Quadruple combination of quarter doses of blood pressure-lowering agents: a string QUARTET in the symphony of hypertension management?

Comment on ‘Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose monotherapy in patients with hypertension (QUARTET): a phase 3, randomised, double blind, active-controlled trial’ published in The Lancet (https://doi.org/10.1016/S0140-6736(21)01922-X). QUARTET1 was a multicentre, double-blind, parallel-group, phase-3 trial funded by the National Health and Medical Research Council of Australia, and conducted in 591 hypertensive patients (mean age 59 ± 12 years, 60% male), who were untreated (54%) or receiving monotherapy (46%). They were randomized to a single pill containing quadruple combination of quarter doses (quadpill) of blood pressure (BP)-lowering agents (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg) or an indistinguishable capsule containing irbesartan 150 mg (monotherapy control). If BP was not at target, additional medications could be added in both groups, starting with amlodipine 5 mg. The primary outcome was the difference in unattended office systolic BP (SBP) at 12 weeks. A subgroup of 417 patients continued randomly assigned allocation to 12 months to assess long-term effects. Secondary outcomes were unattended office diastolic BP (DBP) at 12 and 52 weeks and unattended SBP at 52 weeks; BP control (standard office BP <140/90 mmHg) at 6, 12, 26, and 52 weeks; tight BP control (standard office BP <120/80 mmHg); ambulatory SBP and DBP overall, daytime and night-time at 12 and 52 weeks; percentage requiring step-up treatment at 6 weeks and over 52 weeks; and safety and tolerability. After 12 weeks, the percentage of patients requiring additional BP medications was 15 in the intervention group compared to 40 in the control group. SBP was 6.9 mmHg lower [95% confidence interval (CI), 4.9–8.9 mmHg; P < 0.0001] in the intervention group, with a higher percentage of patients achieving standard BP control [76% vs. 58%; relative risk (RR), 1.30; 95% CI, 1.15–1.47; P < 0.0001] and tight BP control (46% vs. 26%; RR 1.75; 95% CI, 1.38–2.22; P < 0.0001) compared to the group receiving initial monotherapy. At 52 weeks, mean unattended SBP remained 7.7 mmHg (95% CI, 5.2–10.3 mmHg) lower and BP control rates higher in the intervention group compared to the control group (81% vs. 62%; RR 1.32; 95% CI, 1.16–1.50). The mean unattended DBP was reduced in the intervention group compared with the control group (−5.8 mmHg; 95% CI, −4.4 to −7.2; P < 0.0001). The percentages of participants who required additional medications were higher at 6, 12, 26, and 52 weeks in the control group. At 52 weeks, therapeutic adherence was 77% vs. 74% in the intervention and control groups, respectively. Three and one percentage of patients in the intervention and control groups, respectively, experienced serious adverse events. There was no significant difference in adverse event-related treatment withdrawals at 12 weeks between groups (intervention 4.0% vs. control 2.4%; P = 0.27). Although several antihypertensive agents are available in clinical practice, only a small proportion of patients achieve recommended BP targets, ranging from 15% to 60% in recent analyses.2,3 This issue is of particular interest since most recent guidelines recommend to aim for the rapid achievement of stringent BP goals (within 3 months) through the immediate use of dual combination therapy in the majority of patients.4–6 The benefits of combination strategies with three or four BP-lowering drugs at low doses in the same pill have been investigated over the last years as a potentially effective approach to achieve BP therapeutic goals while reducing side effects and improving adherence. In the TRIUMPH (Triple Pill vs. Usual Care Management for Patients With Mild-to-Moderate Hypertension) study conducted in 700 mild-to-moderate hypertensive subjects, treatment with a single pill containing low doses of three antihypertensive drugs (telmisartan 20 mg, amlodipine 2.5 mg, and chlorthalidone 12.5 mg) led to an increased proportion of patients achieving BP goal at 6 months compared to usual care (70% vs. 55%, respectively; P < 0.001).7 In another small, preliminary cross-over trial including 21 patients, those receiving a single pill containing four BP-lowering drugs each at quarter-dose (irbesartan 37.5 mg, amlodipine 1.25 mg, hydrochlorothiazide 6.25 mg, and atenolol 2.5 mg) achieved a placebo-corrected reduction of 19 mmHg in 24-h SBP and 22/13 mmHg in office BP (P < 0·0001).8 A review of 42 trials involving 20 284 participants showed that the BP differences achieved by single, dual, and quadruple quarter-dose combinations were +3.7/+2.6 mmHg (P < 0.001), +1.3/−0.3 mmHg (not significant), and −13.1/−7.9 mmHg (P < 0.001), respectively, compared to standard-dose monotherapy, without an increased risk of adverse events.9 In this context, the QUARTET trial confirms the potential advantages of a quadpill based on a quarter of the standard dosage as an early therapeutic strategy compared to monotherapy, with a favourable safety profile.1 Beside some important strengths of this trial, such as the blinded assessment of this novel strategy and a sufficiently long follow-up period, the potential limitations need also to be outlined. First, most recent international guidelines4,5 recommend starting antihypertensive treatment with combination strategies based on dual therapy in a single pill (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers associated with calcium channel blockers or thiazide diuretics), reserving monotherapy only to frail or very old (>80 years) patients. The same guidelines4,5 recommend upgrading the treatment to a three-drug single pill when BP targets are not achieved. Moreover, in patients receiving multiple medications simultaneously, the risk of potential over-treatment and therapeutic futility of one or more agents needs to be considered. Second, unattended BP levels were considered in this study among prespecified primary and secondary outcomes. Since there was an expected and clear discrepancy between baseline office (153/89 mmHg in the intensive group and 152/88 mmHg in the control group) and unattended BP (142/86 mmHg in the intensive group and 140/83 mmHg in the control group), a further aspect not addressed in the paper relates to the issue of the adequacy of unattended BP measurement in clinical trials.10 An additional limitation is related to the characteristics of the enrolled population, since this was composed of relatively young subjects (mean age 59 years), with good renal function (mean estimated glomerular filtration rate, 78 mL/min), and a low prevalence of diabetes (about 7%) and a previous history of coronary artery disease (about 4%). As a consequence, the achieved results can hardly be extrapolated to older patients or patients with a higher cardiovascular risk profile. Finally, the trial did not reach its recruitment target due to the COVID-19 pandemic, thereby limiting the precision of subgroup analyses and comparisons of some secondary outcomes. In conclusion, the results of the QUARTET trial confirm the BP-lowering efficacy and satisfactory tolerability and safety of a quadpill-based strategy in the early management of hypertension, potentially conferring an additional risk reduction in the long term. Further studies, however, should be aimed at assessing its efficacy and tolerability as compared with the currently recommended single-pill dual combination regimens as the first-line therapy. Conflict of interest: M.