Introduction

Acute intracerebral hemorrhage (ICH) is the most serious and least treatable form of stroke, which accounts for approximately 20% of nearly 20 million new cases of stroke that occur in the world each year¹. Compared to modern reperfusion therapy with thrombolytics and endovascular clot retrieval which has transformed systems of care for patients with acute ischemic stroke, there has not been any clearly proven medical or surgical treatment for ICH. This has led to disorganized and widely variable patterns of care for patients with ICH, a sense of nihilism among clinicians, and frustration in the research community. Fortunately, this situation has now changed with the positive results announced for several completed randomized and controlled trials (RCTs) in ICH in early 2023, led by the third intensive care bundle with blood pressure (BP) reduction in acute cerebral hemorrhage trial (INTERACT3)².

INTERACT3 was undertaken to resolve the controversy over the effects of early intensive BP lowering treatment in acute ICH. Although elevated BP is common after the onset of ICH and strongly associated with poor outcomes, RCTs that have evaluated early intensive BP control have produced inconsistent results that have been limited to patients with mild-moderate ICH who do not require neurosurgical intervention³. This level of evidence has restricted the uptake of a relatively simple and low-cost management strategy in clinical practice, and where guidelines have generally produced an intermediate strength to the recommendations given toward treatment⁴.

What we now know?

INTERACT3 was a landmark study in producing a positive result through conduct on an international scale and overcoming the adversity of the COVID-19 pandemic. It used a novel, quality improvement, and stepped-wedge cluster randomized "implementation" design across 121 hospitals in 10 countries, including Mexico, between December 2017 and December 2021, to show that the early intervention of bundled care with time- and target-based metrics can substantially improve outcomes for patients who suffer ICH. The care bundle protocol included the early lowering of systolic BP (target < 140 mmHg), strict glucose control (target 6.1-7.8 mmol/L in those without diabetes and 7.8-10.0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature ≤ 37.5°C), and rapid reversal of warfarin-related anticoagulation (target international normalized ratio < 1.5) within 1 h of treatment, in patients where these variables were abnormal. The likelihood of a poor functional outcome, measured on the distribution of full range of scores on the modified Rankin Scale (mRS), was less in the care bundle group (common odds ratio 0.86, 95% confidence interval 0.76-0.97; p = 0.02). The favorable shift in scores on the mRS in the care bundle group was generally consistent across a range of sensitivity analyses. Patients in the care bundle group had significantly improved survival, better health-related quality of life, shorter time in hospital, and fewer serious adverse events, than those in the usual care group. Treatment with the care bundle in every 35 patients was estimated to prevent one patient from death or major disability.

What are the implications on INTERACT3?

The INTERACT3 results provide strong support for the rapid control of BP and other physiological variables to be incorporated into clinical practice as a part of active management plan for this serious disease. Given requirements to standardize best practice and use quality performance indicators to reduce unwarranted clinical variation in healthcare, the care bundle protocol is a welcome addition to the list of evidence-based management strategies to compliment reperfusion and other protocols that are now in place for patients with acute ischemic stroke. The combination allows an implementation strategy to enhance stroke services in both low- and middle-income countries (LMIC) as well as in many parts of high-income countries. The global stroke community and accreditation organizations should be engaged to standardize recommendations over the incorporation of the care bundle protocol in guidelines and as advocates for relevant education activities and updates of policies.

As a hybrid effectiveness-implementation trial, INTERACT3 simultaneously tested the effect of a simple and widely applicable intervention while measuring the implementation processes and addressing contextual factors that may have impacted on the uptake of the intervention in routine clinical practice. Some implementation difficulties were noted through a process evaluation embedded in INTERACT3. Of note were concerns that health professionals had that the protocol-defined targets for systolic BP and glycemic control might harm patients, and there being contextual factors in relation to staffing processes and medication supply in low-resource areas⁵. Thus, before implementation can proceed, efforts need to be made to reduce such safety concerns in clinicians and nurses over the care bundle and in finding solutions to ensure equipment (i.e., infusion pumps and electronic BP monitors) and intravenous antihypertensive agents are readily available.

What next?

Several INTERACT3 investigators are collaborating with the World Stroke Organization (WSO) to incorporate the care bundle as a recommendation in the organization’s Living Clinical Guidelines to improve clinical practice for ICH management. Efforts are also being made to seek donations and sponsorship to support the availability of resources (e.g., electronic BP monitors, infusion pumps for insulin, and intravenous antihypertensive medications) in LMIC. Ongoing communication, engagement, and partnerships with a variety of stakeholders, and the broader stroke community network, will facilitate the translation of the care bundle into clinical practice.

A broad multifaceted implementation program will help to promote the uptake of the care bundle globally and identify implementation strategies that are appropriate at regional/national levels. Training and education could be incorporated under such a program to improve knowledge and assist behavioral change for local adaption of the care bundle. In the minimal setting of Sub-Saharan Africa (SSA), for example, stroke services are often configured within general medical services, and there are few established stroke units/essential services. Through WSO, an implementation program incorporating the INTERACT3 care bundle together with thrombolysis management and other evidence-based care strategies, training, policies, and investment could help advance the quality of care and minimize the burden of stroke in SSA. Such a program could be a welcome additional to enhancing stroke services in Mexico where current systems are not optimal for the recovery and survival of patients who suffer from ICH.