Do the Benefits of Blood Pressure Control in ICH Outweigh the Risks?

Jessica Magid-Bernstein, MD, PhD1; Santosh B. Murthy, MD, MPH2

2025년04월 21일

JAMA Neurol. Published online April 21, 2025. (Editorial)

DOI: 10.1001/jamaneurol.2025.0238

Nearly one-third of patients with intracerebral hemorrhage (ICH) have acute punctate infarcts on the diffusion-weighted imaging (DWI) sequence of magnetic resonance imaging (MRI) scans in the first week after symptom onset.1 These DWI lesions portend poor long-term prognoses and are independently associated with 2-fold higher odds of major disability or death.2 From a mechanistic standpoint, underlying cerebral small-vessel disease is purported to cause DWI lesions.2 Whether intensive blood pressure (BP) lowering contributes to these lesions is highly contested. Several prior studies have shown a significant relationship between the magnitude of BP reduction in the first 24 hours and the occurrence of DWI lesions.3 In contrast, a pooled, individual patient–level meta-analysis of 1750 patients showed that admission BP, and not change in BP, was independently associated with DWI lesions.4 More recently, intensive systolic BP (SBP) control did not result in DWI lesions compared with liberal SBP management in a post hoc analysis of the INTERACT2 trial (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial).5 Additionally, in the ICHADAPT trial (Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial), intensive (SBP <150 mm Hg) vs liberal (SBP <180 mm Hg) BP control did not lead to significant reduction in blood flow in the perihematomal or watershed border zones in patients with an acute ICH, indicating that acute BP reduction does not result in ischemia in these patients.6 Given these conflicting findings, the role of BP management after acute ICH, particularly in the context of incident DWI lesions, remains poorly understood.

In this issue of JAMA Neurology, Butcher et al7 sought to evaluate the question of optimal BP control after ICH with respect to DWI lesions in the setting of a dedicated clinical trial. The authors performed ICHADAPT-2 (Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial 2), a multicenter, randomized, open-label, blinded–end point trial investigating the effect of SBP targets of less than 140 mm Hg vs less than 180 mm Hg on the primary outcome of occurrence of DWI lesions within 48 hours after ICH onset.7 Similar to prior studies of acute SBP management in ICH, enrolled patients were randomized to an SBP target within 6 hours of symptom onset, with a goal to achieve the assigned target within 1 hour after randomization. Accounting for issues with obtaining brain MRI scans within 48 hours of ICH symptom onset in at least half of the patients, the trial aimed for a target sample size of 270 participants. However, due to loss of clinical equipoise following the publication of the INTERACT3 trial, the authors were only able to randomize 162 patients, of whom 79 participants had a brain MRI scan.

The primary outcome, incidence of DWI lesions on 48-hour brain MRI scan, was similar in patients with an SBP target of less than 140 mm Hg (31%) compared with a target of less than 180 mm Hg (38%), with an odds ratio of 0.74 (95% CI, 0.12-4.64). Additionally, there was also no difference in the morphology of DWI lesions between the 2 groups, including the number, location, and total volume of DWI lesions. Interestingly, higher ICH volume was associated with incidence of DWI lesions in the fully adjusted regression model. Given the small sample size of this trial, the authors performed an individual patient-level meta-analysis combining the 79 participants in ICHADAPT-2 with 171 participants in the ATACH-2 (Antihypertensive Treatment of Acute Cerebral Hemorrhage II) trial with brain MRI scans. This combined analysis similarly found no effect of intensive BP lowering on the incidence of DWI lesions (relative risk, 0.92 [95% CI, 0.62-1.38]). The results of the study should be interpreted with caution given some noteworthy limitations. First, the trial was underpowered due to the small sample size. Second, the ultra-early MRI requirement likely precluded the inclusion of patients who were unstable for the MRI scan, presumably due to large ICH volumes, high National Institutes of Health Stroke Scale scores, and medical instability. Third, the study did not account for the presence of cerebral small-vessel disease, which has been shown to be independently associated with DWI lesions.2

These limitations notwithstanding, there are important implications of the results of ICHADAPT-2. The management of ICH in the hyperacute period has undergone a major paradigm shift over the last decade. The INTERACT2 trial, which compared intensive BP control (<140 mm Hg) with guideline-recommended BP control (target SBP <180 mm Hg) did not show a significant reduction in the primary outcome of death or severe disability at 90 days, but did demonstrate a shift in modified Rankin Scale scores toward improved outcomes in the intensive BP lowering group.8 In the ATACH-2 trial, which compared intensive BP lowering (110-139 mm Hg) with standard reduction to a goal of 140 to 179 mm Hg, found no difference in the rate of death or disability in the intensive SBP group.9 However, post hoc analyses of these trials have shown that fluctuations in BP in the first 24 hours after symptom onset are associated with hematoma expansion and major disability or death,10 and, similarly, ultra-early BP reduction can result in improved functional outcomes.11 Moreover, the INTERACT4 trial demonstrated improved functional outcomes with ultra-early intensive BP control in patients with ICH when implemented in the prehospital setting. As a result, the current American Heart Association guidelines for the management of ICH provide Class 2 recommendations for early BP lowering, maintaining a stable BP while avoiding fluctuations, and targeting an SBP goal of 130 to 150 mm Hg.12 With prior studies implicating the magnitude of BP reduction in the acute period as a possible mechanism of DWI lesions after ICH, the results from the ICHADAPT-2 trial lend support to the contrary. The mechanism of DWI lesions in acute ICH is perhaps not primarily related to relative cerebral hypoperfusion, and the benefits of prevention of hematoma expansion and the negative effects of severe hypertension on the brain outweigh the risk of rapid SBP reduction to a normal range in this setting. Maintenance of a stable SBP below 140 mm Hg and avoidance of significant BP variability may be more important than cautious lowering of SBP in patients with ICH, at least in patients with an initial presenting SBP of less than 250 mm Hg.10,13 Nevertheless, it still remains poorly understood if intensive BP reduction in the setting of underlying cerebral small-vessel disease is safe, and future research is warranted to further study this relationship. It is therefore important to acknowledge that personalized BP targets based on physiological data may be an optimal strategy for post-ICH BP management, but this approach is not yet feasible for broad clinical application.

• 뇌내출혈(ICH) 환자의 약 3분의 1은 증상 발생 후 첫 일주일 내에 자기공명영상(MRI)의

  확산강조영상(DWI)에서 급성 미세경색(punctate infarcts)이 관찰된다. 이러한 DWI 병변은 장기

  예후가 나쁠 가능성을 시사하며, 주요 장애 또는 사망의 위험이 2배 이상 증가하는 것과 독립적으로 연관되어 있다.

• 기전적으로는 뇌의 소혈관 질환(cerebral small-vessel disease)이 이러한 DWI 병변의 원인으로

  추정되며, 집중적인 혈압 강하가 이러한 병변을 유발하는지에 대한 논란이 계속되고 있다.

• 기존의 여러 연구에서는 첫 24시간 내 혈압 강하의 정도와 DWI 병변 발생 사이에 유의미한 관련성을 제시한 반면, 1750명의 환자를 포함한 메타분석에서는 입원 시 혈압이 DWI 병변과 관련 있었을 뿐,혈압 변화량은 독립적인 요인이 아니었다고 보고되었다.

• 최근에는 INTERACT2 임상시험의 사후 분석에서도, 집중적인 수축기 혈압(SBP) 조절이 느슨한

  조절과 비교했을 때 DWI 병변 발생을 증가시키지 않았으며, ICHADAPT 임상시험에서는 집중적인 혈압 조절(SBP &lt;150 mmHg)과 느슨한 조절(SBP &lt;180 mmHg) 사이에 출혈 주변 또는 경계영역의 혈류 감소가 관찰되지 않았다, 이는 급성기 혈압 감소가 뇌 허혈을 유발하지 않는다는 것을 시사한다.

ICHADAPT-2 연구

이번 JAMA Neurology에서 Butcher 등은 ICHADAPT-2 임상시험을 통해

집중적인 혈압 조절(SBP &lt;140 mmHg)과 일반적인 조절(SBP &lt;180 mmHg)이

DWI 병변에 미치는 영향을 평가하였다.

• 총 162명이 무작위로 배정되었고, 그 중 79명이 48시간 이내 MRI를 촬영하였다.

• 주요 결과: DWI 병변 발생률은 집중 혈압 조절군에서 31%, 일반 조절군에서 38%로 유의한

  차이가 없었다 (OR 0.74, 95% CI 0.12–4.64).

• 병변의 모양, 개수, 위치, 크기에도 두 군 간 차이가 없었다.

• 단, ICH 부피가 클수록 DWI 병변 발생과 연관이 있었다.

• 연구는 소규모 표본, MRI 스캔 지연, 그리고 소혈관 질환 상태 미반영 등 제한점이 있음을

  언급하였다.

메타분석 및 가이드라인 맥락

• INTERACT2: 90일 내 사망이나 심각한 장애는 유의한 차이 없었으나, 기능 회복 면에서

  개선된 경향.

• ATACH-2: 사망률 및 장애에 있어 집중 조절군과 일반 조절군 간 차이 없음.

• 그러나 혈압 변동성은 예후 악화와 연관되며, 초기 혈압 안정화가 중요함이 여러 분석에서

  제시됨.

• INTERACT4: 병원 도착 전 집중 혈압 조절이 기능적 예후를 향상시킴. 따라서 미국심장학회(AHA) 가이드라인은

• 130–150 mmHg 범위의 안정적인 혈압 유지,

• 급격한 혈압 변화 방지,

• 가능한 조기 조절(6시간 이내)을 권고하고 있다 (Class II 권고).

결론 요약

• ICH 환자에서 SBP를 &lt;140 mmHg로 낮추는 것이 DWI 병변 증가와 관련이 없다는 증거가

  강화되었다.

• DWI 병변은 혈류 감소보다는 기저의 뇌소혈관질환이 주요 원인일 가능성이 있다.

• 따라서, 출혈 크기 증가를 막고, 고혈압의 뇌 손상 영향을 줄이는 집중 혈압 조절의 이점이위험보다 크다고 평가된다.

• 단, 소혈관 질환 환자에서의 안전성에 대해서는 향후 추가 연구가 필요하다.

• 개인 맞춤형 혈압 조절 전략이 이상적일 수 있으나, 현재 임상적으로는 제한적이다.