7.13 ± 5.14 ± 7.75 ± 4.42 LDL ± ± ± ± HDL ± 5.65 ± 6.38 ± 6.98 ± 7.47 Total cholesterol ± ± ± ± Triglycerides ± ± ± ± JAPI VOL. 52 MARCH

5 SGOT prior to treatment was ± 6.69 as compared to ± 5.17 after treatment (= 0.83). In the Amlodipine treated group, the corresponding values were ± 6.67 before treatment and ± 4.95 after treatment (p = 0.77). In both the groups the change in the SGOT levels was not found to be significant. SGPT prior to treatment was ± 7.27 as compared to ± 5.14 (p = 0.69). In the Amlodipine treated group, the corresponding values were ± 7.75 before treatment and 15.1 ± 4.42 after treatment (p = 0.75). In both the groups the change in the SGPT levels was not found to be significant. LDL prior to treatment was ± After treatment, the mean LDL levels reduced to ± (p = 0.25). In the Amlodipine treated group, the corresponding values were ± before treatment and ± after treatment (p = 0.47). In both the groups the change in the levels was not found to be statistically significant. HDL prior to treatment was ± After treatment, the values reduced to ± 6.87 (p = 0.81). In the Amlodipine treated group, the corresponding values were ± 6.98 before treatment and ± 7.47 after treatment (p = 0.77). In the both groups the change in the levels was not found to be significant. total cholesterol prior to treatment was ± After treatment, the values reduced to ± (p = 0.33). In the Amlodipine treated group, the corresponding values were ± before treatment and ± after treatment (p = 0.61). In both the groups the change in the levels was not found to be significant. triglycerides prior to treatment was ± After treatment, the values reduced to ± (p = 0.86). In the Amlodipine treated group, the corresponding values were ± before treatment and ± after treatment (p = 0.99). In both the groups the change in the levels was not found to be significant. The reduction in the average systolic and diastolic blood pressure in the two treatment groups was not found to be significant, which confirms that, S-Amlodipine 2.5 mg is equivalent in efficacy and tolerability to Amlodipine (5 mg) in the treatment of mild to moderate hypertension. DISCUSSION Amlodipine is a well-proven therapy for the treatment of mild to moderate hypertension. It is a racemic mixture of R- Amlodipine and S-Amlodipine, both present in equal amounts. Experimental studies have shown that S-Amlodipine has more selectivity and better activity than R-Amlodipine. This study was aimed to determine the efficacy of S- Amlodipine compared to conventional amlodipine in the treatment of mild to moderate hypertension. The observere bias has been taken care of by the double blind double dummy study design where the investigator and patient were kept unaware throughout the study period regarding the medication. The Amlodipine dose used in the present study is a therapeutic dose of 5 mg and a corresponding half strength of S-Amlodipine was used. In both the treatment groups there was a significant reduction in the blood pressure, although the difference between the two treatment groups was not found to be statistically significant. There was no statistically significant change in the levels of serum creatinine, SGOT, SGPT, HDL, LDL, triglyceride and total cholesterol in patients receiving Amlodipine 5 mg. The reduction in total cholesterol as well as triglycerides was found to be higher in the S-Amlodipine treatment group, where as the other parameters did not show any statistically significant change. This observation carries significance in clinical practice, since Indian population is known to suffer from hypertriglyceridemia as well as hypercholesterolemia. Thus S-Amlodipine on long term use may help to improve the lipid profile of the hypertensive patients, who are usually associated with hyperlipidemia. Amlodipine is usually associated with side effects like peripheral oedema, skin erythema, facial flushing and fatigue. Rarely, it may cause gingival hypertrophy and gynecomastia. It was observed in the current study that neither S-Amlodipine nor Amlodipine group reported any side effects over a period of six weeks, but its long term clinical use will determine the tolerability and safety profile. Hence presently, based on the above findings, it may be concluded that 2.5 mg daily dose of S-Amlodipine has a better effect on the lipid profile of the patients, where as its blood pressure lowering activity is similar to that of 5 mg daily dose of racemic Amlodipine. Further long term studies may confirm the better safety profile of S-Amlodipine as compared to the racemic Amlodipine. From the present study it can be concluded that, S- Amlodipine 2.5 mg is equivalent in efficacy to Amlodipine 5 mg in the treatment of mild to moderate hypertension. Acknowledgement This multicenter study received unrestricted research clinical trial grant from Emcure Pharmaceuticals. Emcure Pharmaceutical has commercial interest in the product S- amlodipine. REFERENCES 1. Antihyeprtensive agents and drug therapy of hypertension Oates JA et al in Goodman Gilman s The Pharmacological Basis of Therapeutics. Tenth ed., Mc Graw Hill Publications. USA 2001; Arterial Hypertension Angina Pectoris Myocardial Infarction. Laurence DR et al. In Clinical Pharmacology eighth edition, Churchill Livingstone 1997; Webster J, RObb OJ, Jeffers TA, Scott AK, Petric JC, Towler HM. Once daily amlodipine in the treatment of mild to moderate hypertension. Br J Clin Pharmacol 1987;24: JAPI VOL. 52 MARCH

6 4. Deanfield JE, Detry JM, Lichtlen PR, Magnani B, Sellier P, Thauow E. Amlodipine reduces transient myocardial ischemia in a patients with coronary artery disease : double-blind Circadian Anti-Ischaemia Program in Europe (CAPE Trial). J Am Coll Cardiol 1994;24: Pharmacotherapy of Hypertension. Ch. 26 Satoskar RS, et al. in Pharmacology and Pharmacotherapeutics. Popular Prakashan Arrowsmith JE, et al. Long acting dihydropyridine calcium antagonists. 1.2-Alkoxymethyl derivatives incorporating basis substituents. J Med Chem 1986;29: Burges RA, Gardiner DG, Gwilt M, Higgins AJ, Blackburn KJ, Campbell SF, Cross PE, Stubbs JK. Calcium channel blocking properties of amlodipine in vascular smooth muscles and cardiac muscle in vitro: evidence for voltage modulation of vascular dihydropyridine receptors. J Cardiovasc Pharmacol 1987;9: Laufen H, Leitold M. Enantioselective disposition of oral amlodipine in healthy volunteers. Chirality 1994;6: Goldman S, Stolefuss J, Born L. Determination of the absolute configuration of the active amlodipine enantiomers (-) S :a correction. J Med Chem 1992;35: Announcement - JAPI PRACTI-MED 2004 Sri Ramachandra Deemed University, The New England Journal of Medicine, Harvard Medical International and The Journal of Association of Physicians of India invite you to PRACTI-MED focussing education on the frontlines of care on March 13-14, 2004 at Sri Ramachandra Medical College and Research Institute, Deemed University), Porur, Chennai , India. Conference Focus At the end of the conference, the participant will be able to incorporate into his/her practice recent advances in: * Dyslipidemias * Asthma * Newer coronary risk factors * COPD * Cardiovascular risk reduction * Depression in primary care * Hypertension * Cancer - prevention, management and palliation * Newer respiratory infections and epidemics * HIV/AIDS Rs.600/- Early bird for conference only Rs.850/- Early bird + Breakfast with the professor Rs.750/- Regular for conference only Rs.1000/- Regular + Breakfast with the professor Rs.1000/- Late registration conference only Rs.1250/- Late registration + Breakfast with the professor Rs.500/- Trainee - conference only Rs. 750/- Trainee + Breakfast with the professor (enclosed proof of status) Make all cheques and DDs payable to Sri Ramachandra Medical College- Practimed account Mail to : PRACTIMED, A1 Private Clinic, Sri Ramachandra Medical College and Research Institute (Deemed University), Porur, Chennai For further details please write to Prof. S Thanikachalam, Chairman Steering Committee, Vice Chancellor, Sri Ramachandra Medial College and Research Institute, (Deemed University), Porur, Chennai srmcdfh@hotmail.com/smrc79@eth.net JAPI VOL. 52 MARCH