A nationwide cohort study comparing the effectiveness of diuretics and calcium channel blockers on top of renin-angiotensin system inhibitors on chronic kidney disease progression and mortality

Abstract

It is unknown whether initiating diuretics on top of renin-angiotensin system inhibitors (RASi) is superior to alternative antihypertensive agents such as calcium channel blockers (CCBs) in patients with chronic kidney disease (CKD). For this purpose, we emulated a target trial in the Swedish Renal Registry 2007-2022 that included nephrologist-referred patients with moderate-advanced CKD and treated with RASi, who initiated diuretics or CCB. Using propensity score-weighted cause-specific Cox regression, we compared risks of major adverse kidney events (MAKE; composite of kidney replacement therapy [KRT], experiencing over a 40% eGFR decline from baseline, or an eGFR under 15 ml/min per 1.73m2), major cardiovascular events (MACE; composite of cardiovascular death, myocardial infarction or stroke), and all-cause mortality. We identified 5875 patients (median age 71 years, 64% men, median eGFR 26 ml/min per 1.73m2), of whom 3165 started a diuretic and 2710 a CCB. After a median follow-up of 6.3 years, 2558 MAKE, 1178 MACE and 2299 deaths occurred. Compared to CCB, diuretic use was associated with a lower risk of MAKE (weighted hazard ratio 0.87 [95% confidence interval: 0.77-0.97]), consistent across single components (KRT: 0.77 [0.66-0.88], over 40% eGFR decline: 0.80 [0.71-0.91] and eGFR under 15ml/min/1.73m2: 0.84 [0.74-0.96]). The risks of MACE (1.14 [0.96-1.36]) and all-cause mortality (1.07 [0.94-1.23]) did not differ between therapies. Results were consistent when modeling the total time drug exposure, across sub-groups and a broad range of sensitivity analyses. Thus, our observational study suggests that in patients with advanced CKD, using a diuretic rather than a CCB on top of RASi may improve kidney outcomes without compromising cardioprotection. It is unknown whether initiating diuretics on top of renin-angiotensin system inhibitors (RASi) is superior to alternative antihypertensive agents such as calcium channel blockers (CCBs) in patients with chronic kidney disease (CKD). For this purpose, we emulated a target trial in the Swedish Renal Registry 2007-2022 that included nephrologist-referred patients with moderate-advanced CKD and treated with RASi, who initiated diuretics or CCB. Using propensity score-weighted cause-specific Cox regression, we compared risks of major adverse kidney events (MAKE; composite of kidney replacement therapy [KRT], experiencing over a 40% eGFR decline from baseline, or an eGFR under 15 ml/min per 1.73m2), major cardiovascular events (MACE; composite of cardiovascular death, myocardial infarction or stroke), and all-cause mortality. We identified 5875 patients (median age 71 years, 64% men, median eGFR 26 ml/min per 1.73m2), of whom 3165 started a diuretic and 2710 a CCB. After a median follow-up of 6.3 years, 2558 MAKE, 1178 MACE and 2299 deaths occurred. Compared to CCB, diuretic use was associated with a lower risk of MAKE (weighted hazard ratio 0.87 [95% confidence interval: 0.77-0.97]), consistent across single components (KRT: 0.77 [0.66-0.88], over 40% eGFR decline: 0.80 [0.71-0.91] and eGFR under 15ml/min/1.73m2: 0.84 [0.74-0.96]). The risks of MACE (1.14 [0.96-1.36]) and all-cause mortality (1.07 [0.94-1.23]) did not differ between therapies. Results were consistent when modeling the total time drug exposure, across sub-groups and a broad range of sensitivity analyses. Thus, our observational study suggests that in patients with advanced CKD, using a diuretic rather than a CCB on top of RASi may improve kidney outcomes without compromising cardioprotection. Lay SummaryIn patients with chronic kidney disease, it is unknown whether initiating a diuretic on top of renin-angiotensin system inhibitors is superior to other alternative antihypertensive agents such as calcium channel blockers. We emulated a target trial in the Swedish Renal Registry 2007 to 2022 including patients with chronic kidney disease stages G3–G5 and hypertension who had good adherence to renin-angiotensin system inhibitors and further initiated either a diuretic (n = 3165) or a calcium channel blocker (n = 2710). Compared with patients initiating a calcium channel blocker, those initiating a diuretic had a significantly lower risk of chronic kidney disease progression and a similar risk of cardiovascular events and all-cause mortality. Our study suggests that in patients with moderate to advanced chronic kidney disease, antihypertensive therapy with diuretics may be associated with further kidney benefits and similar cardioprotection compared with calcium channel blockers. In patients with chronic kidney disease, it is unknown whether initiating a diuretic on top of renin-angiotensin system inhibitors is superior to other alternative antihypertensive agents such as calcium channel blockers. We emulated a target trial in the Swedish Renal Registry 2007 to 2022 including patients with chronic kidney disease stages G3–G5 and hypertension who had good adherence to renin-angiotensin system inhibitors and further initiated either a diuretic (n = 3165) or a calcium channel blocker (n = 2710). Compared with patients initiating a calcium channel blocker, those initiating a diuretic had a significantly lower risk of chronic kidney disease progression and a similar risk of cardiovascular events and all-cause mortality. Our study suggests that in patients with moderate to advanced chronic kidney disease, antihypertensive therapy with diuretics may be associated with further kidney benefits and similar cardioprotection compared with calcium channel blockers. As chronic kidney disease (CKD) progresses to advanced stages, impaired kidney sodium and water excretion often results in fluid overload and salt-sensitive hypertension, which are independently associated with resistant hypertension,1Vidal-Petiot E. Metzger M. Faucon A. et al.Extracellular fluid volume is an independent determinant of uncontrolled and resistant hypertension in chronic kidney disease: a NephroTest cohort study.J Am Heart Assoc. 2018; 7e010278Crossref PubMed Scopus (14) Google Scholar need of kidney replacement therapy (KRT), cardiovascular events, and mortality.2Faucon A.L. Leffondré K. Flamant M. et al.Trajectory of extracellular fluid volume over time and subsequent risks of end-stage kidney disease and mortality in chronic kidney disease: a prospective cohort study.J Intern Med. 2021; 289: 193-205Crossref PubMed Scopus (4) Google Scholar, 3Faucon A.L. Flamant M. Metzger M. et al.Extracellular fluid volume is associated with incident end-stage kidney disease and mortality in patients with chronic kidney disease.Kidney Int. 2019; 96: 1020-1029Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 4Tsai Y.C. Tsai J.C. Chen S.C. et al.Association of fluid overload with kidney disease progression in advanced CKD: a prospective cohort study.Am J Kidney Dis. 2014; 63: 68-75Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 5Tsai Y.C. Chiu Y.W. Tsai J.C. et al.Association of fluid overload with cardiovascular morbidity and all-cause mortality in stages 4 and 5 CKD.Clin J Am Soc Nephrol. 2015; 10: 39-46Crossref PubMed Scopus (102) Google Scholar, 6Hung S.C. Lai Y.S. Kuo K.L. Tarng D.C. Volume overload and adverse outcomes in chronic kidney disease: clinical observational and animal studies.J Am Heart Assoc. 2015; 4e001918Crossref Scopus (100) Google Scholar, 7Tai R. Ohashi Y. Mizuiri S. et al.Association between ratio of measured extracellular volume to expected body fluid volume and renal outcomes in patients with chronic kidney disease: a retrospective single-center cohort study.BMC Nephrol. 2014; 15: 189Crossref PubMed Scopus (38) Google Scholar Targeting optimal extracellular fluid volume status is thus critical to the clinical management of these patients and may be achieved by adjusting diuretic therapy and/or decreasing sodium intake.8Vasavada N. Agarwal R. Role of excess volume in the pathophysiology of hypertension in chronic kidney disease.Kidney Int. 2003; 64: 1772-1779Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar The 2021 Kidney Disease: Improving Global Outcomes Guidelines recommend that renin-angiotensin system inhibitors (RASi) be used as the first-line antihypertensive drug in patients with CKD,9Cheung A.K. Chang T.I. Cushman W.C. et al.Executive summary of the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.Kidney Int. 2021; 99: 559-569Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar is for the antihypertensive therapy in CKD, of a of trial The the of therapy the in the of use of antihypertensive in with CKD N. A. M. et in and antihypertensive in chronic kidney disease.Kidney Int. 2019; 96: Full Text Full Text PDF PubMed Scopus (38) Google Scholar the use of a calcium channel blocker or a for and in and et Guidelines for the management of Heart 2018; PubMed Scopus Google Scholar therapy may over CCB antihypertensive and diuretics are to the et of sodium and on the of Am Soc Nephrol. PubMed Scopus Google Scholar, A. et and sodium results in to Am Soc Nephrol. PubMed Scopus Google Scholar, A. with than PubMed Scopus Google Scholar, et of the of by sodium be by PubMed Scopus Google Scholar, et of sodium and on in a clinical 2014; Full Text Full Text PDF PubMed Scopus Google Scholar, E. E. et diuretics the of renin-angiotensin blockers in patients with chronic kidney disease.Kidney Int. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar, K. S. of volume on renal progression and mortality in chronic kidney disease a prospective 2018; PubMed Scopus (14) Google Scholar, et of on results of the Int. Full Text Full Text PDF PubMed Scopus Google Scholar and R. et of on in chronic kidney disease a PubMed Scopus Google Scholar of RASi in may a associated with kidney and cardiovascular et al.Association of and diuretics with cardiovascular events in patients with chronic kidney disease stages 2021; PubMed Scopus Google Scholar the of diuretics be of to patients with CKD and hypertension in whom is by the CCB therapy an in of on renal outcomes in a PubMed Scopus Google Scholar and may CKD the of diuretics in patients with CKD or whether over as antihypertensive therapy is were often et of sodium and on the of Am Soc Nephrol. PubMed Scopus Google et of sodium and on in a clinical 2014; Full Text Full Text PDF PubMed Scopus Google E. 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Chen S.C. et al.Association of fluid overload with kidney disease progression in advanced CKD: a prospective cohort study.Am J Kidney Dis. 2014; 63: 68-75Abstract Full Text Full Text PDF PubMed Scopus (72) Google and kidney PubMed Scopus Google Scholar, M. et and extracellular fluid excess in stages of chronic kidney PubMed Scopus Google Scholar, S.C. Kuo K.L. et overload with cardiovascular risk in patients with chronic kidney disease.Kidney Int. 2014; Full Text Full Text PDF PubMed Scopus Google and diuretics of et of sodium and on the of Am Soc Nephrol. PubMed Scopus Google Scholar, A. et and sodium results in to Am Soc Nephrol. PubMed Scopus Google Scholar, A. with than PubMed Scopus Google Scholar, et of the of by sodium be by PubMed Scopus Google Scholar, et of sodium and on in a clinical 2014; Full Text Full Text PDF PubMed Scopus Google Scholar, E. 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