DOPPS data suggest a possible survival benefit of renin angiotensin-aldosterone system inhibitors and other antihypertensive medications for hemodialysis patients
Authors: Angelo Karaboyas, Hairong Xu, Hal Morgenstern, Francesco Locatelli, Michel Jadoul, Kosaku Nitta, Indranil Dasgupta, Francesca Tentori, Friedrich K. Port, Bruce M. Robinson
Journal: Kidney International (2018)

The benefits of renin angiotensin-aldosterone system inhibitors (RAASi) are well-established in the general population, particularly among those with diabetes, congestive heart failure (CHF), or coronary artery disease (CAD). However, conflicting evidence from trials and concerns about hyperkalemia limit RAASi use in hemodialysis patients, relative to other antihypertensive agents, including beta blockers and calcium channel blockers. Therefore, we investigated prescription patterns and associations with mortality for RAASi and other antihypertensive agents using data from the international Dialysis Outcomes and Practice Patterns Study (DOPPS). Cox regression was used to estimate the effect of the prescription of RAASi and other antihypertensive agents at study entry on mortality in 11,421 incident (120 days or less) hemodialysis and 37,124 prevalent (over 120 days) hemodialysis patients from DOPPS phases 2-5 (2002-2015). Over 95% of RAASi were angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. RAASi prevalence was 39% and varied minimally by CHF and CAD. The adjusted hazard ratio for RAASi (vs. no RAASi) was 0.89 (95% confidence interval 0.80-0.99) among incident and 0.94 (0.90-0.99) among prevalent hemodialysis patients, with no convincing evidence of interaction with diabetes, CAD or CHF. Inverse associations with mortality were also observed for beta blockers and calcium channel blockers, and were stronger for angiotensin receptor blockers than angiotensin-converting enzyme inhibitors, but this latter finding requires further study. Thus, our observations suggest a relatively small survival benefit of RAASi and other antihypertensive agents in hemodialysis patients, though randomized prospective studies are needed to potentially change prescribing criteria. The benefits of renin angiotensin-aldosterone system inhibitors (RAASi) are well-established in the general population, particularly among those with diabetes, congestive heart failure (CHF), or coronary artery disease (CAD). However, conflicting evidence from trials and concerns about hyperkalemia limit RAASi use in hemodialysis patients, relative to other antihypertensive agents, including beta blockers and calcium channel blockers. Therefore, we investigated prescription patterns and associations with mortality for RAASi and other antihypertensive agents using data from the international Dialysis Outcomes and Practice Patterns Study (DOPPS). Cox regression was used to estimate the effect of the prescription of RAASi and other antihypertensive agents at study entry on mortality in 11,421 incident (120 days or less) hemodialysis and 37,124 prevalent (over 120 days) hemodialysis patients from DOPPS phases 2-5 (2002-2015). Over 95% of RAASi were angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. RAASi prevalence was 39% and varied minimally by CHF and CAD. The adjusted hazard ratio for RAASi (vs. no RAASi) was 0.89 (95% confidence interval 0.80-0.99) among incident and 0.94 (0.90-0.99) among prevalent hemodialysis patients, with no convincing evidence of interaction with diabetes, CAD or CHF. Inverse associations with mortality were also observed for beta blockers and calcium channel blockers, and were stronger for angiotensin receptor blockers than angiotensin-converting enzyme inhibitors, but this latter finding requires further study. Thus, our observations suggest a relatively small survival benefit of RAASi and other antihypertensive agents in hemodialysis patients, though randomized prospective studies are needed to potentially change prescribing criteria. Renin angiotensin-aldosterone system inhibitors (RAASi), a group of antihypertensive medication classes that predominantly includes angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), have been shown to improve outcomes for individuals without kidney failure at increased risk of cardiovascular (CV) events.1Zaman M.A. Oparil S. Calhoun D.A. Drugs targeting the renin-angiotensin-aldosterone system.Nat Rev Drug Discov. 2002; 1: 621-636Crossref PubMed Scopus (351) Google Scholar, 2Dickstein K. Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal trial in myocardial infarction with angiotensin II antagonist losartan.Lancet. 2002; 360: 752-760Abstract Full Text Full Text PDF PubMed Scopus (1061) Google Scholar, 3Wing L.M. Reid C.M. 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Amyot R. et al.Prescription patterns of pharmacological agents for left ventricular systolic dysfunction among hemodialysis patients.Am J Kidney Dis. 2006; 48: 645-651Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar regarding the use of specific antihypertensive agents found that the most common reason (88%) for not prescribing an ACEi for HD patients was "concerns about adverse reactions." Therefore, it remains unclear whether RAASi are underused in HD patients relative to other antihypertensive medications such as beta-blockers (BB), calcium channel blockers (CCB), and diuretics (i.e., whether there is a class effect). In this study, we investigated worldwide patterns of RAASi prescription and the relationship between RAASi use and mortality in an international cohort of HD patients. We hypothesized that the benefits of RAASi use in CV risk reduction post-ischemia and preserving residual kidney function27Casas J.P. Chua W. 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Given these potential mechanisms, we also hypothesized that RAASi use would especially benefit patients new to dialysis who generally have residual kidney function and/or those with diagnosed congestive heart failure (CHF) or coronary artery disease (CAD). Figure 1 illustrates that the vast majority of RAASi prescriptions were for either an ACEi or an ARB; relatively few were prescriptions for aldosterone receptor antagonists, direct renin inhibitors, or a combination of ACEi+ARB. ACEi prescription was twice as common as ARB prescriptions in North America and slightly more common than ARB prescriptions in Europe/Australia and New Zealand; in Japan, most RAASi prescriptions were for an ARB. RAASi prescription was less common among incident (vs. prevalent) HD patients in North America, but slightly more common in Europe/Australia and New Zealand and Japan. No clear trends in RAASi prescription were observed across Dialysis Outcomes and Practice Patterns Study (DOPPS) phases, except in Japan where the use of ARBs alone increased from 19% in DOPPS 2 (2002–2004) to 40% in DOPPS 5 (2012–2015). Table 1 provides patient characteristics by region and RAASi prescription (yes/no) for incident HD patients. Patients prescribed a RAASi were younger and less likely to have a history of cancer, but were more likely to be diabetic. Reflecting an indication for the treatment, patients prescribed a RAASi had higher systolic blood pressure (SBP) and were more likely to be diagnosed as hypertensive and to be prescribed other antihypertensive medications. Similar relationships were observed in our prevalent HD cohort (Table 2). Table 3 shows that RAASi prescription prevalence was less frequent among nondiabetics in all 3 regions for both incident and prevalent HD patients, but similar for patients with and without CHF or CAD. In contrast to RAASi, BB prescription increased sharply over time in all 3 regions; prescription of a CCB and a diuretic was constant or increased slightly (Table 4).Table 1Patient characteristics by RAASi prescription among incident (vintage ≤120 days) patients, by regionPatient characteristicsNorth AmericaEurope + A/NZJapanNo RAASiRAASiNo RAASiRAASiNo RAASiRAASiPatients, no. (%)2845 (65)1538 (35)3288 (59)2245 (41)713 (47)792 (53)Characteristics Age (yr)64.4 ± 15.061.0 ± 15.266.9 ± 14.262.7 ± 14.866.4 ± 13.163.8 ± 13.0 Sex (% male)585863636967 Race (% black)20252200 Vintage (days)49 (15, 84)48 (11, 82)40 (4, 80)39 (2, 77)37 (8, 78)48 (17, 86)Hemodialysis-related characteristics < 1 mo pre-HD nephrologist care (%)282524181818 Central venous catheter use (%)69664842117 Intradialytic weight loss (%)2.4 ± 1.72.5 ± 1.62.0 ± 1.61.8 ± 1.62.2 ± 1.92.4 ± 1.8 Treatment time (min)217 ± 33218 ± 33219 ± 38224 ± 41207 ± 39208 ± 36 Dialysate potassium (mEq/l)2.5 ± 0.62.4 ± 0.62.3 ± 0.72.4 ± 0.82.0 ± 0.12.0 ± 0.1Laboratory and biometric measurements Body mass index (kg/m2)28.1 ± 7.028.0 ± 6.825.9 ± 5.326.7 ± 5.621.6 ± 3.722.0 ± 3.4 Predialysis SBP (mm Hg)143 ± 23149 ± 23141 ± 22145 ± 22147 ± 22153 ± 21 Hemoglobin (g/dl)10.7 ± 1.510.8 ± 1.510.5 ± 1.610.6 ± 1.69.5 ± 1.79.7 ± 1.5 Serum creatinine (mg/dl)6.1 ± 2.76.5 ± 2.96.7 ± 2.46.7 ± 2.67.8 ± 2.88.0 ± 2.7 Serum albumin (g/dl)3.48 ± 0.553.50 ± 0.543.49 ± 0.623.52 ± 0.633.45 ± 0.603.39 ± 0.58 WBC count (103 cells/mm3)7.8 ± 2.87.6 ± 2.77.7 ± 2.87.6 ± 2.56.4 ± 2.46.3 ± 2.1 Serum calcium (mg/dl)8.7 ± 0.88.7 ± 0.88.8 ± 1.08.8 ± 0.98.2 ± 0.98.2 ± 0.8 Serum phosphorus (mg/dl)5.0 ± 1.65.2 ± 1.75.1 ± 1.85.3 ± 1.85.3 ± 1.65.3 ± 1.4 Serum potassium (mEq/l)4.4 ± 0.74.5 ± 0.74.7 ± 0.84.8 ± 0.84.4 ± 0.74.5 ± 0.8 Serum potassium >5.5 mEq/l (%)671417710K-binding resin prescription (%)1161057Antihypertensive agents (%) Any (non-RAASi) AHA799076877792 Beta-blocker586643501725 Calcium channel blocker455341525178 Diuretic314147645261Comorbid conditions (%) Coronary artery disease454738412725 Cerebrovascular disease141514161511 Heart failure383726253127 Peripheral vascular disease252525281311 Other cardiovascular disease282330292420 Cancer (nonskin)15101914128 Diabetes576635444457 Gastrointestinal bleeding656453 Hypertension diagnosis859282918089 Lung disease1615141233 Neurologic disease1071010126 Psychiatric disorder2119161654 Recurrent cellulitis, gangrene895743AHA, antihypertensive agent; A/NZ, Australia/New Zealand; HD, hemodialysis; RAASi, renin angiotensin-aldosterone system inhibitor; SBP, systolic blood pressure; WBC, white blood cell.Values shown are mean ± SD or %. Vintage: time since dialysis initiation. Open table in a new tab Table 2Patient characteristics by RAASi prescription among prevalent (vintage >120 days) patients by regionPatient characteristicsNorth AmericaEurope + A/NZJapanNo RAASiRAASiNo RAASiRAASiNo RAASiRAASiPatients, no. (%)7566 (58)5451 (42)11,118 (65)5879 (35)3986 (56)3124 (44)Characteristics Age (yr), mean ± SD63.0 ± 15.261.1 ± 15.065.3 ± 14.762.9 ± 15.163.7 ± 12.763.1 ± 12.3 Sex (% male)555658626066 Race (% black)28302200 Vintage (yr)2.7 (1.2, 5.4)2.8 (1.2, 5.2)3.0 (1.2, 6.4)2.7 (1.1, 5.7)5.9 (2.3, 12.3)4.6 (1.7, 9.1)Hemodialysis-related characteristics Central venous catheter use (%)2524222111 Intradialytic weight loss (%)3.1 ± 1.73.3 ± 1.72.8 ± 1.62.8 ± 1.73.9 ± 1.74.0 ± 1.7 Treatment time (min)220 ± 35221 ± 33242 ± 38245 ± 38239 ± 31236 ± 29 Dialysate potassium (mEq/l)2.2 ± 0.62.1 ± 0.52.1 ± 0.72.1 ± 0.72.0 ± 0.12.0 ± 0.1Laboratory and biometric measurements Body mass index (kg/m2)28.3 ± 7.027.5 ± 6.725.6 ± 5.325.4 ± 5.421.0 ± 3.221.1 ± 3.4 Predialysis SBP (mm Hg)144 ± 23153 ± 23136 ± 23145 ± 22145 ± 23155 ± 20 Hemoglobin (g/dl)11.4 ± 1.411.4 ± 1.311.6 ± 1.511.5 ± 1.410.4 ± 1.310.3 ± 1.2 Serum creatinine (mg/dl)8.3 ± 3.18.5 ± 3.08.3 ± 2.78.3 ± 2.710.8 ± 2.910.7 ± 2.9 Serum albumin (g/dl)3.75 ± 0.463.79 ± 0.443.71 ± 0.523.76 ± 0.543.75 ± 0.423.78 ± 0.42 WBC count (103 cells/mm3)7.1 ± 2.47.1 ± 2.47.1 ± 2.37.2 ± 2.36.0 ± 2.05.9 ± 1.9 Serum calcium (mg/dl)9.1 ± 0.89.1 ± 0.89.2 ± 0.89.1 ± 0.99.0 ± 0.99.0 ± 0.9 Serum phosphorus (mg/dl)5.3 ± 1.65.5 ± 1.75.0 ± 1.75.4 ± 1.85.5 ± 1.55.5 ± 1.4 Serum potassium (mEq/l)4.7 ± 0.74.8 ± 0.75.1 ± 0.85.2 ± 0.84.9 ± 0.85.0 ± 0.8 Serum potassium >5.5 mEq/l (%)121526301924K-binding resin prescription (%)2317201113Antihypertensive agents (%) Any (non-RAASi) AHA698856805085 Beta-blocker526833501325 Calcium channel blocker355524453275 Diuretic162226402131Comorbid conditions (%) Coronary artery disease465041463231 Cerebrovascular disease171617191414 Heart failure394026311920 Peripheral vascular disease272830331616 Other cardiovascular disease302837363227 Cancer (nonskin)141016131010 Diabetes546130392942 Gastrointestinal bleeding565545 Hypertension diagnosis869278916488 Lung disease1616141333 Neurologic disease1111121297 Psychiatric disorder2120171654 Recurrent cellulitis, gangrene101091144AHA, antihypertensive agent; A/NZ, Australia/New Zealand; HD, hemodialysis; RAASi, renin angiotensin-aldosterone system inhibitor; SBP, systolic blood pressure; WBC, white blood cell.Values shown are mean ± SD or % shown. Vintage: time since dialysis initiation. Open table in a new tab Table 3Number and percentage of HD patients prescribed RAASi, by region, time on dialysis, and subgroup of selected patient variablesSubgroupNorth AmericaEurope + A/NZJapanIncidentPrevalentIncidentPrevalentIncidentPrevalentN% RAASiN% RAASiN% RAASiN% RAASiN% RAASiN% RAASiDiabetic No16753054963833333711,3083173446462439 Yes25483971734521214655804175759245553Congestive heart failure No22993666424140614112,24633106454569344 Yes13953442954214134046813943049139546Coronary artery disease No203434569440336539966533111453486644 Yes16913652374321454272503738151222543Hypertension diagnosis No479221239297762529971822838179921 Yes32253796824347014313,85638125955525952A/NZ, Australia/New Zealand; RAASi, renin angiotensin-aldosterone system inhibitor.Incident, on dialysis ≤120 days at study entry; prevalent, on dialysis >120 days at study entry. Open table in a new tab Table 4Prescription of antihypertensive medications, by region, DOPPS phase, and time on dialysisDOPPS phaseaD2, DOPPS phase 2: 2002–2004; D3, phase 3: 2005–2008; D4, phase 4: 2009–2011; D5, phase 5: 2012–2015.North AmericaEurope + A/NZJapanD2D3D4D5D2D3D4D5D2D3D4D5Incident HD patientsbIncident, on dialysis ≤120 days at study entry; prevalent, on dialysis >120 days at study entry. No. of patients131329411911585199761315891334463225312505Prescription (%) Beta-blocker476367673841505513222030 CCB454748514440455063676170 Diuretic353332375149556052585661Prevalent HD patientsbIncident, on dialysis ≤120 days at study entry; prevalent, on dialysis >120 days at study entry. No. of patients236123104272407439764994495330741605201216751818Prescription (%) Beta-blocker445662643038434711172124 CCB444343432929333351534951 Diuretic151719212330333720262628A/NZ, Australia/New Zealand; CCB, calcium channel blocker; DOPPS, Dialysis Outcomes andPractice Patterns Study; HD, hemodialysis.a D2, DOPPS phase 2: 2002–2004; D3, phase 3: 2005–2008; D4, phase 4: 2009–2011; D5, phase 5: 2012–2015.b Incident, on dialysis ≤120 days at study entry; prevalent, on dialysis >120 days at study entry. Open table in a new tab AHA, antihypertensive agent; A/NZ, Australia/New Zealand; HD, hemodialysis; RAASi, renin angiotensin-aldosterone system inhibitor; SBP, systolic blood pressure; WBC, white blood cell. Values shown are mean ± SD or %. Vintage: time since dialysis initiation. AHA, antihypertensive agent; A/NZ, Australia/New Zealand; HD, hemodialysis; RAASi, renin angiotensin-aldosterone system inhibitor; SBP, systolic blood pressure; WBC, white blood cell. Values shown are mean ± SD or % shown. Vintage: time since dialysis initiation. A/NZ, Australia/New Zealand; RAASi, renin angiotensin-aldosterone system inhibitor. Incident, on dialysis ≤120 days at study entry; prevalent, on dialysis >120 days at study entry. A/NZ, Australia/New Zealand; CCB, calcium channel blocker; DOPPS, Dialysis Outcomes and Practice Patterns Study; HD, hemodialysis. Among incident HD patients, the crude all-cause mortality rate was 0.169/year in North America, 0.144/year in Europe, and 0.054/year in Japan. Median follow-up was 1.6 years in patients both prescribed and not prescribed a RAASi. RAASi prescription was associated with a lower mortality rate (hazard ratio [HR]: 0.71, 95% confidence interval [CI] 0.64–0.78) in the unadjusted model (Table 5, Model 0). Adjustment for potential confounders attenuated this association; in Model 6, the HR (95% CI) of mortality comparing patients with versus without a RAASi prescription was 0.89 (0.80–0.99).Table 5Association between RAASi and all-cause mortality by level of adjustmentModelCovariate adjustmentIncident HD patientsaIncident, on dialysis ≤120 days at study entry; prevalent, on dialysis >120 days at study entry.(N = 11,421; 1906 events)Prevalent HD patientsaIncident, on dialysis ≤120 days at study entry; prevalent, on dialysis >120 days at study entry.(N = 37,124; 8217 events)0Stratified by DOPPS phase, country0.71 (0.64–0.78)0.89 (0.85–0.94)1M0 + age0.82 (0.74–0.90)0.95 (0.91–1.00)2M1 + sex, black race, vintage0.82 (0.74–0.90)0.95 (0.91–1.00)3M2 + 13 comorbiditiesbComorbidities listed in Table 1.0.86 (0.78–0.95)0.95 (0.90–0.99)4M3 + HD treatmentscLess than 1 month of pre-HD nephrologist care (incident HD cohort only), catheter use, treatment time, intradialytic weight loss, dialysate K, K-binding resin.0.89 (0.80–0.98)0.94 (0.89–0.99)5M4 + BMI, albumin, calcium,phosphorus, hemoglobin0.88 (0.80–0.98)0.93 (0.88–0.97)6M5 + beta-blocker, CCB, diuretic0.89 (0.80–0.99)0.94 (0.90–0.99)BMI, body mass index; CCB, calcium channel blocker; DOPPS, Dialysis Outcomes and Practice Patterns Study; HD, hemodialysis; RAASi, renin angiotensin-aldosterone system inhibitor.Hazard ratio (95% CI) of all-cause mortality for RAASi versus no RAASi shown.a Incident, on dialysis ≤120 days at study entry; prevalent, on dialysis >120 days at study entry.b Comorbidities listed in Table 1.c Less than 1 month of pre-HD nephrologist care (incident HD cohort only), catheter use, treatment time, intradialytic weight loss, dialysate K, K-binding resin. Open table in a new tab BMI, body mass index; CCB, calcium channel blocker; DOPPS, Dialysis Outcomes and Practice Patterns Study; HD, hemodialysis; RAASi, renin angiotensin-aldosterone system inhibitor. Hazard ratio (95% CI) of all-cause mortality for RAASi versus no RAASi shown. Crude all-cause mortality rates were similar for prevalent HD patients as they were for incident HD patients. In this prevalent HD cohort, the unadjusted HR of mortality was 0.89 (95% CI 0.85–0.94) for patients prescribed versus not prescribed a RAASi. After adjustment for confounders, especially age, this association was attenuated to HR: 0.94 (95% CI 0.90–0.99) in Table 5, Model 6. Little or no evidence of effect modification was observed by diabetes, CHF, CAD, or hypertension (Table 6) in either the incident or prevalent HD cohorts.Table 6Effect modification for association between RAASi and mortalitySubgroupIncident HD patientsPrevalent HD patientsHR (95% CI) for RAASi versus non-RAASiIntxP valueHR (95% CI) forRAASi versus non-RAASiIntxP valueOverall0.89 (0.80–0.99)0.94 (0.90–0.99)Diabetes0.200.62 No0.83 (0.71–0.97)0.93 (0.87–1.00) Yes0.95 (0.82–1.08)0.95 (0.89–1.02)Congestive heart failure0.950.99 No0.90 (0.78–1.03)0.94 (0.88–1.01) Yes0.89 (0.77–1.03)0.94 (0.87–1.02)Coronary artery disease0.420.89 No0.85 (0.73–0.99)0.95 (0.88–1.02) Yes0.92 (0.81–1.06)0.94 (0.88–1.00)Hypertension diagnosis0.560.86 No0.82 (0.59–1.13)0.93 (0.81–1.07) Yes0.90 (0.81–1.01)0.94 (0.90–1.00)CI, confidence incidence; HR, hazard ratio; Incident, on dialysis ≤120 days at study entry; Intx, interaction; prevalent, on dialysis >120 days at study entry; RAASi, renin angiotensin-aldosterone system inhibitor.HR for RAASi versus non-RAASi, adjusted as in Table 5, Model 6.Intx P value reflects a test of the null hypothesis that the RAASi effect (HR) is the same for patients with and without each comorbidity listed in the table (i.e., no effect modification of the HR). Open table in a new tab CI, confidence incidence; HR, hazard ratio; Incident, on dialysis ≤120 days at study entry; Intx, interaction; prevalent, on dialysis >120 days at study entry; RAASi, renin angiotensin-aldosterone system inhibitor. HR for RAASi versus non-RAASi, adjusted as in Table 5, Model 6. Intx P value reflects a test of the null hypothesis that the RAASi effect (HR) is the same for patients with and without each comorbidity listed in the table (i.e., no effect modification of the HR). Among incident HD patients, the adjusted all-cause mortality HR for BB (0.93, 95% CI 0.84–1.03) was similar to that observed for RAASi (Figure 2). In contrast, we observed a stronger association with mortality for CCB (HR: 0.79, 95% CI 0.72–0.88) and little association for diuretics (HR: 1.08, 95% CI 0.97–1.21) in adjusted models. Among prevalent HD patients, the HR ranged from 0.91 to 0.98 for these 3 antihypertensive medications. Results for CCB were unchanged when restricted to dihydropyridine CCB. When analyzing RAASi subtypes in adjusted models, a stronger inverse association with mortality was observed for ARB than for ACEi, especially in the prevalent HD cohort (Figure 2). A direct comparison among patients prescribed a RAASi showed an ∼10% lower mortality rate for ARB-only versus ACEi-only (reference group): the HRs (95% CI) were 0.91 (0.76–1.10) among incident HD patients and 0.88 (0.81–0.96) among prevalent HD patients. Next, additional adjustment for serum K had no impact on the RAASi-mortality association in either the incident or prevalent HD cohort. Analyses of medication-region interaction terms revealed no evidence of an effect modification by reg