Three Low-Dose Antihypertensive Agents in a Single Pill after Intracerebral Hemorrhage

Craig S. Anderson, MBBS, PhD. et al.

2026년 4월 22일

N Engl J Med 2026;394:1571-1582

DOI: 10.1056/NEJMoa2515043

Abstract

Background

Blood-pressure reduction is the only proven treatment to prevent stroke due to intracerebral hemorrhage. Whether a single pill that combines three antihypertensive drugs at low doses, in addition to standard antihypertensive treatment, can lower blood pressure more than standard care alone and reduce the risk of recurrent stroke after intracerebral hemorrhage is uncertain.

Methods

We conducted a multinational, double-blind, randomized, placebo-controlled trial involving patients with a history of intracerebral hemorrhage. Patients were eligible for the trial if they had a systolic blood pressure of 130 to 160 mm Hg at baseline and were in clinically stable condition. After a 2-week active run-in phase during which all the patients received a once-daily pill containing three antihypertensive agents at low doses (telmisartan at 20 mg, amlodipine at 2.5 mg, and indapamide at 1.25 mg; the triple pill), the patients were randomly assigned to continue receiving the triple pill or to receive matching placebo. The primary outcome was the first recurrent stroke. Secondary outcomes included blood-pressure control, major cardiovascular events, death from cardiovascular causes, and safety.

Results

Of 1670 patients who underwent randomization, 833 were assigned to receive the triple pill and 837 to receive placebo. The mean age of the patients was 58 years. At a median follow-up of 2.5 years, recurrent stroke had occurred in 38 patients (4.6%) in the triple-pill group and 62 (7.4%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.41 to 0.92; P=0.02). The mean systolic blood pressure during follow-up was 127 mm Hg and 138 mm Hg, respectively. The incidence of major cardiovascular events was lower with the triple pill than with placebo (6.6% vs. 9.8%; P=0.04). Serious adverse events occurred in 23.2% of the patients in the triple-pill group and 26.0% of those in the placebo group. Early discontinuation of the trial regimen due to an adverse event occurred in 13.6% and 6.0%, respectively. The most common adverse event leading to discontinuation was an increase of 20% or more in the serum creatinine level.

Conclusions

Among patients with intracerebral hemorrhage, treatment with a combination of three low-dose antihypertensive agents in a single pill, in addition to standard care, was associated with a lower incidence of recurrent stroke and major cardiovascular events than placebo. (Funded by the National Health and Medical Research Council of Australia and the Brazilian Ministry of Health; TRIDENT ClinicalTrials.gov number, NCT02699645; Australian New Zealand Clinical Trials Registry number, ACTRN12616000327482.)

요약

·         배경 : 뇌내출혈 후 재발성 뇌졸중을 예방하는 데 있어 효과가 입증된 유일한 치료는 혈압 강하이다. 그러나 기존의 표준 항고혈압 치료에 세 가지 저용량 항고혈압제를 하나의 복합제(single-pill combination)로 추가 투여하는 전략이, 표준 치료 단독에 비해 혈압을 더욱 효과적으로 조절하고 뇌내출혈 이후 재발성 뇌졸중의 위험을 감소시킬 수 있는지는 아직 확립되지 않았다.

·         방법 :

• 뇌내출혈 병력이 있는 환자를 대상

• 다국가, 이중맹검, 무작위 위약 대조 임상시험

• 기저 수축기혈압이 130~160 mmHg이고 임상적으로 안정된 상태인 경우 연구에 등록

• 모든 환자는 먼저 2주간의 활성 런인(active run-in) 기간 동안 세 가지 저용량 항고혈압제(텔미사르탄 20 mg, 암로디핀 2.5 mg, 인다파마이드 1.25 mg)를 포함한 복합제(triple pill)를 하루 한 번 복용

• 이후 환자들은 3제 복합제를 계속 투여받는 군 또는 동일한 외형의 위약(placebo)을 투여받는 군에 무작위로 배정

  
  

• 1차 평가 지표(primary outcome):

o    첫 번째 재발성 뇌졸중(first recurrent stroke)의 발생

•   2차 평가 지표(secondary outcomes)

o    혈압 조절 정도

o    주요 심혈관 사건(major cardiovascular events)

o    심혈관 원인에 의한 사망

o    안전성(safety)

 ·         결과 :

• 총 1,670명의 환자가 무작위 배정을 받음

  (833명은 3제 저용량 복합제(triple pill)군, 837명은 위약군에 배정)

• 평균 연령은 58세

  중앙값 2.5년의 추적관찰 기간 동안,

•   재발성 뇌졸중

o    복합제군: 38명(4.6%)

o    위약군: 62명(7.4%)

->위험비(hazard ratio)는 0.61(95% 신뢰구간, 0.41–0.92; P=0.02)

복합제군에서 유의하게 낮았다.

•   평균 수축기 혈압

o    복합제군: 127 mmHg

o    위약군: 138 mmHg

•   주요 심혈관 사건 발생률

o    복합제군: 6.6%,

o    위약군: 9.8%

->복합제군에서 유의하게 낮았다(P=0.04)

• 중대한 이상반응

o    복합제군: 23.2%

o    위약군: 26.0%

->두 군 간에 큰 차이는 없었다.

• 중대한 이상반응으로 인해 시험약 투여를 조기에 중단한 비율

o    복합제군: 13.6%

o    위약군: 6.0%

->복합제군에서 더 높았다.

• 시험약 중단의 가장 흔한 원인

o    혈청 크레아티닌(creatinine) 수치가 기저치보다 20% 이상 증가한 경우

·         결론 :

뇌내출혈 환자에서 표준 치료에 저용량 3제 항고혈압 복합제를 추가한 치료는, 위약에 비해 재발성 뇌졸중과 주요 심혈관 사건의 발생 위험을 유의하게 감소시켰다