Impact of Angiotensin Receptor Blockers (ARB) versus Other Antihypertensive Medication on Blood Pressure in Patients on Dialysis: A Meta-Analysis

Introduction

For patients with end-stage renal disease (ESRD), hemodialysis is a life-sustaining therapy.¹ Yet, a documented consequence of hemodialysis is the potential for blood pressure (BP) to shift frequently both during and in between treatments.¹ Large variability in BP measurements during hemodialysis is a risk factor for mortality.² In general, BP is poorly controlled in patients on dialysis.³ The main causes of mortality among these patients under hemodialysis are cardiovascular (CV) complications, with high BP being an important risk factor.⁴

According to the National Kidney Foundation Kidney Disease (NKFKD) Outcomes Quality Initiative guidelines (2004), hypertension (HTN) in hemodialysis patients is diagnosed when pre-dialysis BP is >140/90 mmHg or when post-dialysis BP is >130/80 mmHg.⁵ The intradialytic HTN is defined as “an increase in BP during or immediately after hemodialysis which results in post-dialysis HTN.” The potential pathophysiologic mechanisms for such intradialytic HTN varies include volume overload, sympathetic overactivity, activation of the renin–angiotensin–aldosterone system, endothelial dysfunction, dialysis-specific factors, medications (erythropoietin-stimulating agents) and vascular stiffness.^6,7 Given the established pathophysiology, non-pharmacologic therapies, such as dietary sodium restriction, improved salt removal with dialysis, and probing dry weight is the considered first steps in achieving BP control in these patients.^7-9 Though these therapeutic approaches were considered to be challenging, as several factors contribute to it.^9,10

A pooled analysis of randomized studies revealed that reducing BP lowers CV morbidity and mortality in dialysis patients, especially in those with high BP.^7,8,11,12 Among the antihypertensive agents, losartan, a selective angiotensin-II receptor blocker (ARB), has shown an efficacy similar to angiotensin-converting enzyme inhibitors (ACEIs), with a low incidence of side effects¹³ and also well tolerated by patients with chronic kidney disease.¹⁴ Additionally, it helps prevent pathological CV remodeling by having an inhibitory influence on ambulatory short-term BP variability during the night.¹⁵ The most common treatment-related adverse events (AEs) were hypotension during or after dialysis and a mild increase in potassium levels.^16,17 Studies showed that overall mortality was 1% when losartan was continued for 6 months.¹⁷ However, a “one-size-fits-all” approach for BP management may not be appropriate for all patients.¹⁸ The adjusted increased risk of death at 2 years was estimated to be 6% for every 10 mmHg increase in systolic blood pressure (SBP) during hemodialysis.¹⁹

Despite these advancements in this field, there is currently no comprehensive review of the effectiveness of ARBs such as Losartan in comparison with other anti-hypertensive drugs. This systematic review and meta-analysis aims to assess the overall outcomes of the effectiveness of ARBs such as Losartan and its impact on BP in patients on dialysis.

Methods

This protocol was prospectively registered with PROSPERO and conducted with the requirements of the reporting rules in the “Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines”.²⁰ Because this work is a systematic review, the heterogeneity was present within the acceptable range, meta-analysis was performed.

Eligibility criteria

Criteria for included studies were defined as adults aged ≥ 18 years who were on dialysis. The full eligibility criteria are available in the eMethod 1 in Supplementary File 1. Studies were included if they studied adults of both sexes aged ≥ 18 years undergoing hemodialysis or dialysis receiving antihypertensive medication; were randomized controlled trials (RCTs) with individual or cluster-type, observational studies, assessed the effects of ARB and other antihypertensive agents (calcium channel blocker [CCB], alpha and beta blocker, diuretic) or placebo.

Results

Study selection and characteristics

A total of 1,679 studies were initially retrieved following the removal of duplicates. Of those, 15 studies met the inclusion criteria. However, 2 of the 15 studies were presented with already published patient information and were removed. Therefore, 13 studies were ultimately included for the qualitative and quantitative analyses [Table 1].^15,25-36

Table 1: Qualitative characteristics of the included studies for the effect of ARB (an angiotensin receptor blocker) on hemodialysis patients (n = 13)

First Author	Year	Objective	Study duration	Study design	Intervention drug	Control drug	Results	Major limitation of the study	Type of dialysis	Complications >20% of n (even if anyone drug)
Aftab RA et al.25	2017	To assess the effectiveness of Losartan in reducing BP among post-dialysis euvolemic patients and assessing their survival trends	12 months	Multicentric, prospective, randomised, parallel design, single-blind trial	Losartan	Other antihypertensive drugs	BP Improved, Losartan 50 mg achieve an overall significant decline in blood pressure among post-dialysis euvolemic hypertensive patients	Small sample size, region specific population,	Hemodialysis	Events such as hyperkalaemia, cough, dizziness, and dyspepsia
Bikos A et al.28	2018	To evaluate the effects of a single or weekly administration of nebivolol and irbesartan on peri-dialytic, intradialytic, and ambulatory BP in patients with intradialytic hypertension.	3 months	Single-blind randomized-cross-over study	Irbesartan	Nebivolol	BP improved. Nebivolol was slightly more effective than irbesartan in reducing BP during weekly administration	Small sample size, short duration	Hemodialysis	Not mentioned
Huber M et al.29	2013	To study the effect of telmisartan compared to placebo on top of a standard antihypertensive medication without treatment of other RAS blockers in HD patients.	18 weeks	Placebo-controlled, double-blinded, cross-over randomization study	Telmisartan	Placebo	No average significant BP influence of telmisartan was observed compared to placebo. The latter may be due to a large inter-individual variability of BP responses.	Small sample size, Complicated standardization of concomitant medication and other confounding factors,	Hemodialysis	On telmisartan - leukocyte count was lowered
Ichihara A et al.30	2005	To determine the low-dose effects of the ARB losartan and the angiotensin-converting enzyme inhibitor trandolapril on PWV, which predicts cardiovascular morbidity and mortality in hemodialysis patients.	12 months	Multicentre, randomized, prospective study	Losartan	Trandolapril	In hemodialysis patients, trandolapril is as effective as losartan in decreasing PWV independent of its depressor effect and in suppressing elevated IDL-C levels	Less sample size, no blinding	Hemodialysis	Not mentioned
Peters CD et al.26	2015	To describe central hemodynamics during dialysis newly started HD patients randomized to ARB (irbesartan) or placebo, aiming at a pre-dialytic SBP target of 140mmHg in both groups.	12 months	Randomized Double-Blind Placebo-Controlled Trial	Irbesartan	Placebo	Over the one-year period, pre-dialytic SBP decreased significantly, but similarly in both groups.	Not mentioned	Hemodialysis	Not mentioned
Shigenaga A et al.33	2009	To examine whether addition of an ARB, candesartan, or valsartan, to conventional antihypertensive treatment could improve BP in HTN patients on peritoneal dialysis	6 months	Randomised controlled trial	Valsartan	Other than ACE inhibitors	Both showed similarly controlled 24-hour ambulatory BP values in hypertensive patients on peritoneal dialysis. ARB treatment is beneficial for the suppression of pathological CV remodelling with a decrease in BP variability.	Small sample size, peritoneal function not mentioned, norepinephrine level not mentioned, short duration.	Peritoneal dialysis	Not mentioned
Suzuki H et al.34	2008	To evaluate the efficacy of long-term use of ARBs on CV outcomes in patients undergoing HD	3 years	Prospective, controlled, randomized, open label trial	Losartan	Enalapril	There were 93 fatal or nonfatal CVD events (52%); 34 (19%) in the ARB group and 59 (33%) in the non-ARB group.	Small sample size, ARB were analysed as the group not as individual drugs, choice of the ARB was dependent based on the patients	Hemodialysis
Suzuki H et al.35	2004	To assess the effects of an ACE inhibitor, an AT1 antagonist and their combination on the regression of LVH in diabetic patients on dialysis therapy.	1 year	Randomized controlled trial	Losartan	Enalapril	BP improved overall. An initial steady in blood pressure decline was observed for up to 6 months followed by maintenance and then a fall toward the end of the study.	The therapeutic window for intervention to prevent progressive cardiac enlargement	Hemodialysis	Intolerable cough
Peters CD et al.26	2015	To describe central hemodynamics during dialysis newly started HD patients randomized to ARB (irbesartan) or placebo, aiming at a pre-dialytic SBP target of 140mmHg in both groups.	12 months	Randomized Double-Blind Placebo-Controlled Trial	Irbesartan	Placebo	Over the one-year period, pre-dialytic SBP decreased significantly, but similarly in both groups.	Not mentioned	Hemodialysis	Not mentioned
Shigenaga A et al.33	2009	To examine whether addition of an ARB, candesartan, or valsartan, to conventional antihypertensive treatment could improve BP in HTN patients on peritoneal dialysis	6 months	Randomised controlled trial	Valsartan	Other than ACE inhibitors	Both showed similarly controlled 24-hour ambulatory BP values in hypertensive patients on peritoneal dialysis. ARB treatment is beneficial for the suppression of pathological CV remodelling with a decrease in BP variability.	Small sample size, peritoneal function not mentioned, norepinephrine level not mentioned, short duration.	Peritoneal dialysis	Not mentioned
Suzuki H et al.34	2008	To evaluate the efficacy of long-term use of ARBs on CV outcomes in patients undergoing HD	3 years	Prospective, controlled, randomized, open label trial	Losartan	Enalapril	There were 93 fatal or nonfatal CVD events (52%); 34 (19%) in the ARB group and 59 (33%) in the non-ARB group.	Small sample size, ARB were analysed as the group not as individual drugs, choice of the ARB was dependent based on the patients	Hemodialysis
Suzuki H et al.35	2004	To assess the effects of an ACE inhibitor, an AT1 antagonist and their combination on the regression of LVH in diabetic patients on dialysis therapy.	1 year	Randomized controlled trial	Losartan	Enalapril	BP improved overall. An initial steady in blood pressure decline was observed for up to 6 months followed by maintenance and then a fall toward the end of the study.	The therapeutic window for intervention to prevent progressive cardiac enlargement does not remain open much beyond 1 year, this study would not apply to diabetic patients who had already received dialysis therapy >1 year prior.	Hemodialysis	Intolerable cough
Takahashi A et al.27	2006	To investigate whether candesartan, an ARB type I, reduces the incidence of CV events in Hemodialysis patients.	3 years	Prospective, randomized, open blinded trial	Candesartan	Placebo	BP was not different between the two groups and no changes were noted in the either group during follow-up. Candesartan therapy significantly reduces CV events and mortality in patients on chronic maintenance hemodialysis, independent of their anti-hypertensive effect.	Small size, short duration	Hemodialysis	Heart failure

BP: Blood pressure; CV: cardiovascular; ARB: Angiotensin receptor blocker; SBP: Systolic blood pressure; HD: Hemodialysis; HTN: Hypertension; PWV: pulse wave velocity; RAS: Renin angiotensin system; IDL c: Intermediate density lipid cholesterol; CKD: chronic kidney disease; AVF: Arterio venous fistula; ESRD: End stage renal disease; SBP: systolic blood pressure; LVH: left ventricular hypertrophy; ACE: Angiotensin converting enzyme; AT1: angiotensin 1 receptor; OSI: oxidative stress index.

Of the 13 studies, seven studies focused on Losartan, and the remaining studies focused on other ARBs. When using the NIH quality assessment tool, seven studies had a low risk of bias, two studies had a moderate risk of bias, and the rest of four studies had a high risk of bias [eTable 1 in Supplementary File 2].^15,25-36 The PRISMA flowchart for the study selection is available in Figure 1. The major limitation was the small sample size in seven studies and the short duration in three studies. BP reductions were found to be similar in both groups in six studies. Hyperkalaemia was found in two studies in >20% of the study sample as a complication.

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Figure 1:

Preferred reporting items for systematic review and meta-analysis protocols (PRISMA) flow diagram of the study selection process.

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Effectiveness of ARB drug on SBP and DBP among patients undergoing haemodialysis

A meta-analysis of 13 eligible RCT studies involving 745 subjects received ARBs and the 717 controls received other anti-hypertensive agents and placebo. The random model effects showed the pooled mean difference (MD) between the pre-dialysis and post-dialysis BP of the ARB agents and the other antihypertensive agents. The pooled standard MD for the SBP among pre-dialysis was 0.11 [95% CI: −0.09–0.31], [Figure 2a] when compared to the post-dialysis were 0.35 (95% CI: −0.33–1.02), [Figure 2b] which does not favor the effect of ARB agent on SBP when compared with other anti-hypertensive agents. Heterogeneity was found regarding the use of the ARB agent for SBP management among the studies included in the analysis (I²: 63% and 97%, respectively). Similarly, the pooled standard MD for the DBP among the pre-dialysis was −0.08 (95% CI: −0.42–0.26) with considerable heterogeneity (I²: 88%) [Figure 3a] when compared with the post-dialysis as 0.11 (95% CI: −0.18–0.40) [Figure 3b] and 82% was the heterogeneity. Complications by the ARB agents were assessed and found that the pooled risk ratio was 1.01 (95% CI: 0.59–1.75) with a heterogeneity of 75% and statistically non-significant [Figure 4].

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Figure 2:

Effectiveness of ARB drugs on the systolic blood pressure (SBP) among the patients undergoing pre- and post-hemodialysis (n = 13). (a) Pre-hemodialysis, (b) Post-hemodialysis. CI: Confidence interval, ARB: Angiotensin receptor blocker, SD: standard deviation.

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Figure 3:

Effectiveness of ARB drugs on the diastolic blood pressure (DBP) among the patients undergoing pre- and post-hemodialysis (n = 13). (a) Pre-hemodialysis, (b) Post-hemodialysis. CI: Confidence interval, ARB: Angiotensin receptor blocker, SD: standard deviation.

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Figure 4:

Complications by angiotensin receptor blockers (ARB) agents among patients who underwent dialysis (n = 6). M-H: Mantel-Haenszel. CI: Confidence Interval.

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Subgroup analysis

We performed subgroup analysis [Figures 5 and 6] to assess the heterogeneity and difference in the effect size of the ARB agent losartan across the types of ARB agents. For the pre-dialysis SBP, the pooled standard MD was 0.17 (95% CI: −0.21–0.55) and the post-dialysis was 0.35 (95% CI: −0.17– 1.02); yet, both were statistically non-significant, implying that there was no difference between losartan and ARB drugs where both had the same effect on the SBP. For the DBP, the pooled MD for pre-dialysis was −0.01 (95% CI: −0.65–0.63) and post-dialysis was 0.03 (95% CI: −0.24– 0.30) and statistically non-significant.

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Figure 5:

Subgroup analysis of the effectiveness of losartan (study group) and other ARB drugs (control group) on systolic blood pressure (SBP) among the patients undergoing hemodialysis. (a) Pre-dialysis, (b) Post-dialysis. CI: Confidence interval, ARB: Angiotensin receptor blocker, SD: standard deviation.

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Figure 6:

Subgroup analysis of the effectiveness of losartan (study group) and other ARB drugs (control group) on diastolic blood pressure (DBP) among patients undergoing hemodialysis. (a) Pre-dialysis, (b) Post-dialysis. ARB: Angiotensin receptor blocker, CI: confidence interval, SD: standard deviation.

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Discussion

Hypertension in patients undergoing dialysis is associated with adverse clinical outcomes. Current clinical guidelines emphasize targeting SBP of <130 mmHg post-hemodialysis for chronic hemodialysis patients. The available literature on intradialytic hypertension shows a trend of SBP rise >10 mmHg from pre- to post-dialysis in the hypertensive range in at least four to six consecutive dialysis treatments³⁷ showing that 8 to 30% of dialysis patients develop intradialytic hypertension. This newly developed hypertension is associated with a 2.5-fold increased risk for hospitalization and cardiovascular (CV) mortality.³⁸ As the underlying pathophysiology is multifactorial, the treatment decision for intradialytic hypertension should be individualized.

Overall, we demonstrated that patients on hemodialysis who received ARB for hypertension in 13 studies included in this meta-analysis did not have better outcomes when compared with the use of other anti-hypertensive medications. In terms of SBP, our study findings are similar to Agarwal et al.’s⁷ study that showed that despite the use of two anti-hypertensive agents, on average, SBP is uncontrolled in the large majority of patients on drug therapy. In addition, these results were concordant with the report of Cannella et al.,³⁹ who found that left ventricular hypertrophy (LVH) was caused by a high prevalence of inadequately or partially controlled hypertension. These studies implied varied effects of ARB on the BP, which might be due to the measurement of the BP at different periods of follow-up. Yet, these agents significantly reduced the mortality and the AE in patients with hemodialysis, with improved prognosis and survival. Additionally, we did not find any significant difference in the post-DBP (pooled MD: 1.21). This finding parallels a study that examined the effects of olmesartan on CV outcomes and mortality. Although the study observed a reduction in BP, it did not find any statistically significant differences in the measured outcomes.³¹ Intriguingly, numerous studies have demonstrated the positive impact of ARBs on DBP during follow-up periods, yielding significant favorable outcomes. ARB showed a significant reduction in DBP after intervention during the follow-up in 12 months,²⁵ 8 months,¹⁶ 6 months,⁴⁰ and 2 weeks duration.⁷ Added to that DBP was not an independent factor for the development of the CV event in dialysis patients.⁴¹ All these studies that showed positive results implied that the prolonged use of ARB resulted in a significant reduction of DBP with a significant reduction in CV mortality. Yet, assessment of high DBP is very unlikely to be isolated from SBP.¹⁷ Although high-quality evidence evaluating high DBP is limited due to its low incidence, we found no significant difference between ARB and other antihypertensive medications to reduce post-diastolic BP.

The existing literature showed that the effect of the ARB agent on hemodialysis patients helps maintain adequate BP and is well tolerated.^26,27 However, as per our analysis, patients might require other antihypertensive agents to maintain appropriate BP.⁴²

In the present study, we could observe studies with losartan had a significant influence on the SBP and DBP when compared to the other studies. The pooled MD and heterogeneity level of the losartan group for SBP was 0.21 (95% CI: −0.32, 0.73; I²: 79%), and for DBP was 2.06 (95% CI: −2.98, 7.10; I²: 86%); yet, it was statistically non-significant and considerable heterogeneity.

Studies showed that post-dialysis BP was observed to significantly decrease over time when hypertensive patients received losartan 50 mg.¹⁶ After 6 months, it significantly lowered SBP and DBP by about 10 and 5 mmHg, respectively. Also, the overall mortality was 1% when losartan was continued for 6 months.¹⁷

Yet, the other studies that used other groups of ARB agents for adequate SBP control also showed positive effects, when studies that used losartan were excluded. The pooled MD for SBP was 0.05 (95% CI: −0.23, 0.34) and for DBP was 0.24 (95% CI: −4.28, 4.77), respectively, and non-significant. They both showed very minimal heterogeneity (SBP I²: 0%; DBP I²: 52%) when compared with other antihypertensive agents. Studies have shown that losartan is also considered to have less AE.^13-17,25 The results of this study support the role of losartan as an antihypertensive drug helping in maintaining HTN in hemodialysis patients although it is statistically non-significant in optimal control of hypertensive dialysis patients when compared to other antihypertensives.

Our systematic review has some limitations. As far as the lack of sufficient data with regard to losartan and other ARB agents, most studies published were observational studies and case series that concerned the exclusion criteria, and hence were susceptible to bias and confounding. The limited RCT that used ARB was only reviewed, which resulted in limited data. Due to the lack of proper random sequencing and allocation concealment, the effect of the ARB was potentially overestimated. Furthermore, due to the smaller sample size in each study and single-centered studies, it cannot be extrapolated to general studies.

Conclusion

Our review of completed clinical trials to date comparing ARBs and other antihypertensive medications, revealed that both exhibited promising outcomes. Losartan appears to facilitate optimal hypertension management in dialysis patients accompanied by minimal AEs. We propose further exploration involving the combination of additional antihypertensive agents with ARBs to ascertain the most effective BP management strategy.