Efficacy and Safety of Quarter-Dose Blood Pressure–Lowering AgentsNovelty and Significance
A Systematic Review and Meta-Analysis of Randomized Controlled Trials
There is a critical need for blood pressure–lowering strategies that have greater efficacy and minimal side effects. Low-dose combinations hold promise in this regard, but there are few data on very-low-dose therapy. We, therefore, conducted a systematic review and meta-analysis of randomized controlled trials with at least one quarter-dose and one placebo and standard-dose monotherapy arm. A search was conducted of Medline, Embase, Cochrane Registry, Food and Drug Administration, and European Medicinal Agency websites. Data on blood pressure and adverse events were pooled using a fixed-effect model, and bias was assessed using Cochrane risk of bias. The review included 42 trials involving 20 284 participants. Thirty-six comparisons evaluated quarter-dose with placebo and indicated a blood pressure reduction of −4.7/−2.4 mm Hg (P<0.001). Six comparisons were of dual quarter-dose therapy versus placebo, observing a −6.7/ −4.4 mm Hg (P<0.001) blood pressure reduction. There were no trials of triple quarter-dose combination versus placebo, but one quadruple quarter-dose study observed a blood pressure reduction of −22.4/−13.1 mm Hg versus placebo (P<0.001). Compared with standard-dose monotherapy, the blood pressure differences achieved by single (37 comparisons), dual (7 comparisons), and quadruple (1 trial) quarter-dose combinations were +3.7/+2.6 (P<0.001), +1.3/−0.3 (NS), and −13.1/−7.9 (P<0.001) mm Hg, respectively. In terms of adverse events, single and dual quarter-dose therapy was not significantly different from placebo and had significantly fewer adverse events compared with standard-dose monotherapy. Quarter-dose combinations could provide improvements in efficacy and tolerability of blood pressure–lowering therapy.
See Editorial Commentary, pp 32–34
High blood pressure is the leading cause of preventable morbidity and mortality globally.1 Yet control of blood pressure is poor, with only 1 in 3 people on treatment achieving blood pressure targets.2–5 The largest global survey of hypertension practice showed that while 88% of those aware of hypertension receive some pharmacological treatment, only 34% of those treated were controlled. Overall, 61% of those treated only received monotherapy5 even though combination therapy is usually required to achieve acceptable levels of blood pressure control.6 In the absence of more effective new blood pressure drug classes, better blood pressure control is likely to require more use of existing agents in combination.
Minimization of side effects is critical for long-term treatment of a largely asymptomatic condition such as high blood pressure. Several studies suggest that low-dose combinations may provide the best ratio of side effects to blood pressure reduction, because at low doses most side effects are avoided and most benefit is realized.7 Given that blood pressure dose–response gradients are typically shallow above quarter standard dose,7 combinations containing quarter doses of several antihypertensive agents may be of particular benefit. One small trial reported in 2007 a large blood pressure reduction from quadruple quarter-dose combination therapy compared with monotherapy,8 and a small trial recently completed also showed large reductions compared with placebo.9 We, therefore, conducted a systematic review of randomized trials of quarter-dose blood pressure–lowering agent(s) to place these trials in the context of all evidence concerning quarter-dose therapy and to assess the potential clinical role of quarter-dose monotherapy and combination therapy.
The review methods are detailed in the protocol (online-only Data Supplement) and were written in accordance with the preferred Cochrane Collaboration–reporting items for systematic reviews and meta-analyses.
Search Strategy and Selection Criteria
Electronic searches were conducted in EMBASE (inception to June 2016), MEDLINE (inception to June 2016), Cochrane Central Registry of Controlled Trials (inception to June 2016) and the Food and Drug Administration and European Medicines Agency websites. Searches of trial registers were performed for any ongoing trials including World Health Organization International Clinical Trials Registry Platform, Australia New Zealand Clinical Trial Register, and Clinical Trials Registry – India. Retrieval of studies from reference lists of key clinical trials, systematic reviews, and published articles was also undertaken. The Medline search has been included in the online-only Data Supplement).
During the initial phase of the search, 2 reviewers (A.B., M.C.) independently performed the searches assessing titles and abstracts, excluding any studies that did not qualify. Both the reviewers then inspected the full text of those selected articles identified in the initial phase. A third reviewer (A.R.) resolved any disagreement on the included articles.
Types of Studies
Randomized controlled trials (either parallel or crossover) with a treatment and follow-up of at least 2 weeks were sought. Uptitration studies must have had blood pressure or safety data for at least the first 2 weeks before titration occurred. Studies were included only if there were efficacy or safety data that were measured for at least 1 of the 5 major classes of blood pressure–lowering medications: calcium channel blockers, β-blockers, angiotensin receptor II antagonists, angiotensin-converting enzyme inhibitors, and thiazide diuretics (TZs). All included medications were registered for use by the Food and Drug Administration or European Medicines Advisory and indicated for the treatment of hypertension.
Studies were eligible for inclusion if participants were ≥18 years of age and written and published in English. No study was excluded on the basis of baseline blood pressure, presence or absence of disease, or year performed. Studies were only considered if at least one arm was allocated quarter-dose therapy (with one or multiple agents) and at least one arm allocated placebo or standard-dose monotherapy (to allow comparison with the 2007 trial8). In this review, the standard dose was defined as the most reported usual maintenance dose recorded by the British National Formulary, Martindale and Monthly Index of Medical Specialties, similar to the method of Law et al.7 The World Health Organization Defined Daily Dose was used as a tiebreaker if no consensus was found. If there was still no consensus between the selected pharmacopoeias, the most reported dose was judged as the standard dose (Table 1). However, there were 2 exceptions. A quarter dose of hydrochlorothiazide of 6 and 5 mg were used for the studies by Jounela et al10 and Pool et al11 because there was no 6.25 mg arm.
Efficacy was assessed using the mean absolute difference between the intervention and control deltas (mean changes in systolic blood pressure [SBP] and diastolic blood pressure [DBP] from baseline to end of study). Safety was defined as adverse events (all and side effect related, as defined by each trial) at follow-up, and change in biochemical data (potassium and uric acid) from baseline to follow-up.
Data Extraction and Risk of Bias
Two reviewers (A.B. and M.C.) independently extracted data using a standard extraction form. The variables extracted included study design, sample size, mean age, percentage of female patients, randomization, blinding, intervention, dose(s), follow-up, percent lost to follow-up, and study outcomes. In studies where numeric blood pressure changes were not presented (n=5), a visual estimate was made based on the figures provided. Both reviewers independently estimated the difference, with the average of the 2 being used.
The 2 reviewers (A.B. and M.C.) also independently assessed the risk of bias in each trial based on the Cochrane Collaboration’s risk of bias tool12 (Figure S8 in the online-only Data Supplement). This estimates the risk based on sequence generation, allocation concealment, selective outcome reporting, potential threats to validity, blinding of participants, personnel and outcome assessors, and incomplete data. The risk of bias in each included trial was reported as low, unclear, or high. A third reviewer (A.R.) resolved any differences.
One reviewer (A.B.) entered the data into Microsoft Excel and then into the Comprehensive Meta-analysis Software.13 A second reviewer (H.-M.D.) checked the data for accuracy with a third reviewer (A.R.) resolving any disagreements. The data were analyzed according to intention to treat when possible. Binary outcomes were analyzed using the Mantel–Haenszel approach and summarized as risk ratios with 95% confidence intervals (CIs). Continuous outcomes were summarized as difference in means with 95% CIs. Individual trial results were pooled using fixed-effect meta-analysis with inverse variance weighting. Heterogeneity was quantified by Q test, I2, and τ statistics14,15 (Table S2). Publication bias was assessed and reported using a funnel plot (Figure S6).
Given the role of baseline blood pressure in determining the extent of blood pressure reduction from blood pressure–lowering drugs16 and because there was heterogeneity across trials in mean baseline levels, blood pressure was standardized to that expected from a baseline of 150/95 mm Hg. This involved a 0.1 mm Hg reduction in a given study’s SBP change score for each mm Hg baseline SBP over 150 mm Hg, and a 0.1 mm Hg increase for each mm Hg baseline SBP below 150 mm Hg. Similarly, 0.11 mm Hg was subtracted or added for each mm Hg DBP above or below 95 mm Hg.16 If no baseline blood pressure was reported for a given trial, then for that comparison, the mean of the included trials was used.
To analyze all randomized comparisons of quarter-dose therapy versus placebo and versus standard-dose monotherapy, some participants contributed to more than one analysis, and not all comparisons within multiarm trials were included. For example, Frishman et al17 conducted a 4×3 factorial dose–response trial of 2 agents, with 12 cells labeled A through L in Table 2.
These cells contributed to the different analyses as shown in Table 3.
Variability data were absent in 12 trials, in which cases the SD was imputed as a pooled SD derived from other trials with similar study arms.18 Although not ideal, this approach has been used in such occasions as outlined by the Cochrane Handbook of Systematic Reviews of Interventions.19 All biochemical data reported had missing variability data, and, thus, a common SD was used, derived for potassium from the ALLHAT (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack)20 and for uric acid from the review by Weidmann.21 Meta-regression was used to undertake subgroup analysis of the effect that age and treatment period (>6 weeks) had on efficacy. Also, 3 sensitivity analyses were undertaken, to compare fixed-effect versus random-effects models, standardized versus nonstandardized blood pressure differences, and the impact of imputation for studies with missing variability data.
The initial search identified 1730 studies, with 1554 screened after exclusion of duplicate citations (Figure 1). Fifty-eight studies with extractable data met the inclusion criteria, and 16 studies were excluded after full-text evaluation. A total of 42 studies were included in the meta-analysis (online-only Data Supplement).
Table S1 details the characteristics of included studies. On average, the trials were published 17 years ago, and 85% of trials had eligibility criteria based solely on DBP. Of the 42 studies, 38 reported quarter-dose monotherapy, 7 reported dual quarter-dose combination therapy, and 2 reported quadruple quarter-dose therapy compared with either placebo or each component at a standard dose. Follow-up ranged from 4 to 12 weeks, averaging 7 weeks. Most studies were dose–response trials testing 3 to 4 doses of one agent versus placebo. Fourteen trials (included trials 8, 10, 12, 13, 15, 17, 18, 20, 21, 22, 24, 34, 35, and 37, for more details, please see online-only Data Supplement) were factorial dose–response trials, testing several doses of 2 agents. Only 1 out of the 42 studies did not have at least one arm containing standard-dose monotherapy, and all but 2 included a placebo control arm. Overall, there were 20 284 participants with a mean age of 54 years, 61% were men, and mean baseline blood pressure was 154/101 mm Hg.
Quarter-Dose Therapy Versus Placebo
The efficacy in blood pressure lowering of single quarter-dose therapy versus placebo was assessed in 4721 participants in 36 trials (Figure 2). Overall, placebo-corrected single quarter-dose therapy reduced blood pressure by −4.7 (95% CI, −5.4 to −3.9)/−2.4 (−2.8 to −1.9) mm Hg. There was broad consistency in treatment effect across the 5 major treatment classes (I2 SBP: 3, DBP: 0), and each was separately significant except for calcium channel blockers.
Six trials measured the efficacy of dual quarter-dose therapy compared with placebo (Figure 2). All but one trial used a TZ diuretic in the dual quarter-dose combination. In the 312 participants assessed, the effect of the dual quarter-dose combination was an overall blood pressure drop of −6.7 (−8.6 to −4.8)/−4.4 (−5.5 to −3.3) mm Hg. There was some evidence of heterogeneity present across the different dual combinations (I2 SBP: 18, DBP: 37). No studies measured triple quarter-dose therapy versus placebo. One study (included trial 40, for more details, please see online-only Data Supplement) measured efficacy of quadruple quarter-dose therapy versus placebo and showed an office blood pressure reduction of −22.4 (−28.3 to −16.5)/−13.1 (−17.3 to −8.8; Figure 2). This was the only trial to report effects on 24-hour blood pressure profile, with reductions in 24 hour, day-time, and night-time BP of −18.7/−14.2, −22.3/−15.3, and −10.4/−12.5 mm Hg, respectively.
Quarter-Dose Therapy Versus Standard-Dose Monotherapy
Figure 3 illustrates the comparisons of single, dual, and quadruple quarter-dose therapy compared with standard-dose monotherapy on blood pressure reductions. Single quarter-dose therapy was less efficacious than standard-dose monotherapy by 3.7 (3.0–4.5)/2.6 (2.2–3.1) mm Hg (I2 SBP: 24.3; DBP: 10.2). Dual quarter-dose therapy showed an equivalent blood pressure–lowering effect compared with standard-dose monotherapy. Only one study8 assessed blood pressure lowering with quadruple quarter-dose therapy versus standard-dose monotherapy and showed a substantially greater blood pressure reduction in the quarter-dose group of −13.1 (−20.1 to −6.1)/−7.9 (−12.1 to −3.7) mm Hg.
Safety and Tolerability
Fifteen studies provided data on adverse events. Overall, compared with placebo, no significant difference in the risk of adverse events in the 14 single quarter-dose comparisons (relative risk, 1.0 [0.91–1.2], I2: 20.8). This was also observed in 6 dual quarter-dose comparisons (0.93 [0.29–2.9]) and in a solitary quadruple (2.0 [0.2–20.2]) quarter-dose placebo comparison (Figure 4). Moreover, no individual medication class was associated with a greater risk of adverse events compared with placebo. Both single and dual quarter-dose therapy produced significantly fewer adverse events than standard-dose monotherapy (Figure 4). In terms of tolerability of quadruple quarter-dose therapy, in the 2007 trial compared with standard-dose therapy, the only information available was that therapy was well tolerated by all of the participants, and, in particular, there was no case of hypotension.(J. Feely, personal communication). In the 2017 trial, no patient withdrew because of side effects.9 However, in each trial, treatment was for only 4 weeks and a total of 40 patients received quadruple quarter-dose therapy.
Biochemical Adverse Effects
Table 4 compares the mean difference from baseline to follow-up in biochemical measures, for placebo, single quarter-dose, dual quarter-dose, and standard-dose therapy. Overall, data on potassium concentrations were reported in 10 studies; of these, 8 were amenable to pooling. Compared with placebo, none of the single (n=5), dual (n=3), or quadruple (n=1) quarter-dose therapy comparisons showed a significant difference in potassium concentration. Treatment with TZ standard-dose monotherapy (n=4) resulted in a significantly greater reduction in potassium concentration compared with single quarter-dose TZ, dual quarter β-blockers+quarter TZ and dual quarter angiotensin-converting enzyme inhibitor+quarter TZ. Similar trends were seen in 2 trials reporting the proportion of patients below a certain potassium level (<3.5 mmol/L)22 or the number of participants who developed a >0.05 mmol change in potassium concentration.23
Three studies reported data on uric acid concentrations in a format that allowed the data to be pooled. Compared with placebo, no significant differences were observed for single or dual quarter-dose treatment arms; however, quadruple quarter-dose therapy did result in a small increase compared with placebo (0.03, 95% CI, 0.001–0.04 mmol/L; P=0.003). Standard-dose TZ resulted in greater uric acid concentration versus single quarter-dose TZ, versus dual quarter angiotensin receptor II antagonists+quarter TZ and versus dual quarter β-blockers+quarter TZ. These findings are comparable to one trial that only reported percentage change from baseline.24 There was a also a small difference in creatinine compared with quadruple quarter-dose therapy compared with placebo (4.4, 95% CI, 0.9–7.8 mmol/L; P=0.02), but no patient had more than a 12% increase.9
Effects on heart rate were generally not reported but were available for both quadruple quarter-dose combinations: Chow et al,9 reported a reduction of 6.5 bpm (95% CI, 2.3–10.6) compared with placebo and Mahmud and Feely8 reported a reduction from baseline of 6 SD 3 bpm.
Quality of Evidence
The Trim and Fill approach did not suggest evidence of publication bias (Figure S6). The risk of bias was assessed in all 42 studies (Figure S8). Overall, 8 studies described the method of sequence generation; 7 described the method of concealment and 28 described and dealt with missing data. In the absence of detailed study protocols, it was not possible to assess whether outcomes were selective. Likewise, other potential threats to validity could not be assessed. Blinding of participants and personnel was undertaken in some capacity for 41 trials (40 of which were double-blinded, 1 single blinded, and 1 open label).
Subgroup analyses undertaken using meta-regression did not suggest any significant correlation between DBP lowering and age (P=0.38) or >6 week treatment (P=0.18; Figure S7).
The mean blood pressure reduction for a single quarter dose versus placebo was essentially the same using the random-effects model (−4.7 [−5.4 to −3.9]/−2.3 [−2.8 to −1.9] mm Hg), compared with the fixed-effect model (−4.7 [−5.4 to −3.9]/−2.4 [−2.8 to −1.9] mm Hg). Exclusion of studies with missing data on variability also did not substantially affect this estimate (−5.0 [−5.7 to −4.2]/−2.4 [−2.9 to −1.8] mm Hg). Finally, pooling of nonstandardized changes in blood pressure, rather than changes standardized to a baseline blood pressure of 150/95 mm Hg provided an overall estimate of −5.0 (−5.8 to −4.3)/−2.9 (−3.4 to −2.3) mm Hg for quarter-dose therapy versus placebo.
This review is the first to compare quarter-dose therapy to both standard dose and placebo and indicates a potential clinical advantage in terms of reducing side effects and, with the use of quadruple combinations, increasing efficacy. Single quarter-dose therapy reduced blood pressure by ≈−4.7/−2.4 mm Hg compared with placebo (about half as much as standard-dose monotherapy), with no apparent side effects. Dual quarter-dose therapy had about the same efficacy as standard-dose monotherapy, with fewer side effects. The data on quadruple quarter-dose therapy was limited to 2 small trials that indicated that these combinations are significantly more efficacious than placebo and standard-dose monotherapy. A clear dose response in efficacy was seen between single, double, and quadruple quarter-dose therapy.
Strengths and Weaknesses of the Study
This review has several strengths. It was conducted in line with recommended systematic review methodology and included a relatively large number of studies, doubling the number of trials of quarter-dose therapy included in a previous systematic review.9 Several studies were identified in regulatory submissions that had not been published in the medical literature. The large number of trials allowed precise estimates of treatment effects, at least for single and dual combinations, and assessment of consistency of results across major drug classes. The review also has some limitations. We did not review non–English language trials. No individual-patient data were used, and data were not checked with original trialists because most trials were completed more than 17 years ago. There were some missing data, particularly on variability, but sensitivity analyses did suggest the findings were reasonably robust. Only one trial assessed effects on 24-hour BP profile, and it remains unknown whether better night-time BP reduction can be achieved with different components. Finally, defining standard-dose–involved some assumptions, but to minimize their impact, the authors used data from 4 pharmacopoeias.
Context of Other Evidence
Law et al undertook the most relevant previous review in 2003, which assessed placebo-controlled trials of blood pressure–lowering drugs available at that time.7 The principal aim of that review was to quantify effects of standard doses of blood pressure–lowering agents and dose response. Analysis of low-dose therapy was largely restricted to half dosages, indicating that half-dose blood pressure treatment was ≈80% as efficacious as standard dose and that side effects generally rose steeply with dose. In terms of results for quarter-dose therapy, there were limited data on efficacy, and no analyses on side effects from the 19 studies quantifying single quarter-dose effects in the Law 2003 review. The present review included a further 23 trials of quarter-dose therapy. As with the current review, Law et al did not find any clear evidence that one drug class was more effective than any other. However, as with other systematic reviews of dose response within treatment classes,25 Law et al also noted that there is considerable variability in potency per mg, and so the choice of standard dose is relevant to such comparisons. In the context of other low-dose combination therapy trials, the most relevant compared triple half-dose therapy (amlodipine 2.5 mg, losartan 25 mg, hydrochlorothiazide 12.5 mg) with placebo and also observed a large blood pressure reduction, of −17.9/−9.8 mm Hg.26
This review suggests a potentially broader clinical role for low-dose blood pressure–lowering drugs. Use of dual quarter-dose blood pressure–lowering therapy may be preferable to standard-dose monotherapy, given comparable blood pressure reduction with better tolerability. Alternatively, addition of a single quarter-dose agent to existing therapy is likely to confer an extra 3 to 4 mm Hg systolic blood pressure reduction without additional side effects and thus could be preferable to doubling the dose of the existing agent, which on average confers only about a 1–2 mm Hg extra systolic blood pressure reduction at the expense of increased side effects.7,27 Currently, there are a few low-dose combinations available to clinicians: for example, a bisoprolol–hydrochlorothiazide combination is on the market in the United States (Ziac), with a dual quarter-dose version indicated for initial treatment of hypertension; a perindopril–indapamide combination is available that includes half dose and quarter dose, supported by clinical trial data showing improved rates of adverse event-free blood pressure control compared with sequential monotherapy or stepped care.28 Quarter doses are available for many β-blockers and are obtainable for other classes from halving existing half-doses. However, for many patients, more blood pressure reduction than that given by standard-dose monotherapy or dual quarter-dose therapy is needed.29 This review suggests considerably more research is required, to examine the potential of triple or quadruple quarter-dose combinations to determine whether they could provide substantial blood pressure–lowering with little or no drug-specific side effects, that is, more or less pure blood pressure lowering. Future trials should explore this hypothesis, testing quarter-dose combinations as initial therapy and also for those uncontrolled on monotherapy who need additional blood pressure reduction and for particular patient groups of interest, such as the elderly or those with impaired renal function. Further information on tolerability of such combinations is critical, given the near absence of data in this regard. Relevant clinical trials should also assess patient acceptability and the potential for low-dose combination pills to improve long-term adherence.
We would like to acknowledge the contributions of Professor Henry Krum who passed away in 2015. A. Bennett drafted the protocol and data collection forms and conducted search, data abstraction, and data checking as first reviewer; led statistical analysis; and drafted and revised the article. C.K. Chow contributed to the conception of the review, revision of the protocol, review of data analyses, and review of the article. M. Chou contributed to the literature search, trial identification, data abstraction, and data checking as second reviewer and to review of data analyses and the article. H.-M. Dehbi contributed to data checking as second reviewer and to review of data analyses and the article. R. Webster, A. Salam, A. Patel, B. Neal, D. Peiris, H. Krum, J. Thakkar, J. Chalmers, M. Nelson, C. Reid, G.S. Hillis, M. Woodward, S. Hilmer, T. Usherwood, and S. Thom contributed to the conception of the review, revision of the protocol, review of data analyses, and review of the article. A. Rodgers conceived the review and supervised research staff working on the project. A. Rodgers is the guarantor.
Sources of Funding
This work was supported by a National Health and Medical Research Council Program Grant. C.K. Chow is supported by a National Health and Medical Research Council (NHMRC) Career Development Fellowship, cofunded by a National Heart Foundation Future Leader Fellowship and the Sydney Medical Foundation. B. Neal is supported by an NHMRC Principal Research Fellowship. A. Patel was supported by a Senior Research Fellowship and Program Grant from NHMRC. C. Reid is supported by a National Health and Medical Research Council Senior Fellowship. M. Woodward is supported by a National Health and Medical Research Council Principal Fellowship. A. Rodgers is supported by a National Health and Medical Research Council Principal Research Fellowship.
B. Neal reports grants for a clinical trial from Abbvie, Dr Reddy’s Laboratories, Jannsen, Merck Schering-Plough, and Roche; speaking fees from Abbott, Novartis, Pfizer, Roche, and Servier; travel fees from Janssen, Roche, and Servier; fees for advisory board membership from Janssen; is Chair of the Steering Committee for 2 ongoing large-scale trials of an SGLT2 inhibitor and member of the Steering Committee for a third. All honoraria and travel fees are paid to B. Neal’s institution, not as personal fees. J. Chalmers reports research grants and honoraria from Servier for the ADVANCE trial, outside the submitted work. D. Peiris reports grants from NHMRC, the National Heart Foundation of Australia, and University of Sydney, during the conduct of the study. S. Thom reports personal fees from Amgen, Lilly, Pfizer, and Sanofi, outside the context of the submitted work and acknowledges support by the UK National Institute of Health Research (NIHR) Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London. M. Woodward reports consultant fees from Amgen, outside the submitted work. George Health Enterprises, the social enterprise arm of The George Institute for Global Health, has applied for patents in this research area, on which C.K. Chow and A. Rodgers are named as inventors; George Health Enterprises has also received investment to develop fixed-dose combinations containing aspirin, statins, and blood pressure–lowering drugs. The other authors report no conflicts.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.117.09202/-/DC1.
- Received February 6, 2017.
- Revision received February 26, 2017.
- Accepted April 13, 2017.
- © 2017 American Heart Association, Inc.
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Novelty and Significance
What Is New?
There are few data on the efficacy or tolerability of ultralow-dose blood pressure combinations.
What Is Relevant?
Dual quarter-dose therapy is as effective as standard-dose monotherapy, with fewer side effects.
Quadruple quarter-dose therapy seems to be around twice as efficacious as standard-dose monotherapy, but there are few data on side effects.
Quarter-dose combinations could provide improvements in efficacy and tolerability of blood pressure–lowering therapy.