Will You Take the Blue or Red Pill?

Calcium channel blockers (CCBs) and renin-angiotensin-system inhibitors (RASi) are two classes of antihypertensive medications frequently used as initial therapy for hypertension.

Some uncertainty exists, however, with regards to which regimen best optimizes outcomes in patients with advanced chronic kidney disease (CKD). For these patients therapy is aimed not only at blood pressure control but at renoprotection as well. Published literature emphasizes the importance of controlling hypertension to slow the progression of renal disease and reduce cardiovascular morbidity and mortality.

The current KDIGO guideline recommends the use of RASi (angiotensin converting enzyme inhibitor [ACEi] or angiotensin II receptor blocker [ARB]) in patients with hypertension, chronic kidney disease, and albuminuria, (with or without diabetes) as they have been shown to delay the progression of CKD. Most of the studies to support this guideline, however, were performed for early stages of CKD (stage 3), and there are fewer studies to support its use in patients with CKD stage 4 and beyond. There are also concerns with the continued use of RASi for patients with advanced CKD.  These include hyperkalemia as a result of aldosterone secretion inhibition, and GFR reduction from low intraglomerular pressure due to decreased resistance at the efferent glomerular arteriole.

CCBs are also widely used as antihypertensives. Most of the available CCBs suppress the L type calcium channels in the glomerular afferent arterioles, causing afferent arteriole vasodilation while the efferent arteriole is not affected, thereby causing glomerular hypertension. Because of this mechanism of action, CCBs may increase proteinuria and are less than ideal to use in patients with concomitant CKD. Nonetheless this medication class has been utilized time and time again either as an adjunct or as a head-to-head comparator with RASi in studies to demonstrate renal, as well as cardiovascular outcomes in patients with CKD. The ACCOMPLISH trial showed that the ACE-I and CCB combination was superior to the ACE-I and thiazide diuretic combination in reducing cardiovascular events in high-risk patients with hypertension.

This poses a significant but common clinical dilemma. In a recent AJKD article Fu et al attempt to provide us insight with real world evidence by looking into the risks of initiating kidney replacement therapy (KRT) in patients with advanced CKD who were initiating either RASi or CCB, including mortality and major adverse cardiovascular events (MACE). It is important to note that their cohort included patients from a Swedish registry with CKD G 4-5 (estimated glomerular filtration rate [eGFR] <30mL/min/1.73m2) not on KRT.

Table 2 from Fu et al, AJKD © National Kidney Foundation

The result of this study seem to favor RASi  in patients with advanced CKD as the inhibitors slowed the progression of CKD and were associated with lower incidence rates of being started on KRT.  However, there were no significant differences with regards to MACE and mortality.

Figure 1 from Fu et al, AJKD © National Kidney Foundation


Figure 2 from Fu et al, AJKD © National Kidney Foundation

Although the result of this might certainly be reassuring, we must bear in mind that this is an observational study with inherent limitations (eg, confounding variables).  Despite this study, we think that the jury is still out. Trials like the STOP-ACE trial, a multi-center randomized controlled trial of ACEi/ARB withdrawal in advanced kidney disease, may help give us more information for this common conundrum.

–  Post prepared by Angela Pauline Calimag @CalimagPauline, AJKDBlog Guest Contributor and  Edgar Lerma @edgarvlermamd, AJKD Social Media Advisory Board member. 


To view Fu et al [Open Access] please visit AJKD.org.

Title: Comparative Effectiveness of Renin-Angiotensin System Inhibitors and Calcium Channel Blockers in Individuals With Advanced CKD: A Nationwide Observational Cohort Study
Authors: Edouard L. Fu, Catherine M. Clase, Marie Evans Bengt Lindholm, Joris I. Rotmans, Friedo W. Dekker, Merel van Diepen, Juan-Jesus Carrero
DOI: 10.1053/j.ajkd.2020.10.006

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