Combining angiotensin receptor blockers with chlorthalidone or hydrochlorothiazide – which is the better alternative? A meta-analysis

Hypertension is a major global public-health challenge affecting approximately 1 billion individuals worldwide, with a projection to increase to 1.56 billion by 2025 given the increasingly aging population [1]. Hypertension is a disease with significant clinical and socio-economic consequences. Globally, cardiovascular diseases account for approximately 17 million deaths per year. More than a half of these cases are due to complications resulting from hypertension [2, 3]. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure describes the relationship between BP and risk of cardiovascular disease (CVD) as “continuous, consistent, and independent of other risk factors” [4]. The chances of heart attack, heart failure, stroke, and kidney diseases increase with BP increments. Meta-analysis of observational studies showed that the risk of cardiovascular death increases continuously from BP levels of 115 mmHg systolic and 75 mmHg diastolic [5].

The reduction in cardiovascular mortality and morbidity in patients treated for hypertension is directly related to the magnitude of blood pressure reduction. The utility of diuretics in the prevention of cardiovascular complications has been shown in major clinical trials [4], and these agents have a long history of safety and efficacy [6, 7]. Thiazide-like/type diuretics, such as chlorthalidone (CTLD) and hydrochlorothiazide (HCTZ), respectively, are important options for use in uncomplicated hypertension, without the presence of comorbid conditions. There has been debate about whether thiazide-like diuretics such as chlorthalidone and indapamide should be given preference over classical thiazide diuretics (e.g., hydrochlorothiazide and bendrofluazide), but their superiority on outcomes has never been tested in head-to-head RCTs [8]. For instance, CTLD is 1.5 to 2.0 times more potent than HCTZ on an mg:mg basis, and has a considerably longer half-life (45–60 h vs 8–15 h) and duration of action (48–72 h vs 16–24 h) after long-term dosing. Meta-analyses also suggest that CTLD is superior to HCTZ in preventing cardiovascular events [9, 10]. A meta-analysis [11] and a network meta-analysis (being prepared for publication) performed by our team also point to a prevalence for CTLD with regard to systolic and diastolic blood pressure control.

However, many treated hypertensive patients have inadequate blood pressure control and do not attain treatment goal [12, 13]. Although a single antihypertensive agent is considered to be the ideal in terms of convenience and compliance, many patients with essential hypertension require a combination drug regimen [14, 15].

Combination therapy with a renin-angiotensin system (RAS) inhibitor (either an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker [ARB]) plus a diuretic is a widely used and effective approach that has become an established component of evidence-based hypertension treatment guidelines [16‐18]. The combination of an ARB with a thiazide diuretic has been shown to be efficacious and well tolerated in numerous clinical trials [19‐29]. This combination could be of particular value in hypertensive patients with additional cardiovascular risk factors or in populations whose BP is traditionally poorly controlled, such as elderly persons, persons with diabetes mellitus and black patients [19, 30]. However, the question of which diuretic—chlorthalidone or hydrochlorothiazide has not been widely discussed.

Our search returned 2745 titles. Once duplicate reports and studies not relevant to the analysis were excluded, 51 full text articles remained to be subjected to assessment. After evaluation based on the inclusion criteria described in the methods, only 15 studies presenting data for 28 separate dose regimens remained to be included in the analysis comparing the efficacy of the combination of angiotensin receptor blocker and chlorthalidone to the effect of the combined use of angiotensin receptor blocker and hydrochlorothiazide in patients with hypertension (Fig. 1).

Characteristics of the studies included in the meta-analysis are outlined in Table 1 and data about baseline systolic and diastolic blood pressure is presented in Table 2. All 15 studies [20‐29, 32‐36] are randomized and all but 3 [23, 27, 36] are double blinded. There are 10 studies comparing ARB/HCTZ with HCTZ [20‐22, 24‐29, 32], one study comparing ARB/CTLD with CTLD [33] and 4 studies comparing ARB/CTLD with ARB/HCTZ [23, 34, 36]. In 4 studies, the ARB used is olmesartan [20, 34‐36], in 3 [21, 26, 27] it is valsartan, in 3 [22, 23, 27] it is candesartan, and in 3 it is telmisartan [24, 25, 27]. There is one study discussing each of the following: fimasartan [28], eprosartan [29], and losartan [32]. Azilsartan is used for treatment in 4 studies [33‐36]. Most commonly studies last 8 weeks although Cushman et al. [34] and Makita et al. [27] use duration of 12 weeks, Fogari et al. [20]—16 weeks, and Neutel et al. [36]—52 weeks. The number of patients involved varies a lot between studies but as a whole 2515 patients are treated with angiotensin receptor blocker, 4095 are treated with the combination of ARB/HCTZ, and 2795 are treated with the combination ARB/CTLD. The quality of the studies has been estimated as poor, moderate, or strong using the effective public health practice project. Results are presented in Table S1 the Supplementary material.

The combination of ARB and thiazide diuretics is highly effective for the treatment of hypertension and is well tolerated at the same time [39, 40]. This combination can be given as initial therapy (where appropriate) or later in the course of treatment [4]. Most commonly, the ARB is combined with hydrochlorothiazide despite the existence of various diuretics [40]. Recent studies suggest that chlorthalidone may be a suitable if not better alternative for hydrochlorothiazide [34‐36, 41]. NICE guidelines for the diagnosis and treatment of hypertension recommend ARB or angiotensin converting enzyme inhibitors as a starting regimen and advise the addition of thiazide-like diuretics as CTLD as opposed to hydrochlorothiazide [42]. However, elderly patients with hypertension often have other comorbidities which require additional medications. Polypharmacy is associated with increased risk of adverse events (fall injury, hyperkalemia and hypokalemia, heart failure, and blood pressure exacerbation), polypharmacy mismanagement, drug-drug interaction, and increased costs [43]. For such patients, treatment should be individualized and innovative approaches such as use of a fixed-dose combination pill, ingestible sensor system, electronic reminder system, medical audits, and the integration of a pharmacist in the care of patients should be implemented to avoid polypharmacy mismanagement [43]. A retrospective observational medical chart review study suggests that adopting the clinical pharmacist’s recommendations in a collaborative care approach could reduce the number of prescribed potentially inappropriate medications in patients aged 65 years or more therefore reducing the harmful drug-drug interactions and improving the adherence to treatment guidelines [44]. Another study also suggests that a collaborative approach to address the risks of drug–drug interactions and that the potential use of drug–drug interaction checkers could be beneficial [45].

Considering all said above, optimal control of blood pressure in hypertensive patients should be the goal. Although that may not always be achievable results of meta-analysis which used data from 147 randomized clinical trials showed that blood pressure reduction of 10 mmHg systolic and 5 mmHg diastolic was associated with a 41% (33 to 48%) reduction in stroke for all trials, 46% (35-55 %) in primary prevention trials, 44% (21-44 %) in secondary prevention trials, and 35% (20-47 %) in trials including subjects with a history of coronary heart disease [37]. Other authors claim that even reductions of −2 mmHg can be considered clinically significant [38, 46].

Our analysis suggest as many have before us [33, 47‐52] that the combination of ARB and a thiazide diuretic is more effective for the control of systolic and diastolic blood pressure than the use of the ARB or diuretic alone. When it comes to a comparison between the combinations ARB/HCTZ and ARB/CTLD pooled results show a WMD of −6.30 mmHg (−7.30, −5.29) in favor of the combination containing CTLD for control of systolic blood pressure. A WMD of −3.57 mmHg (−4.17, 2.98) for control of diastolic blood pressure is in favor of CTLD again. Our results suggest a prevalence for CTLD over HCTZ when the two are combined with ARB and used for blood pressure reduction in patients with hypertension.

It should be noted that a certain degree of heterogeneity exists in the studies which were deemed eligible and were included in the analysis. This can be attributed to multiple factors such as variety of study design and outcomes; differences in the inclusion and exclusion criteria; the way of measuring BP; different ARBs used; and varying doses of diuretics. We have, however, attempted to determine the significance of those differences by performing sensitivity analysis.

Interest in CTLD was renewed of late. MRFIT is the first trial to suggest superiority of CTLD. Results from MRFIT show that replacement of HCTZ with CTLD might lead to lower coronary heart disease mortality [53]. Dorsch et al. conducted a retrospective cohort analysis of MRFIT and concluded that after a follow-up period of 6 years cardiovascular events were less frequent in the CTLD group—21% lower than with HCTZ (p = 0.0016) [54]. This estimation was confirmed by a network meta-analysis which declared that CTLD was better for preventing cardiovascular events in patients with hypertension reducing them by 21% [10]. At the same time another observational cohort study does not find any association between reduction of cardiovascular events and CTLD use while at same time it shows an increase in the cases of electrolyte disturbances, specifically hypokalemia [55]. We have also attempted to estimate the effect of the combination of CTLD and HCTZ with ARB on the serum levels of sodium and potassium. Only two studies [35, 36] reported data on levels of serum potassium. The WMD in this case was only 0.01 mEq/L suggesting lack of difference in the effect of the two combinations. Data for levels of serum sodium was unfortunately scarce.

There are several studies investigating the effect of CTLD and HCTZ on blood pressure. Greater reduction in SBP was recorded in a small randomized, single-blinded, crossover study comparing CTLD 12.5 mg/day (force-titrated to 25 mg/day) and HCTZ 25 mg/day (force-titrated to 50 mg/day) [56] and in a double-blind, double-dummy, randomized, parallel group, comparative, multicentric trial [57]. A meta-analysis comparing the dose response of HCTZ, CTLD, and bendroflumethiazide on blood pressure predicted that reduction of 10 mmHg of SBP could be achieved by 1.4, 8.6, and 26.4 mg of bendroflumethiazide, CTLD and HCTZ respectively [58].

We evaluated a large number of sources in our attempt to examine the interchangeability of HCTZ and CTLD when they are used in combination with an ARB by assessing their effect on systolic and diastolic blood pressure. We tried to draw conclusions only by referring to trials we deemed to be of satisfactory quality (see Supplementary material). Even though we used a lot of sources and included numerous patients in the analysis which is a prerequisite for reduction of bias we also used funnel plots in order to assess bias (see Supplementary material). Additionally, we did not manage to find another paper be it a meta-analysis or a systematic review focusing on our topic and comparing the efficacy of the combination of angiotensin receptor blocker (ARB) and chlorthalidone (CTLD) to the combination of ARB and hydrochlorothiazide (HCTZ) in patients with hypertension.

There are a number of limitations intrinsic to the analysis. First of all, high quality trials investigating the efficacy of CTLD combined with ARB are scarce. Secondly, we have evaluated the effects of HCTZ and CTLD using data for combined doses. Almost all studies included in our statistical analysis were conducted relatively recently and all but two were funded by industry. Additionally, we did not take into consideration any existing comorbidities of the patients.

The combination of an ARB with a diuretic is a widely used method for addressing hypertension as a first or subsequent line of treatment. The most commonly used diuretic seems to be HCTZ. Our analysis suggests that CTLD should be considered as a valuable alternative for HCTZ and an option for fixed dose combinations with an ARB due to its tentative prevalence in blood pressure control when compared to HCTZ.