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Dewan, B., Shinde, S., Kondekar, S., & Motwani, N. (2024). A Prospective Efonidipine Efficacy Evaluation in Cardiovascular and Renal Outcomes in

Hypertensive Patients: The PERFECT Trial. British Journal of Healthcare and Medical Research, Vol - 11(5). 50-64.

URL: http://dx.doi.org/10.14738/bjhmr.115.17583.

proteinuria compared to Cilnidipine (from 161.64 ± 8.9 to 152.10 ± 3.9 7.8 mg/g Cr,

p=4240). An independent decrease in proteinuria relative to blood pressure

reduction was observed with Efonidipine. Adverse events were similar between

groups, with no incidences of peripheral edema. Conclusion: Efonidipine and

Cilnidipine effectively controlled blood pressure and reduced proteinuria. The

antiproteinuric effect was more apparent with Efonidipine. Efonidipine improves

cardiovascular and renal outcomes and may be considered an initial treatment

option in hypertensive patients.

Keywords: Efonidipine, Hypertension, Cardioprotection, Renoprotection, Calcium

Channel Blocker

INTRODUCTION

The prevalence of hypertension has doubled in the last decade, posing a considerable threat to

millions of people globally [1] and exacerbating chronic kidney disease (CKD) [2]. Proteinuria,

a marker of kidney dysfunction, is also a recognized risk factor for cardiovascular disease (CVD)

in hypertensive individuals [3]. Hypertension and proteinuria elevate the risk of kidney

damage, especially when both coexist [4]. Therefore, precisely managing these factors is

essential to reduce the CVD risk and CKD progression.

Effective blood pressure control can improve the prognosis of CKD. Calcium channel blockers

(CCBs) have emerged as the preferred initial therapy for hypertension [5, 6]. A consistent blood

pressure-lowering effect and minimal side effects are observed for CCBs [7] primarily with

dihydropyridines (DHPs), a type of CCB [8]. However, selecting a DHP subtype based on its

properties presents significant challenges. Typical DHPs mainly block L-type calcium channels,

leading to reflex tachycardia [9]. Newer agents, with slow-onset and long-acting properties,

target L- and T/N-type calcium channels, providing renal-protective effects by reducing

glomerular hypertension [10, 11].

Efonidipine, a long-acting dual L- and T-type DHP-CCB, induces vasodilation by selectively

inhibiting L-type calcium channels in vascular smooth muscle cells and regulates heart rate by

inhibiting T-type calcium channels in the sinoatrial node (SA) [12]. Efonidipine is recognized

for its negative chronotropic effect [13]. Efonidipine demonstrates a potent dilation of afferent

and efferent arterioles to an equal extent in in-vitro [14] and in-vivo [15] studies. Furthermore,

its beneficial effects in reducing proteinuria, as observed in clinical studies [16, 17], support its

renoprotective action. Efonidipine is more effective in managing mild-to-moderate

hypertension and renal functions compared to Amlodipine [18-20], Nifedipine [21] and ACE

inhibitors [22]. Therefore, Efonidipine can favourably reduce CVD risk and CKD progression.

Similarly, the antihypertensive literature reports the use of Cilnidipine (L- and N-Type CCB) in

hypertensive patients and renal impairment compared with other first-line antihypertensive

drugs commonly used in practice [22, 23].

Dual-acting DHP-CCBs have the potential to provide more benefits compared to those only

targeting L-type channels. However, there is a limited direct comparative analysis of dual- acting DHP-CCBs. The objective of this study is to evaluate the cardiovascular and

renoprotective effects of dual-acting Efonidipine and Cilnidipine in hypertensive patients.

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British Journal of Healthcare and Medical Research (BJHMR) Vol 11, Issue 05, October-2024

Services for Science and Education – United Kingdom

MATERIALS AND METHODS

Patients

Adults aged 18 years or older were enrolled in the study. The criteria for diagnosing

hypertension with a blood pressure of ≥140/90 mmHg was as per the 7th Joint National

Committee (JNC) hypertension guideline [24]. Naïve patients or patients who were not

responding to their current blood pressure medication, necessitating a switch to alternative

treatment were enrolled. Patients with cerebrovascular disease, congestive heart failure, sick

sinus syndrome, cardiac rhythm abnormalities like sinus bradycardia or second- or third- degree atrioventricular block, hypersensitivity, or contraindication to the study medications

were excluded from the study. Pregnant or lactating women and those with childbearing

potential who were not using adequate birth control were excluded from the study.

Study Design

This was a randomized, double-blind, multicentre, parallel-group, comparative trial conducted

from May 2019 to August 2023 in 15 hospitals in 7 cities across India. The study followed the

ethical standards outlined in the Declaration of Helsinki, the Good Clinical Practice guidelines

laid down by the International Council for Harmonization, and the New Drugs Clinical Trial

Rules, 2019, India. Approval for the study protocol was obtained from the ethics committees at

each study centre. The written informed consent was obtained from the patients. The trial was

prospectively registered with the ‘Clinical Trials Registry – India’ under registration number

CTRI/2019/03/018167. The patients underwent eligibility assessment, informed consent,

clinical and physical examinations for their eligibility in the study. Following the screening,

eligible patients were randomly assigned to the Efonidipine group (Efonidipine 40 mg tablets)

and the Cilnidipine group (Cilnidipine 10 mg tablets) in a 3:1 ratio. Centralized block

randomization-maintained study blinding for both patients and investigators. The patients

adhered to their assigned treatments for a duration of 90 days, and dosing compliance was

monitored through the assessment of diary cards.

Patients were followed up on the Day 30, 60, and 90 post-randomizations for blood pressure

measurements and laboratory tests. Seated blood pressure was measured using a standard

manual cuff sphygmomanometer at screening, baseline (before randomization), and each

follow-up day. Blood pressure readings were averaged from three consecutive measurements

of the dominant arm, with the first reading taken after 15 minutes of rest and the subsequent

two readings recorded at 2-minute intervals. Heart rate was measured concurrently with blood

pressure. Laboratory measurements mainly focused on renal function tests and analysis of

urine samples.

Assessment

The primary endpoint was to assess the efficacy of Efonidipine compared to Cilnidipine in

reducing mean sitting blood pressure among hypertensive patients. Secondary endpoints

included the change in urine albumin/creatinine ratio (UACR) after 90 days of treatment,

change in mean sitting blood pressure after 30 and 60 days of treatment, and the number of

patients who achieved the target goal blood pressure after 90 days of treatment as per JNC 8

guideline. Safety was evaluated by monitoring adverse events (AEs) throughout the study and

assessed as per the World Health Organization-Uppsala Monitoring Centre Causality

Categories.