Hypertension in Hemodialysis Patients: The Role of Antihypertensive Medications

Abstract

Commentary on Heerspink HJL, Ninomiya T, Zoungas S, et al. Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials. Lancet. 2009;373(9668):1009-1015. Commentary on Heerspink HJL, Ninomiya T, Zoungas S, et al. Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials. Lancet. 2009;373(9668):1009-1015. Hypertension affects the vast majority of hemodialysis patients.1Agarwal R. Nissenson A.R. Batlle D. et al.Prevalence, treatment, and control of hypertension in chronic hemodialysis patients in the United States.Am J Med. 2003; 115: 291-297Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar Unfortunately, there is a paucity of prospective data to support the safety and efficacy of treating hemodialysis patients to the National Kidney Foundation's current Kidney Disease Outcomes Quality Initiative (KDOQI) guideline of a predialysis blood pressure (BP) < 140/90 mm Hg. Recently, Heerspink et al2Heerspink H.J.L. Ninomiya T. Zoungas S. et al.Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials.Lancet. 2009; 373: 1009-1015Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar conducted a meta-analysis of randomized clinical trials performed in dialysis patients to assess the impact of antihypertensive therapy on cardiovascular events, cardiovascular mortality, and all-cause mortality. The meta-analysis included 8 randomized trials encompassing 1,679 participants and 495 cardiovascular events. Because populations, interventions, and comparators varied significantly across studies (Table 1), a random-effects model was used to handle heterogeneity. None of the included studies treated patients to specific BP targets, but rather the studies compared outcomes in patients treated with a specified antihypertensive agent (active treatment) versus those receiving either another or no antihypertensive agent (control). Baseline mean systolic BP (SBP) and diastolic BP in the 8 studies ranged from 134-155 and 75-93 mm Hg, respectively. Overall, the rate of discontinuation of antihypertensive therapy caused by intolerance was low and did not differ significantly across study arms. Active treatment was associated with mean decreases of 4.3 and 2.3 mm Hg in SBP and diastolic BP, respectively. Decreases in BP varied across studies, and in 2 studies, the achieved BP was higher in the active-treatment than control arm. Nevertheless, administration of antihypertensive agents was associated with a decrease in cardiovascular events (relative risk, 0.71; 95% confidence interval, 0.55-0.92; P = 0.009), all-cause mortality (relative risk, 0.80; 95% confidence interval, 0.66-0.96; P = 0.01), and cardiovascular mortality (relative risk, 0.71; 95% confidence interval, 0.50-0.99; P = 0.04). In subgroup analyses, results did not differ among patients with hypertension, those with heart failure, or patients receiving angiotensin-converting enzyme inhibitors and/or angiotensin receptor blocking agents. The authors concluded that antihypertensive therapy routinely should be considered in the treatment of hemodialysis patients to reduce cardiovascular events and mortality.Table 1Summary of Study Populations, Interventions, and Comparators in Studies Included in the Heerspink et al2Heerspink H.J.L. Ninomiya T. Zoungas S. et al.Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials.Lancet. 2009; 373: 1009-1015Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar Meta-analysisStudyPopulationInterventionComparatorCice et al,3Cice G. Ferrara L. D'Andrea A. et al.Carvedilol increases two-year survival in dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial.J Am Coll Cardiol. 2003; 41: 1438-1444Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar 2003Dilated cardiomyopathyCarvedilol, 50 mg/dMatched placeboLi et al,4Li P.K. Chow K.M. Wong T.Y. Leung C.B. Szeto C.C. Effects of an angiotensin-converting enzyme inhibitor on residual renal function in patients receiving peritoneal dialysis A randomized, controlled study.Ann Intern Med. 2003; 139: 105-112Crossref PubMed Scopus (219) Google Scholar 2003Peritoneal dialysis patients with BP ≥ 120/70 mm HgRamipril, 5 mg/dConventional treatmentCice et al,5Cice G. Di Benedetto A. D'Isa S. D'Andrea A. De Gregoria P. Calabro R. Effect of telmisartan added to angiotensin converting enzyme inhibitors in reducing morbidity and mortality in haemodialysis patients with chronic heart failure [abstract].J Hypertens Suppl. 2006; 24: S56Google Scholar 2006Congestive heart failure NYHA class 2 or 3 or dilated cardiomyopathy with ejection fraction < 40%Telmisartan, 80 mg/dMatched placeboTakahashi et al,6Takahashi A. Takase H. Toriyama T. et al.Candesartan, an angiotensin II type-1 receptor blocker, reduces cardiovascular events in patients on chronic haemodialysis—a randomized study.Nephrol Dial Transplant. 2006; 21: 2507-2512Crossref PubMed Scopus (177) Google Scholar 2006Age ≥ 35 y, post-HD cardiothoracic ratio on chest radiograph < 50% in men and < 35% in womenCandesartan, 16-32 mg/dConventional treatmentZannad et al,7Zannad F. Kessler M. Lehert P. et al.Prevention of cardiovascular events in end-stage renal disease: results of a randomized trial of fosinopril and implications for future studies.Kidney Int. 2006; 70: 1318-1324Crossref PubMed Scopus (284) Google Scholar 2006Age, 50-80 y; HD for at least 6 mo; left ventricular hypertropyFosinopril, 20 mg/dMatched placeboNakao et al,8Nakao N. Hasegawa H. Fujimori A. Seno H. Toriyama T. Kawahare H. Effects of combined β-blockade and anti-aldosterone antagonist treatment for cardiovascular prevention in patients receiving maintenance dialysis.J Am Soc Nephrol. 2007; 18 ([abstract]): 709AGoogle Scholar 2007HD for at least 6 mo; left ventricular hypertrophyCarvedilol, 20 mg/dMatched placeboSuzuki et al,9Suzuki H. Kanno Y. Sugahara S. et al.Effect of angiotensin receptor blockers on cardiovascular events in patients undergoing hemodialysis: an open-label randomized controlled trial.Am J Kidney Dis. 2008; 52: 501-506Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar 2008Age, 30-80 y; HD for at least 12 mo; systolic BP > 160 mm Hg or > 150 mm Hg if taking antihypertensive agentsCandesartan, 12 mg/d, or losartan 100 mg/d, or valsartan, 160 mg/dConventional treatmentTepel et al,10Tepel M. Hopfenmueller W. Scholze A. Maier A. Zidek W. Effect of amlodipine on cardiovascular events in hypertensive haemodialysis patients.Nephrol Dial Transplant. 2008; 23: 3605-3612Crossref PubMed Scopus (81) Google Scholar 2008Age ≥ 18 y; HD for at least 3 mo; BP ≥ 140/90 mm HgAmlodipine, 10 mg/dMatched placeboAbbreviations: BP, blood pressure; HD, hemodialysis; NYHA, New York Heart Association.Source: Heerspink et al.2Heerspink H.J.L. Ninomiya T. Zoungas S. et al.Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials.Lancet. 2009; 373: 1009-1015Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar Open table in a new tab Abbreviations: BP, blood pressure; HD, hemodialysis; NYHA, New York Heart Association. Source: Heerspink et al.2Heerspink H.J.L. Ninomiya T. Zoungas S. et al.Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials.Lancet. 2009; 373: 1009-1015Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar This meta-analysis has several significant limitations. First, none of the original studies treated patients to specific BP targets, but rather compared outcomes in patients treated with a selected antihypertensive agent (active treatment) versus those receiving either another or no antihypertensive agent (control). Accordingly, the 29% relative risk reduction in cardiovascular mortality observed in the active-treatment group, despite the relatively small decreases in BP, raises the question of whether the observed benefit was caused by an antihypertensive drug class effect (angiotensin-converting enzyme inhibitors or angiotensin receptor blocking agents were used in 5 of 8 studies) as opposed to a BP-lowering effect. Second, although a random-effects model was used to control for heterogeneity across studies, statistical power was inadequate to detect differential effects across subgroups or for specific therapies. Third, details regarding the timing and methods of BP measurements are lacking and may not have been comparable across studies. Most likely routine dialysis unit BP measurements were used, although these are less predictive of clinical outcomes than home or ambulatory BP measurements.11Alborzi P. Patel N. Agarwal R. Home blood pressures are of greater prognostic value than hemodialysis unit recordings.Clin J Am Soc Nephrol. 2007; 2: 1228-1234Crossref PubMed Scopus (178) Google Scholar Fourth, little information relative to management of extracellular fluid volume was provided.12Charra B. Bergstrom J. Scribner B.H. Blood pressure control in dialysis patients: importance of the lag phenomenon.Am J Kidney Dis. 1998; 32: 720-724Abstract Full Text PDF PubMed Scopus (157) Google Scholar In contrast to both the results of this meta-analysis and studies of the general population,13Vasan R.S. Larson M.G. Leip E.P. et al.Impact of high-normal blood pressure on the risk of cardiovascular disease.N Engl J Med. 2001; 345: 1291-1297Crossref PubMed Scopus (1593) Google Scholar most large observational studies of patients undergoing conventional thrice-weekly hemodialysis have consistently shown an increase in mortality with low to normal BP levels.14Port F.K. Hulbert-Shearon T.E. Wolfe R.A. et al.Predialysis blood pressure and mortality risk in a national sample of maintenance hemodialysis patients.Am J Kidney Dis. 1999; 33: 507-517Abstract Full Text Full Text PDF PubMed Google Scholar, 15Zager P.G. Nikolic J. Brown R.H. et al.“U” curve association of blood pressure and mortality in hemodialysis patients.Kidney Int. 1998; 54: 561-569Crossref PubMed Scopus (593) Google Scholar However, observational studies are prone to bias, and most observational studies of BP in hemodialysis patients include both treated and untreated patients. Thus, low or even normal BP levels in hemodialysis patients may reflect cardiovascular disease, other comorbid conditions, or other unidentified confounders rather than a detrimental effect of BP lowering itself. In concert with this hypothesis, lower BPs have been associated with decreased mortality in hemodialysis patients who survive for > 3 years.16Stidley C.A. Hunt W.C. Tentori F. et al.Changing relationship of blood pressure with mortality over time among hemodialysis patients.J Am Soc Nephrol. 2006; 17: 513-520Crossref PubMed Scopus (123) Google Scholar Even in dialysis patients receiving antihypertensive medications, BP levels may not reflect active treatment to specific BP targets. To date, there are no large prospective randomized controlled trials powered for hard outcomes that were designed to compare outcomes among hemodialysis patients randomized to tight versus usual control of hypertension. The recent DRIP (Dry Weight Reduction in Hypertensive Hemodialysis Patients) Study shows a primary role for volume management in controlling BP in hemodialysis patients.17Agarwal R. Alborzi P. Satyan S. et al.Dry-Weight Reduction in Hypertensive Hemodialysis Patients (DRIP): a randomized, controlled trial.Hypertension. 2009; 53: 500-507Crossref PubMed Scopus (269) Google Scholar DRIP randomized 150 hypertensive hemodialysis patients who were clinically at dry weight to aggressive ultrafiltration versus usual care. In patients randomized to aggressive ultrafiltration, the average decrease in dry weight was 1 kg and ambulatory SBP decreased by 10.7 and 13.7 mm Hg at 4 and 8 weeks, respectively. The study lasted only 2 months; thus, long-term adherence to the revised dry weight, duration of the decrease in SBP, and effect of this intervention on clinical outcomes are unknown. Many nephrologists have concerns with lowering BP in hemodialysis patients.18London G. Controversy on optimal blood pressure on haemodialysis: lower is not always better.Nephrol Dial Transplant. 2001; 16: 475-478Crossref PubMed Scopus (27) Google Scholar Two recent studies, one of adults19Dasselaar J.J. Slart R.H.J.A. Knip M. et al.Haemodialysis is associated with a pronounced fall in myocardial perfusion.Nephrol Dial Transplant. 2009; 24: 604-610Crossref PubMed Scopus (124) Google Scholar and one of children,20Hothi D.K. Rees L. Marek J. et al.Pediatric myocardial stunning underscores the cardiac toxicity of conventional hemodialysis treatments.Clin J Am Soc Nephrol. 2009; 4: 790-797Crossref PubMed Scopus (74) Google Scholar showed significant decreases in myocardial perfusion during hemodialysis, even in the absence of intradialytic hypotension. These studies suggest that hemodialysis itself may compromise myocardial perfusion; this could be exaggerated by decreases in diastolic BP in the setting of noncompliant arteries and occlusive arterial disease, common in the hemodialysis population. The evidence supporting BP lowering in patients with chronic kidney disease (CKD) who are not on dialysis therapy also is limited. Two trials, the MDRD (Modification of Diet in Renal Disease) Study and AASK (African American Study of Kidney Disease and Hypertension),21Klahr S. Levey A.S. Beck G.J. et al.The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease Modification of Diet in Renal Disease Study Group.N Engl J Med. 1994; 330: 877-884Crossref PubMed Scopus (2061) Google Scholar, 22Wright Jr, J.T. Bakris G. Greene T. et al.Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.JAMA. 2002; 288: 2421-2431Crossref PubMed Scopus (1639) Google Scholar randomized patients with CKD to standard or low BP targets. Treatment to the low BP target had no effect on kidney disease progression in AASK, whereas a delay in reaching kidney failure was described in the extended follow-up of MDRD Study participants.23Sarnak M.J. Greene T. Wang X. et al.The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the Modification of Diet in Renal Disease Study.Ann Intern Med. 2005; 142: 342-351Crossref PubMed Scopus (435) Google Scholar Furthermore, a number of observational studies in CKD populations show the same relationship (a U or J shape) of BP with cardiovascular outcomes and mortality that has been described in hemodialysis populations.24Agarwal R. Blood pressure components and the risk for end-stage renal disease and death in chronic kidney disease.Clin J Am Soc Nephrol. 2009; 4: 830-837Crossref PubMed Scopus (95) Google Scholar, 25Kovesdy C.P. Trivedi B.K. Kalantar-Zadeh K. et al.Association of low blood pressure with increased mortality in patients with moderate to severe chronic kidney disease.Nephrol Dial Transplant. 2006; 21: 1257-1262Crossref PubMed Scopus (106) Google Scholar, 26Weiner D.E. Tighiouart H. Levey A.S. et al.Lowest systolic blood pressure is associated with stroke in stages 3 to 4 chronic kidney disease.J Am Soc Nephrol. 2007; 18: 960-966Crossref PubMed Scopus (82) Google Scholar Suggesting confounding by case-mix, 1 of these studies showed a J-shaped relationship of SBP with mortality in older patients with CKD, but a linear relationship (such that mortality is decreased at lower BPs) in younger patients who presumably have less comorbidity.24Agarwal R. Blood pressure components and the risk for end-stage renal disease and death in chronic kidney disease.Clin J Am Soc Nephrol. 2009; 4: 830-837Crossref PubMed Scopus (95) Google Scholar More definitive evidence about treating to lower BP goals in nondialysis populations eventually will be available from 2 large randomized clinical trials: SPRINT (Systolic Blood Pressure Intervention Trial) and the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Study. SPRINT will recruit nondiabetic hypertensive subjects, oversampling for subjects with CKD, whereas the ongoing ACCORD Study is evaluating individuals with diabetes.27Cushman S. Grimm Jr, R. Cutler J. et al.Rationale and design for the blood pressure intervention of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial.Am J Cardiol. 2007; 99: 44i-55iAbstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar ACCORD is randomizing participants to an SBP < 140 mm Hg versus < 120 mm Hg, and SPRINT plans to use similar targets. Importantly, results of these trials do not necessarily apply to hemodialysis patients in whom volume control, and therefore BP control, are largely dependent on fluid removal. The meta-analysis by Heerspink et al2Heerspink H.J.L. Ninomiya T. Zoungas S. et al.Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials.Lancet. 2009; 373: 1009-1015Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar shows that modest decreases in BP achieved by the administration of angiotensin-converting enzyme inhibitors, angiotensin receptor blocking agents, β-blockers, or calcium channel blockers in hemodialysis patients with modest hypertension was well tolerated and led to significant decreases in cardiovascular events and cardiovascular and all-cause mortality. However, this study was unable to provide information regarding the appropriate BP target and optimal therapy to decrease BP. Therefore, it is premature to alter practice based on this study. Further research is needed to address several unresolved questions, including (1) what BP measurements should guide management in hemodialysis patients: predialysis, postdialysis, or interdialytic BP measurements obtained through continuous ambulatory or intermittent home monitoring? (2) what level of BP optimizes outcomes in dialysis patients? (3) do certain antihypertensive therapies have benefits independent of BP lowering? and (4) what amount of BP lowering can be achieved and maintained in typical hemodialysis patients through sodium restriction and aggressive ultrafiltration, and when should antihypertensive medications supplement these other interventions? Given the biases inherent with observational data, prospective clinical trials that use a 2 × 2 factorial design in which patients are randomized to 2 different BP goals and 2 different antihypertensive medication classes are needed to answer these important questions. To detect a decrease in mortality of the magnitude seen in this meta-analysis would require a large multicenter study for a trial using a simple design comparing 2 BP arms or 2 antihypertensive drug classes, with as many as 1,500-2,000 hemodialysis patients needed for a study using a 2 × 2 factorial design. Financial Disclosure: Dr Zager is employed by the University of New Mexico, which receives salary support from Dialysis Clinic Inc. Dr Miskulin has no relevant financial interests to report.