Renin–Angiotensin System Blocker Discontinuation and Adverse Outcomes in Chronic Kidney Disease

Carl P. Walther; Wolfgang C. Winkelmayer; Peter A. Richardson; Salim S. Virani; Sankar D. Navaneethan

Disclosures

Nephrol Dial Transplant. 2021;36(10):1893-1899.

Abstract and Introduction

Abstract

Graphical Abstract

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Background: Treatment with renin–angiotensin system inhibitors (RASIs), angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) is the standard of care for those with chronic kidney disease (CKD) and albuminuria. However, ACEI/ARB treatment is often discontinued for various reasons. We investigated the association of ACEI/ARB discontinuation with outcomes among US veterans with non-dialysis-dependent CKD.

Methods: We performed a retrospective cohort study of patients in the Veterans Affairs healthcare system with non-dialysis-dependent CKD who subsequently were started on ACEI/ARB therapy (new user design). Discontinuation events were defined as a gap in ACEI/ARB therapy of ≥14 days and were classified further based on duration (14–30, 31–60, 61–90, 91–180 and >180 days). This was treated as a time-varying risk factor in adjusted Cox proportional hazards models for the outcomes of death and incident end-stage kidney disease (ESKD), which also adjusted for relevant confounders.

Results: We identified 141 252 people with CKD and incident ACEI/ARB use who met the inclusion criteria; these were followed for a mean 4.87 years. There were 135 356 discontinuation events, 68 699 deaths and 6152 incident ESKD events. Discontinuation of ACEI/ARB was associated with a higher risk of death [hazard ratio (HR) 2.3, 2.0, 1.99, 1.92 and 1.74 for those discontinued for 14–30, 31–60, 61–90, 91–180 and >180 days, respectively]. Similar associations were noted between ACEI and ARB discontinuation and ESKD (HR 1.64, 1.47, 1.54, 1.65 and 1.59 for those discontinued for 14–30, 31–60, 61–90, 91–180 and >180 days, respectively).

Conclusions: In a cohort of predominantly male veterans with CKD Stages 3 and 4, ACEI/ARB discontinuation was independently associated with an increased risk of subsequent death and ESKD. This may be due to the severity of illness factors that drive the decision to discontinue therapy. Further investigations to determine the causes of discontinuations and to provide an evidence base for discontinuation decisions are needed.

Introduction

Treatment with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), proven to slow the progression of diabetic and proteinuric kidney diseases, has become the standard of chronic kidney disease (CKD) care over the past 2 decades.^[1] These agents likely provide benefit through several pathways, including a reduction in intraglomerular hydraulic pressure, improvement in endothelial function and modulation of inflammatory and fibrotic pathways.^[2] Current clinical practice guidelines recommend the broad use of these agents in diabetic and proteinuric kidney diseases and as first-line agents for treatment of hypertension in people with and without kidney disease.^[1,3,4] ACEI and ARB therapies have also been shown to be safe and effective even in advanced CKD.^[5]

Despite recommendations for widespread adoption, many patients with CKD do not receive ACEI/ARB therapy. Among nondialysis CKD patients with Medicare Part D in 2015, only 58% had at least one prescription filled for ACEIs/ARBs^[6] and the proportion of patients with CKD who initiate or are maintained on ACEI/ARB therapy declines as CKD advances, a finding demonstrated repeatedly over decades.^[6,7] Over 5 years of follow-up in a Veterans Affairs (VA) cohort, even among those prescribed ACEI or ARB therapy, temporary or permanent discontinuations were frequent.^[7] Reasons commonly cited for ACEI/ARB discontinuation include effects of their primary mechanism of action (serum creatinine elevations, hyperkalemia and hypotension) and side effects related to inhibition of kinin breakdown (cough and angioedema).^[8] They are also commonly discontinued with intercurrent illness, when volume depletion and/or hypotension are present or possible and among hospitalized patients, where reinstitution upon discharge is commonly not done.^[9] Additionally, higher comorbidity burden itself, by placing the patient at risk for serum creatinine elevations classified as acute kidney injury (AKI), may lead to ACEI/ARB avoidance or discontinuation.^[10,11]

To advance our understanding of the patterns of ACEI/ARB discontinuation and associated outcomes, we retrospectively studied outcomes of death and progression to end-stage kidney disease (ESKD) after temporary or permanent cessation of ACEI/ARB therapy among a nationwide cohort of veterans with CKD in the USA.

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Table 1. Baseline characteristics (at the time of incident ACEI/ARB use)
Characteristics	Values^a
Age (years), %	73.7 (10.4)
<40	0.23
40–49	1.27
50–59	8.06
60–69	27.44
70–79	31.06
>80	31.93
Male, n (%)	164 629 (96.7)
Race, n (%)
Black	24 493 (14.39)
White	4063 (2.39)
Other	141 710 (83.23)
BMI (kg/m²), %	29.2 (6.5)
<18.5	0.83
18.5–25	16.46
25.0–30	29.46
>30	29.44
SBP (mmHg), mean (SD)	140.7 (22.8)
DBP (mmHg), mean (SD)	75.5 (13.5)
eGFR (mL/min/1.73 m²), %	49.3 (13.8)
45–59	46.2
30–44	22.7
15–29	5.72
<15	1.84
Diabetes mellitus, n (%)	72 382 (42.5)
CHF, n (%)	29 659 (17.4)
CAD, n (%)	19 803 (11.6)
PVD, n (%)	38 229 (22.5)
COPD, n (%)	56 112 (33.0)
Cerebrovascular disease, n (%)	35 844 (21.1)
Chronic liver disease, n (%)	8038 (4.7)
Malignancy, n (%)	39 699 (23.3)
ACEI/ARB index year, %
2005–08	44.09
2009–11	25.40
2012–15	30.51

^aMissing data: BMI, 23.8%; SBP, 0.75%; DBP, 0.77%.

Table 2. Laboratory values and hospitalizations prior to ACEI/ARB discontinuation
Hospitalizations within 6 months prior to discontinuation	n (%)
None	116 057 (85.8)
Any hospitalization	19 289 (14.5)
0–30 days prior	5774 (4.3)
31–60 days prior	3715 (2.7)
61–90 days prior	3504 (2.6)
91–180 days prior	6296 (4.7)
Outpatient laboratory values within 6 months prior to discontinuation	Measure
Serum creatinine (mg/dL)
Median (IQR)	1.4 (1.2–1.8)
Serum potassium (mEq/L)^a
Median (IQR)	4.4 (4.0–4.7)
5.0–5.4, n (%)	4272 (8.2)
5.5–6.0, n (%)	859 (1.6)
>6.0, n (%)	335 (0.64)

^aSummarized for the 52 285 discontinuation events with serum potassium measurement within 6 months prior to discontinuation.

Table 3. HRs (95% CI) by duration of ACEI/ARB discontinuation (compared with no discontinuation)
b>Discontinuation duration	Univariate	Model 1	Model 2	Model 3
Death (days)
14–30	2.76 (2.66–2.87)	2.74 (2.63–2.84)	2.58 (2.48–2.68)	2.30 (2.21–2.39)
31–60	2.47 (2.36–2.58)	2.41 (2.30–2.52)	2.22 (2.12–2.32)	2.00 (1.91–2.09)
61–90	2.58 (2.45–2.71)	2.48 (2.36–2.61)	2.23 (2.12–2.34)	1.99 (1.89–2.10)
91–180	2.60 (2.51–2.70)	2.47 (2.38–2.56)	2.15 (2.07–2.23)	1.92 (1.85–1.99)
>180	2.31 (2.26–2.37)	2.12 (2.07–2.17)	1.91 (1.87–1.96)	1.74 (1.70–1.78)
Incident ESKD (days)
14–30	2.33 (2.04–2.67)	2.20 (1.92–2.51)	1.72 (1.50–1.96)	1.64 (1.43–1.88)
31–60	2.23 (1.92–2.60)	2.11 (1.81–2.45)	1.50 (1.29–1.74)	1.47 (1.26–1.71)
61–90	2.43 (2.05–2.87)	2.37 (2.01–2.80)	1.56 (1.32–1.84)	1.54 (1.30–1.82)
91–180	2.77 (2.47–3.10)	2.82 (2.52–3.16)	1.67 (1.49–1.87)	1.65 (1.47–1.85)
>180	2.27 (2.12–2.44)	2.58 (2.40–2.77)	1.60 (1.49–1.72)	1.59 (1.48–1.71)

Model 1: Adjusted for age, race and sex.
Model 2: Model 1 + CKD G stage and comorbidities (hypertension, CHF, COPD, cerebrovascular disease, peripheral vascular disease, coronary artery disease, chronic liver disease and malignancy).
Model 3: Model 2 + SBP, DBP, BMI, year of incident ACEI/ARB use and statin discontinuation.