Effects of 2 Drug Classes Compared in Advanced Chronic Kidney Disease

Initiation of antihypertensive therapy with a renin-angiotensin-system inhibitor (RASi) in patients with advanced chronic kidney disease (CKD) may confer additional renal benefits compared with starting patients on a calcium channel blocker (CCB), according to new evidence from high-quality administrative databases in Sweden.¹

Investigators examined the risks for kidney replacement therapy (KRT), mortality, and major adverse cardiovascular events (MACE) in patients with advanced CKD by using 2007 to 2017 data from the Swedish Renal Registry. The study included 2458 and 2345 new users of RASi and CCB, respectively, who had an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73m². Patients had a median age of 74 years, and 38% were women. “We chose this comparison because it mirrors a common clinical scenario, that of starting a first or subsequent antihypertensive medication and choosing between these 2 drug classes,” said study investigator Catherine Clase, MB, MSc, an associate professor at McMaster University in Ontario, Canada.

The RASi group had a significant 21% decreased risk for KRT compared with the CCB group, the investigators reported in the American Journal of Kidney Diseases. The RASi and CCB groups, however, had similar risks for mortality and MACE. The absolute 5-year mortality risk was 48.3% among RASi users and 49.5% among CCB users. The absolute 5-year risk of MACE was 25.0% among RASi users and 25.1% among CCB users. Overall results were consistent across subgroups and in as-treated analyses, according to the investigators.

“This evidence may potentially inform clinical decisions on the choice of antihypertensive therapy for this patient group, minimally included in pivotal trials,” the investigators concluded. 

The investigators defined new users as individuals receiving a RASi or CCB without dispensation of either drug in the previous 6 months. They excluded prevalent users of these agents, individuals with a history of kidney transplantation, individuals with an eGFR greater than 30 mL/min/1.73 m², or those initiating both drugs simultaneously. The majority of patients initiating a RASi received enalapril (37.2%), candesartan (23.4%), losartan (21.4%) or ramipril (9.6%). Among these patients, 249 individuals (10.1%) experienced a cardiovascular hospitalization in the 6 months prior to initiation. Of the patients initiating a CCB, 97.7% received a dihydropyridine, which was primarily amlodipine (55.4%) or felodipine (36.9%). Among these patients, 231 (9.9%) had a cardiovascular hospitalization in the 6 months prior to initiation.

The authors acknowledged a number of study limitations. They noted, for example, despite adjusting for a wide range of potential confounders, residual confounding-by-indication bias cannot be excluded in observational studies. In addition, the reasons why patients were started on these drugs are unknown. “Because only around 10% of individuals starting RASi or CCB in our study had a cardiovascular hospitalization in the 6 months prior to therapy start, we speculate that medications may have been initiated for renoprotection or as antihypertensive agents.”

“The strength of the current study is the number of patients analyzed and the relatively long median follow-up, but the study carries the limitations associated with the observational study design, as well as studying Swedish registry with probably uniformly Caucasian individuals, limiting generalization of results,” commented Emaad Abdel-Rahman, MBBS, PhD, professor of nephrology at the University of Virginia in Charlottesville.

Dr Abdel-Rahman cited a recent observational study of 678 patients with stage 4-5 CKD who participated in the Chronic Renal Insufficiency Cohort (CRIC) study that demonstrated no difference in the rate of progression to end-stage kidney disease or death between participants treated continuously with RASi or not treated at all for the duration of the study.²  

Kausik Umanath, MD, MS, FASN, section head of clinical research in the division of nephrology and hypertension at Henry Ford Hospital in Detroit, Michigan, praised the new study as providing clinically useful information. “It is surprising to note that despite published guidelines for many years, a substantial portion of patients reach CKD stage 4/5 and are not already on a renin-angiotensin system inhibitor,” Dr Umanath said. “I am not surprised that initiating therapy later in the course of CKD still provides benefit in terms of forestalling kidney disease progression. Comparative effectiveness studies like this are particularly valuable when they come out of Europe due to the centralization of healthcare systems, which allows for fairly clean long-term epidemiologic data.”

Julia Breyer Lewis, MD, professor of medicine, nephrology and hypertension at Vanderbilt University Medical Center in Nashville, Tennessee, said the findings from this study support the well-established benefit of RASi in slowing progression of CKD. “It does address a clinically relevant question about the use of RASi in patients with advanced CKD, who have largely been excluded from randomized clinical trials, and the subject of a relative paucity of retrospective analysis or observational studies,” Dr Breyer Lewis said.

She added, “Addressing the issue about starting or, perhaps even more relevant, stopping RASi in advanced CKD is an important one that needs to be addressed in more heterogeneous populations and ideally in prospective studies.”

References

1. Fu EL, Clase CM, Evans M, et al. Comparative effectiveness of renin-angiotensin system inhibitors and calcium channel blockers in individuals with advanced CKD: A nationwide observational cohort study. Published online November 19, 2020. Am J Kidney Dis. doi:10.1053/j.ajkd.2020.10.006
2. Arora N, Katz R, Bansal N. ACE inhibitor/angiotensin receptor blocker use patterns in advanced CKD and risk of kidney failure and death. Kidney Med. 2020;2:248-257. doi:10.1016/j.xkme.2019.12.007