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,The Lancet

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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
The Lancet ( IF 168.9 ) Pub Date : 2021-08-29 , DOI: 10.1016/s0140-6736(21)01922-x
Clara K Chow ₁ , Emily R Atkins ₂ , Graham S Hillis ₃ , Mark R Nelson ₄ , Christopher M Reid ₅ , Markus P Schlaich ₆ , Peter Hay ₇ , Kris Rogers ₈ , Laurent Billot ₉ , Michael Burke ₁₀ , John Chalmers ₉ , Bruce Neal ₁₁ , Anushka Patel ₉ , Tim Usherwood ₂ , Ruth Webster ₁₂ , Anthony Rodgers ₉ ,

Affiliation

Westmead Applied Research Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
Westmead Applied Research Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; The George Institute for Global Health, UNSW, Sydney, NSW, Australia.
Royal Perth Hospital and Medical School, University of Western Australia, Perth, WA, Australia.
Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
School of Public Health & Preventive Medicine Monash University, Melbourne, VIC, Australia; School of Population Health, Curtin University, Perth, WA, Australia.
Dobney Hypertension Centre, Royal Perth Hospital Research Foundation, Medical School, University of Western Australia, Perth, WA, Australia.
Castle Hill Medical Centre, Sydney, NSW, Australia.
The George Institute for Global Health, UNSW, Sydney, NSW, Australia; Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia.
The George Institute for Global Health, UNSW, Sydney, NSW, Australia.
School of Medicine, Western Sydney University, Sydney, Australia.
The George Institute for Global Health, UNSW, Sydney, NSW, Australia; School of Public Health, Imperial College London, London, UK.
The George Institute for Global Health, UNSW, Sydney, NSW, Australia; Centre for Health Economics Research and Evaluation, University of Technology Sydney, Sydney, NSW, Australia.

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.

Funding

National Health and Medical Research Council, Australia.

中文翻译：

在高血压患者中使用含有四分之一剂量血压药物的四倍组合与标准剂量单药治疗（QUARTET）的单一药丸初始治疗：一项 3 期、随机、双盲、主动对照试验

背景

治疗惰性是血压控制的公认障碍，需要更简单、更有效的治疗策略。我们假设从含有超低剂量四联疗法的单一药丸开始的高血压管理策略将比从单一疗法开始的策略更有效。

方法

QUARTET 是一项多中心、双盲、平行组、随机的 3 期试验，针对未经治疗或接受单药治疗的澳大利亚高血压成人（≥18 岁）。参与者被随机分配接受任一治疗，从四丸（含厄贝沙坦 37·5 mg、氨氯地平 1·25 mg、吲达帕胺 0·625 mg 和比索洛尔 2·5 mg）或难以区分的单一疗法对照开始（厄贝沙坦 150 毫克）。如果血压未达到目标值，则可以在两组中添加额外的药物，从 5 mg 的氨氯地平开始。参与者是使用在线中央随机服务随机分配的。有一个 1:1 的分配，按站点分层。除研究产品的制造商和一名未蒙面的统计学家外，所有参与者和研究团队成员（包括调查人员和评估结果的人员）都被蒙蔽了分配。主要结果是 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（标准诊室血压<140/90 mm Hg）、安全性和耐受性。一个亚组继续随机分配到 12 个月以评估长期影响。分析是按意向治疗的。该试验在澳大利亚新西兰临床试验注册处进行了前瞻性注册，ACTRN12616001144404，现已完成。次要结局包括血压控制（标准诊室血压<140/90 mm Hg）、安全性和耐受性。一个亚组继续随机分配到 12 个月以评估长期影响。分析是按意向治疗的。该试验在澳大利亚新西兰临床试验注册处进行了前瞻性注册，ACTRN12616001144404，现已完成。次要结局包括血压控制（标准诊室血压<140/90 mm Hg）、安全性和耐受性。一个亚组继续随机分配到 12 个月以评估长期影响。分析是按意向治疗的。该试验在澳大利亚新西兰临床试验注册处进行了前瞻性注册，ACTRN12616001144404，现已完成。

发现

从 2017 年 6 月 8 日到 2020 年 8 月 31 日，招募了 591 名参与者，其中 743 名被评估为合格，152 名不合格或拒绝，300 名参与者被随机分配到初始四丸治疗干预组，291 名控制组初始标准剂量单药治疗。591 名参与者的平均年龄为 59 岁（标准差 12）；356 人（60%）为男性，235 人（40%）为女性；483 人（82%）为白人，70 人（12%）为亚裔，38 人（6%）为其他种族；基线平均无人值守办公室血压为 141 mm Hg (SD 13)/85 mm Hg (SD 10)。到 12 周时，干预组 300 名参与者中有 44 名（15%）有额外的血压药物，而对照组 291 名参与者中有 115 名（40%）有额外的血压药物。收缩压降低 6·9 mm Hg（95% CI 4·9–8·9；p< 0·0001) 和血压控制率在干预组 (76%) 高于对照组 (58%; 相对风险 [RR] 1·30, 95% CI 1·15–1·47; p<0· 0001)。12 周时与不良事件相关的治疗退出无差异（干预 4·0%与对照相比 2·4%；p=0·27)。在继续治疗的 417 名患者中，对照组参与者比干预参与者更频繁地发生上调（p<0·0001）。然而，在 52 周时，平均无人值守收缩压仍然低 7·7 mmHg（95% CI 5·2-10·3），干预组（81%）的血压控制率高于对照组（62%） ; RR 1·32, 95% CI 1·16–1·50)。在长达 12 周的所有随机分配的参与者中，干预组有 7 例 (3%) 严重不良事件，对照组有 3 例 (1%) 严重不良事件。