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Comparison of Efficacy and Safety Between Benidipine And Open Access Protocol BMJ Open: first published as 10.1136/bmjopen-2016-013672 on 24 February 2017. Downloaded from Comparison of efficacy and safety between benidipine and hydrochlorothiazide in fosinopril- treated hypertensive patients with chronic kidney disease: protocol for a randomised controlled trial Cheng Xue,1,2 Chenchen Zhou,3 Bo Yang,1 Jiayi Lv,1 Bing Dai,1 Shengqiang Yu,1 Yi Wang,3 Guanren Zhao,2 Changlin Mei1 To cite: Xue C, Zhou C, ABSTRACT et al Strengths and limitations of this study Yang B, . Comparison Introduction: Co-administration of a diuretic or of efficacy and safety calcium channel blocker with an ACE inhibitor are both ▪ between benidipine and This is a multicentred, prospective, double-blind, preferred combinations in patients with hypertensive hydrochlorothiazide in randomised, parallel controlled trial involving fosinopril-treated chronic kidney disease (CKD). According to the chronic kidney disease (CKD) patients with hypertensive patients with available evidence, it is still unknown which diabetes and non-diabetes. chronic kidney disease: combination plays a more active role in renal ▪ Outcomes may help future guidelines regarding protocol for a randomised protection. We hypothesised that a combination of antihypertensive combinations in CKD. controlled trial. BMJ Open fosinopril and benidipine may delay the progression of ▪ A limitation may be the relatively short follow-up 2017;7:e013672. CKD more effectively than a combination of fosinopril time. doi:10.1136/bmjopen-2016- and hydrochlorothiazide (HCTZ). ▪ Loss to follow-up, especially non-responders 013672 Methods and analysis: This study will be a within follow-up, is possible. multicentred, prospective, double-blind, randomised ▸ Prepublication history and parallel controlled trial for hypertensive CKD patients http://bmjopen.bmj.com/ additional material is in China. Patients will be randomised to one of two available. To view please visit treatment groups: a combination of benidipine 4–8 mg/ Trial registration number: NCT02646397. the journal (http://dx.doi.org/ day and fosinopril 20 mg/day; or a combination of 10.1136/bmjopen-2016- HCTZ 12.5–25 mg/day and fosinopril 20 mg/day. 013672). Patients will be followed up for 24 months after a INTRODUCTION month’s fosinopril run-in. There will be dose-titration Patients with chronic kidney dysfunction or after 1 and 2 months. The primary endpoint is changes CX and CZ contributed in estimated glomerular filtration rate (eGFR) from injury which has affected their health over a equally. baseline to month 24. Secondary endpoints include 3 month period are diagnosed with chronic on September 24, 2021 by guest. Protected copyright. changes in home blood pressure (BP), ambulatory kidney disease (CKD). China has a high overall Received 9 August 2016 BP, proteinuria, urinary albumin/creatinine ratio, and prevalence of CKD of 10.8% and the number Revised 24 January 2017 composite renal events in 24 months. Inclusion criteria ofCKDpatientsisestimatedtobeapproxi- Accepted 2 February 2017 are: age 18–80 years, non-dialysis CKD patients with mately 119.5 million.1 The prevalence, aware- eGFR >30 mL/min/1.73 m2, home BP >130 mm Hg ness and treatment of hypertension (HTN) in systolic or BP >80 mm Hg diastolic at the screening non-dialysis CKD patients has been reported and randomisation, and 24 hour proteinuria <3.5 g. at 67.3%, 85.8%, and 81.0%, respectively.1 Principal exclusions are hypertensive crisis, However, of the hypertensive CKD patients, transplantation, cancer, severe diabetes complications, only 14.1% had controlled blood pressure (BP) hyperkalaemia and severe allergy. The required sample to <130/80 mm Hg. Racial and geographical For numbered affiliations see size was 511 patients for detecting a difference in the α β differences play important roles in HTN of end of article. change of eGFR (one sided =0.025, power 1- =0.90). Ethics and dissemination: BEAHIT (Benidipine and Chinese CKD patients. With successive CKD Hydrochlorothiazide in Fosinopril Treated Chronic stages, the risk of uncontrolled HTN increased, Correspondence to and uncontrolled HTN was associated with Professor Changlin Mei; Kidney Disease Patients with Hypertension) was [email protected] approved by Changzheng Hospital Ethics Committee renal disease progression. Managing BP effect- Professor Guanren Zhao; (CZ-20160504-16). The outcomes will be published ively in CKD patients is still a large unmet [email protected] in a peer-reviewed journal. medical need in China. Xue C, et al. BMJ Open 2017;7:e013672. doi:10.1136/bmjopen-2016-013672 1 Open Access BMJ Open: first published as 10.1136/bmjopen-2016-013672 on 24 February 2017. Downloaded from Abnormal activation of the renin–angiotensin–aldos- and efferent arteriole) versus L-channel receptors (pre- terone system (RAAS) in CKD plays an important role in dominantly on the afferent arteriole).8 Previous studies the pathogenesis of HTN. Renin–angiotensin system found benidipine had more favourable renoprotective inhibitors (RASI), including ACE inhibitors (ACEIs) and effects when compared with other CCBs.8 T-channel angiotensin II type 1 receptor blockers (ARBs), have blockade leads to a reduction in intra-glomerular pres- been confirmed as having apparent renoprotective sure, and accordingly may lead to a fall in the concentra- effects in patients with CKD. The guidelines recommend tion of urine albumin. This study will use benidipine that ACEI or ARB is the preferred antihypertensive (L/T-type CCB), which is different from ACCOMPLISH agent in CKD patients with HTN or albuminuria. study.7 However, RASI monotherapy does not usually achieve BEAHIT (Benidipine and Hydrochlorothiazide in adequate BP control. Patients with CKD usually need Fosinopril Treated Chronic Kidney Disease Patients with combination antihypertensive therapy to achieve the Hypertension) will test whether the superiority of beni- recommended BP goal of <130/80 mm Hg.2 dipine in protecting renal function exists over 2 years’ Co-administration of diuretics and calcium-channel block- treatment. This trial is large enough for estimates such as ers (CCBs) with ACEIs or ARBs are the most common proteinuria, BP and other related clinical parameters. In combinations. Dihydropyridine-type CCB plus RASI is a consideration of the controversy between diuretic and preferred combination in clinical practice with mild CCB in renal protection, we aim to conduct a large-scale adverse effects.3 Thiazide or thiazide-like diuretic plus study to compare benidipine with HCTZ in fosinopril RASI is another widely used combination, providing the treated hypertensive CKD patients. This protocol was synergistic function of antihypertensive action while off- approved by the Changzheng Hospital Ethics Committee setting mutual adverse effects (such as hyperkalemia and and registered in clinicaltrials.gov (NCT02646397). All impaired glucose tolerance). the items complied with the SPIRIT 2013 guideline.9 In recent years, clinical studies focusing on the add- ition of a CCB or diuretic to RASI have led to inconsist- Primary objectives ent results. The GUARD trial found that the reduction To determine whether the combination of fosinopril and of albuminuria in the hydrochlorothiazide (HCTZ) plus benidipine may delay the progression of CKD more benazepril group was greater than in the amlodipine effectively than the combination of fosinopril and HCTZ. plus benazepril group in hypertensive patients with dia- 4 5 betic nephropathy. Hayashi et al found the addition of Secondary objectives diuretics or CCB to ARB was equally effective for the To demonstrate whether the combination of fosinopril control of HTN in CKD, while diuretics may be better and benidipine may improve proteinuria, HTN or risk than CCB in reducing proteinuria (PROTECT study). of renal events more effectively compared with the com- 6 et al http://bmjopen.bmj.com/ However, Ishimitsu found losartan plus nifedipine bination of fosinopril and HCTZ; and to determine the showed a superior antihypertensive and renoprotective effects on endothelial dysfunction markers and safety in effect in CKD patients compared to losartan plus HCTZ, the two treatment groups. but nifedipine was not associated with lower urinary albumin excretion compared to HCTZ. The ACCOMPLISH study7 concluded that hypertensive METHODS AND ANALYSIS patients treated with benazepril plus amlodipine had a Study design lower risk of progression to CKD than those treated with This study will be a multicentred, prospective, two arm, benazepril plus HCTZ. double-blind, randomised, parallel controlled trial for on September 24, 2021 by guest. Protected copyright. Until now, no large-scale studies have compared the hypertensive CKD patients in China. Patients will be ran- effect of initial treatment with two different combina- domised to either the benidipine+fosinopril group or tions of antihypertensive drugs in CKD patients on the the HCTZ+fosinopril group. Patients will receive treat- progression of kidney disease, especially in subsets of ment for 24 months after a month’s fosinopril run-in. diabetes, non-diabetes, microalbuminuria and macroal- This is a superiority trial with a 1:1 allocation ratio. The buminuria. Moreover, CKD patients have elevated levels design of the trial is outlined in figure 1. The compos- of cardiovascular disease risk and endothelial dysfunc- ition and responsibilities of the principal investigator, tion markers compared with healthy individuals (such as steering committee (SC), trial management committee
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