Asian Journal of Research in Cardiovascular Diseases

Antihypertensive Efficacy and Safety of the Fixed-dose Combination of Efonidipine and Chlorthalidone in Indian Patient

Bhupesh Dewan *

Department of Medical Services, Zuventus Healthcare Ltd., Zuventus House, Plot Y2, CTS No.: 358/A2, Near Nahur Railway Station, Nahur (W), Mumbai, 400078 Maharashtra, India.

Siddheshwar Shinde

Department of Medical Services, Zuventus Healthcare Ltd., Zuventus House, Plot Y2, CTS No.: 358/A2, Near Nahur Railway Station, Nahur (W), Mumbai, 400078 Maharashtra, India.

Shweta Kondekar

Department of Medical Services, Zuventus Healthcare Ltd., Zuventus House, Plot Y2, CTS No.: 358/A2, Near Nahur Railway Station, Nahur (W), Mumbai, 400078 Maharashtra, India.

*Author to whom correspondence should be addressed.

---

Abstract

Aim: This study aimed at evaluating the efficacy and safety of a fixed-dose combination (FDC) of Efonidipine and Chlorthalidone in a randomized, Phase III trial setting.

Study Design: Multicentric, randomized, double-blind, parallel, comparative, active-controlled Phase III.

Place and Duration of Study: Six geographically distributed sites across India were involved in this trial.

Methodology: Present study enrolled patients of Indian origin who were diagnosed with Stage I or Stage II hypertension as per JNC VII guideline. A total of 240 hypertensive patients were randomized (1:1) to receive either FDC of Efonidipine 40 mg + Chlorthalidone 12.5 mg tablet (E+C group) or FDC of Cilnidipine 10 mg + Chlorthalidone 12.5 mg tablet (C+C group) once daily for 90 days. The study site staff, investigator and patients were blinded to the treatment allocation. Patients were evaluated for changes in their blood pressure (BP) from baseline to Day 30, 60 and 90. BP was recorded as the mean of 3 consecutive measurements taken in a sitting position. the number of patients achieving target BP as per JNC VIII guideline was also evaluated. The safety and tolerability were assessed based on the incidences of adverse events (AEs) and serious adverse events (SAEs) reported.

Results: The mean (±SD) Systolic BP (SBP) and Diastolic BP (DBP) at baseline was 159.10±11.43/101.19±10.03 mmHg in the E+C group. After 30 days of treatment with the E+C group, the mean (±SD) reduction in SBP/DBP of 25.13±16.23/16.11±10.35 mmHg was observed whereas at Day 60 reduction of 32.51±19.73/17.91±11.06 mmHg was seen from baseline. The primary endpoint focused on evaluating the mean BP reduction from baseline at Day 90. As compared to baseline, BP decreased from 159.10±11.43/101.19±10.03 mmHg to 118.95±15.31/ 81.59±3.78 mmHg with a mean reduction of 40.15/19.60 mmHg at day 90 in the E+C group. The secondary endpoint of target BP <140/90 mmHg attainment as per JNC VIII guideline, was also achieved in 90.99% of the patients given the E+C group regimen. Furthermore, it was observed that 94% of Stage I and 88% of Stage II hypertensive patients achieved the target BP goal. Overall, 2.54% of patients from the E+C group reported adverse events (AEs) which were mild in severity and resolved without any sequelae at the end of the study. No unexpected AEs were reported, and the E+C group regimen was well tolerated.

Conclusion: It was concluded that the FDC of Efonidipine 40 mg and Chlorthalidone 12.5 mg was efficacious in the management of hypertension in both Stage I and Stage II hypertensive patients. It was evident from the study results that clinically meaningful reductions in blood pressure were observed over a period of 90 days. The test drug was safe and well tolerated by the patients after being administered as a single tablet daily.

Keywords: Hypertension, fixed-dose combination, efonidipine, chlorthalidone, blood pressure

---

---

---

References

Hannan JA, Commodore-Mensah Y, Tokieda N, Smith AP, Gawlik KS, Murakami L, et al. Improving hypertension control and cardiovascular health: An urgent call to action for nursing. Worldviews Evid Based Nurs. 2022;19(1):6-15.

DOI: 10.1111/wvn.12560

WHO. More than 700 million people with untreated hypertension. Last updated on Aug 2021. Available:https://www.who.int/news/item/25-08-2021-more-than-700-million-people-with-untreated-hypertension

Singh S, Shankar R, Singh GP. Prevalence and associated risk factors of hypertension: A cross-sectional study in Urban Varanasi. Int. J Hypertens. 2017; 2017:5491838. DOI:10.1155/2017/5491838

NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: A pooled analysis of 1201 population-representative studies with 104 million participants. Lancet. 2021;398(10304):957-980. Erratum in: Lancet. 2022 Feb 5;399(10324):520. PMID: 34450083.

DOI: 10.1016/S0140-6736(21)01330-1

DiPette DJ, Skeete J, Ridley E, Campbell NRC, Lopez-Jaramillo P, Kishore SP, Jaffe MG, Coca A, Townsend RR, Ordunez P. Fixed-dose combination pharmacologic therapy to improve hypertension control worldwide: Clinical perspective and policy implications. J Clin Hypertens (Greenwich). 2019;21(1):4-15. Epub 2018 Nov 27. PMID: 30480368.

DOI: 10.1111/jch.13426

Mallat SG, Itani HS, Tanios BY. Current perspectives on combination therapy in the management of hypertension. Integr Blood Press Control. 2013;6:69-78. PMID: 23837009.

DOI: 10.2147/IBPC.S33985

Bangalore S, Shahane A, Parkar S, Messerli FH. Compliance and fixed-dose combination therapy. Curr Hypertens Rep. 2007;9(3):184-9. PMID: 17519122.

DOI: 10.1007/s11906-007-0033-3

Satsoglou S, Tziomalos K. Fixed-dose combinations: A valuable tool to improve adherence to antihypertensive treatment. J Clin Hypertens (Greenwich). 2018;20 (5):908-909.

Epub 2018 Apr 27

PMID: 29700948

PMCID: PMC8030904.

DOI: 10.1111/jch.13299

Go AS, Bauman MA, Coleman King SM, Fonarow GC, Lawrence W, Williams KA, et al. An effective approach to high blood pressure control: A science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension. 2014;63:878–885.

Safar ME, Blacher J. Thiazide-like/calcium channel blocker agents: A major combination for hypertension management. Am J Cardiovasc Drugs. 2014;14(6):423-32. Erratum in: Am J Cardiovasc Drugs. 2015;15(1):75.

PMID: 25163857.

DOI: 10.1007/s40256-014-0087-y

Tanaka H, Shigenobu K. Efonidipine hydrochloride: A dual blocker of L- and T-type ca(2+) channels. Cardiovasc Drug Rev. 2002;20(1):81-92. PMID: 12070536.

DOI: 10.1111/j.1527-3466.2002.tb00084.x

Hayashi K, Kumagai H, Saruta T. Effect of efonidipine and ACE inhibitors on proteinuria in human hypertension with renal impairment. American Journal of Hypertension. 2003;16(2):116-22.

Kerndt CC, Patel JB. Chlorthalidone. [Updated 2022 May 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.

Available:https://www.ncbi.nlm.nih.gov/books/NBK553174/

Dominiczak AF, de Champvallins M, Brzozowska-Villatte R, Asmar R; Study coordinators, investigators. Efficacy of a new single-pill combination of a thiazide-like diuretic and a calcium channel blocker (indapamide sustained release/amlodipine) in essential hypertension. J Hypertens. 2019;37(11):2280-2289.

PMID: 31246894.

DOI: 10.1097/HJH.0000000000002177

Rimoldi SF, Messerli FH, Chavez P, Stefanini GG, Scherrer U. Efficacy and safety of calcium channel blocker/diuretics combination therapy in hypertensive patients: A meta-analysis. J Clin Hypertens (Greenwich). 2015;17(3):193-9.

PMID: 25556777.

DOI: 10.1111/jch.12462

Lu F, Zhao Y, Liu Z, Sun H, Zhao Y, Sun S, et al. A 48-week study of amlodipine plus amiloride / hydrochlorothiazide vs. amlodipine plus telmisartan in the treatment of hypertension. Int J Clin Pract. 2012 Aug;66(8):792-799. PMID: 22805271.

DOI: 10.1111/j.1742-1241.2012.02943.x

Morgan TO, Anderson AI, MacInnis RJ. ACE inhibitors, beta-blockers, calcium blockers, and diuretics for the control of systolic hypertension. Am J Hypertens. 2001;14(3):241-7. PMID: 11281235.

DOI: 10.1016/s0895-7061(00)01266-8

Matsuzaki M, Ogihara T, Umemoto S, Rakugi H, Matsuoka H, Shimada K, et al; Combination therapy of hypertension to prevent cardiovascular events trial group. Prevention of cardiovascular events with calcium channel blocker-based combination therapies in patients with hypertension: A randomized controlled trial. J Hypertens. 2011;29(8):1649-59. PMID: 21610513.

DOI: 10.1097/HJH.0b013e328348345d

Masumiya H, Shijuku T, Tanaka H, Shigenobu K. Inhibition of myocardial L- and T-type Ca2+ currents by efonidipine: Possible mechanism for its chronotropic effect. Eur J Pharmacol. 1998;349(2-3):351-7. PMID: 9671117.

DOI: 10.1016/s0014-2999(98)00204-0

Hayashi K, Homma K, Wakino S, Tokuyama H, Sugano N, Saruta T, Itoh H. T-type Ca channel blockade as a determinant of kidney protection. Keio J Med. 2010;59(3):84-95.

PMID: 20881449.

DOI: 10.2302/kjm.59.84

Sasaki H, Saiki A, Endo K, Ban N, Yamaguchi T, Kawana H, et al. Protective effects of efonidipine, a T-and L-type calcium channel blocker, on renal function and arterial stiffness in type 2 diabetic patients with hypertension and nephropathy. Journal of Atherosclerosis and Thrombosis. 2009:16.

Mancia G. Blood pressure reduction and cardiovascular outcomes: past, present, and future. Am J Cardiol. 2007;100(3A):3J-9J. PMID: 17666195.

DOI: 10.1016/j.amjcard.2007.05.008

Gradman AH, Parisé H, Lefebvre P, Falvey H, Lafeuille MH, Duh MS. Initial combination therapy reduces the risk of cardiovascular events in hypertensive patients: A matched cohort study. Hypertension. 2013;61(2):309-18. PMID: 23184383.

DOI:10.1161/HYPERTENSIONAHA.112.201566

James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-20.

DOI:10.1001/jama.2013.284427

Mancia G, Rea F, Corrao G, Grassi G. Two-drug combinations as first-step antihypertensive treatment. Circ Res. 2019;124(7):1113-1123.

DOI:10.1161/CIRCRESAHA.118.313294