澳大利亚悉尼大学Clara K Chow团队比较了高血压患者使用四联药物初始治疗与标准剂量单药初始治疗的疗效。2021年8月28日出版的《柳叶刀》杂志发表了这项成果。
治疗惰性是公认的血压控制障碍，需要更简单、更有效的治疗策略。研究组假设，从一粒含有超低剂量四联疗法的单一药片开始的高血压治疗策略将比从单药治疗开始的策略更有效。
研究组进行了一项多中心、双盲、平行、随机、3期临床试验，招募澳大利亚未接受治疗或接受单药治疗的成年（≥18岁）高血压患者，将其按1：1随机分配，分别接受四联疗法（含厄贝沙坦37.5 mg、氨氯地平1.25 mg、吲达帕胺0.625 mg，比索洛尔2.5 mg）或单药对照治疗（厄贝沙坦150 mg）。
如果血压没达到目标值，两组患者都可以增加药物治疗，从5 mg的氨氯地平开始。主要结局是12周时无人值守办公室收缩压的差异。次要结局包括血压控制（标准办公室血压<140/90 mmhg）、安全性和耐受性。一个亚组继续随机分配12个月，以评估长期效果。根据治疗意向进行分析。
2017年6月8日至2020年8月31日，研究组共招募了591名参与者，300名被随机分配接受初始四联疗法干预，291名接受初始标准剂量单药治疗。591名参与者的平均年龄为59岁，男性356例（60%），女性235例（40%）；483名（82%）为白人，70名（12%）为亚裔，38名（6%）为其他种族；基线平均无人值守办公室血压为141/85 mm Hg。12周时，干预组300名参与者中有44人（15%）服用了额外的降压药，而对照组291名参与者中有115人（40%）。
与对照组相比，干预组的收缩压降低了6.9 mm Hg；干预组的血压控制率为76%，显著高于对照组的58%。在12周时，干预组中有4.0%的参与者因不良事件而退出治疗，对照组中有2.4%，组间无显著差异。在417名继续服药的患者中，对照组患者用药剂量增加的频率显著高于干预组。但在52周时，干预组的平均收缩压仍比对照组低7.7 mm Hg，血压控制率为81%，显著高于对照组的62%。在随机分组的12周内，干预组有7例患者（3%）发生严重不良事件，对照组有3例（1%）。
研究结果表明，与初始单药治疗的普通策略相比，早期固定剂量四联治疗策略达到并维持了更好的降压效果。这项试验证明了四联药物治疗的有效性、耐受性和简单性。
附：英文原文
Title: 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
Author: Clara K Chow, Emily R Atkins, Graham S Hillis, Mark R Nelson, Christopher M Reid, Markus P Schlaich, Peter Hay, Kris Rogers, Laurent Billot, Michael Burke, John Chalmers, Bruce Neal, Anushka Patel, Tim Usherwood, Ruth Webster, Anthony Rodgers, Andrew Hung, Armand Edison, Angalie E Abraham, Daniel Xu, Mark T Bloch, Gemma Figtree, Janis M Nolde, Andrew Black, Shirley Jansen, Sinjini Biswas, Andrew E Ajani, Revathy Carnagarin, Dylan Wynne, Mikhail Altman, Jay Thakkar, Aravinda Thiagalingam, Harry Klimis
Issue&Volume: 2021-08-28
Abstract: Background
Treatment inertia is a recognised barrier to blood pressure control, and simpler, more effective treatment strategies are needed. We hypothesised that a hypertension management strategy starting with a single pill containing ultra-low-dose quadruple combination therapy would be more effective than a strategy of starting with monotherapy.
Methods
QUARTET was a multicentre, double-blind, parallel-group, randomised, phase 3 trial among Australian adults (≥18 years) with hypertension, who were untreated or receiving monotherapy. Participants were randomly assigned to either treatment, that started with the quadpill (containing irbesartan at 37·5 mg, amlodipine at 1·25 mg, indapamide at 0·625 mg, and bisoprolol at 2·5 mg) or an indistinguishable monotherapy control (irbesartan 150 mg). If blood pressure was not at target, additional medications could be added in both groups, starting with amlodipine at 5 mg. Participants were randomly assigned using an online central randomisation service. There was a 1:1 allocation, stratified by site. Allocation was masked to all participants and study team members (including investigators and those assessing outcomes) except the manufacturer of the investigational product and one unmasked statistician. The primary outcome was difference in unattended office systolic blood pressure at 12 weeks. Secondary outcomes included blood pressure control (standard office blood pressure <140/90 mm Hg), safety, and tolerability. A subgroup continued randomly assigned allocation to 12 months to assess long-term effects. Analyses were per intention to treat. This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry, ACTRN12616001144404, and is now complete.
Findings
From June 8, 2017, to Aug 31, 2020, 591 participants were recruited, with 743 assessed for eligibility, 152 ineligible or declined, 300 participants randomly assigned to intervention of initial quadpill treatment, and 291 to control of initial standard dose monotherapy treatment. The mean age of the 591 participants was 59 years (SD 12); 356 (60%) were male and 235 (40%) were female; 483 (82%) were White, 70 (12%) were Asian, and 38 (6%) reported as other ethnicity; and baseline mean unattended office blood pressure was 141 mm Hg (SD 13)/85 mm Hg (SD 10). By 12 weeks, 44 (15%) of 300 participants had additional blood pressure medications in the intervention group compared with 115 (40%) of 291 participants in the control group. Systolic blood pressure was lower by 6·9 mm Hg (95% CI 4·9–8·9; p<0·0001) and blood pressure control rates were higher in the intervention group (76%) versus control group (58%; relative risk [RR] 1·30, 95% CI 1·15–1·47; p<0·0001). There was no difference in adverse event-related treatment withdrawals at 12 weeks (intervention 4·0% vs control 2·4%; p=0·27). Among the 417 patients who continued, uptitration occurred more frequently among control participants than intervention participants (p<0·0001). However, at 52 weeks mean unattended systolic blood pressure remained lower by 7·7 mm Hg (95% CI 5·2–10·3) and blood pressure control rates higher in the intervention group (81%) versus control group (62%; RR 1·32, 95% CI 1·16–1·50). In all randomly assigned participants up to 12 weeks, there were seven (3%) serious adverse events in the intervention group and three (1%) serious adverse events in the control group.
Interpretation
A strategy with early treatment of a fixed-dose quadruple quarter-dose combination achieved and maintained greater blood pressure lowering compared with the common strategy of starting monotherapy. This trial demonstrated the efficacy, tolerability, and simplicity of a quadpill-based strategy.
DOI: 10.1016/S0140-6736(21)01922-X
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01922-X/fulltext
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