Focused Update on Vascular Risk and Secondary Prevention in Survivors of Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is the most disabling and deadly stroke subtype globally. However, an improved understanding of the natural history of ICH, coupled with advances in neurocritical and stroke systems of care, have led to the possibility of higher rates of survival during the index hospitalization. Stroke caregivers, families, and patients now reckon with identifying and successfully implementing strategies for secondary prevention. Many of the clinical and scientific questions in recent years focus on the interplay between thrombosis and recurrent bleeding. ICH survivors and the stroke community struggle with determining these competing risks, applying available therapies, and communicating decision making in both domains. This Focused Updates summarizes the current knowledge of cardiovascular events after ICH, the clinical management of blood pressure, anti-thrombotics, and lipid-lowering medications. Surviving an ICH is the first step towards converting a potentially devasting acute condition into a disease of chronic management. Identifying and implementing strategies that optimize chronic disease management is the next.

In this Focused Update, ICH survivors take center stage, and by definition, they have already defied the odds of not succumbing to the acute hospitalization. In contrast to ischemic stroke, where at least 50% of survivors have no or mild disability, ICH survivors on average have moderate to severe disability. The acute period following an ICH is often marked by an inability to ambulate independently, requiring assistance with activities of daily living, and cognitive decline. Transitions of care frequently include a recovery unit or a skilled nursing facility during a period in which coordination of care between primary care providers, neurologists and frequently cardiologists is needed.

It is easy to see how this portrait can lead to pessimism and disengagement for chronic disease management, on the part of either the patient and family or the providers. Because prospective studies have demonstrated that an upward trajectory is possible in ICH survivors [1, 2], we suggest that ICH survival is a moment when the stroke community should increase their engagement. In this Focused Update, as the contributors outline the current state of science for vascular management, we urge you to ask – how can this state of science reach my patient?

Cardiovascular Events after ICH

After ICH, recurrent vascular events, ischemic or hemorrhagic, are a leading cause of mortality, recurrent hospitalizations, and further decline. This is not altogether a surprise because many of the vascular risk factors that were present and led to the index ICH have not disappeared and as Li and Murthy articulate (3), the ICH may actually increase the probability of a recurrent event. Further, ineffective prevention of a recurrent event is likely to alter any recovery trajectory since a second event is usually not simply additive, and could be fatal. Recurrent events are common for both lobar and non-lobar locations. Although rates of subsequent ischemic events are higher for non-lobar ICH, suggesting a stronger link between systemic vascular risk factors and recurrence, the rates of hemorrhagic events are higher after lobar ICH. Emerging evidence demonstrates the appearance of covert ischemic infarcts seen on diffusion- weighted magnetic resonance imaging (DWI) after ICH; their appearance is associated with an increased risk for recurrent clinical events and worse outcome. A second ICH can provide cumulative devastation, and the mechanism is of ten similar to that of the index ICH. This Focused Update places into context the systemic vascular events that occur after ICH as well, especially myocardial infarction, venous thrombosis, and pulmonary embolism. The risk assessment and communication of that assessment represents borderlands between primary care, neurology, and cardiology. To date, few recent investigations have assessed the potential for improved delivery of care in this area. In daily practice, we believe that patients and providers are familiar with this challenge in communication across these borderlands.

Blood Pressure Control after ICH

In the majority of ICH survivors, blood pressure remains the most important modifiable risk factor. As Mullen and Anderson (4) summarize in this Focused Update, elevated blood pressure is associated with a continuum of central nervous system and systemic events after an ICH. Blood pressure control is often categorized in terms of the acute emergency or inpatient management and the chronic or outpatient component. In the acute setting, clinicians are guided by the two most important phase III trials of blood pressure management, INTERACT2 and ATACH2. The two clinical trials tested different interventions in varied populations, and results differed between them as well. However, individual pooled patient level meta analyses suggest that intensive treatment towards stable blood pressure can lead to improved outcomes [5]. Treatment should be initiated within the first 2 hours of ICH onset. In patients with systolic blood pressure above 220 mm Hg or severe ICH, the safety and efficacy of lowering is less clear. The Focused Update further clarifies the role of ICH location in effect modification of these results. For example, patients with non-lobar ICH may be more likely to benefit from an intensive regimen [6]. Recent analyses also suggest that reducing blood pressure from extreme levels and to significant levels can cause kidney injury or neurological deterioration, so individual patient context and timing should be carefully considered.

With regard to long term prevention, in secondary analyses of stroke prevention trials such as PROGRESS and SPS3, there was a clear causal link between blood pressure reduction and less frequent ICH. Blood pressure management for ICH survivors has often been extrapolated from broader vascular risk populations. Mullen and Anderson provide a rationale to justify doing so, especially considering the consequence of persistent hypertension in ICH survivors and the dose-response link to recurrent ICH, as well as vascular events and a high frequency of cognitive decline. Suboptimal control of blood pressure and its consequences disproportionately affect under-represented populations. In this Focused Update section, the authors place in context ongoing pragmatic trials that focus on low-cost interventions and home blood pressure monitoring as potential strategies.

Oral Anticoagulant Use after ICH

Atrial fibrillation co-exists in as many as 20% of ICH survivors, and with the increase in aged population, this estimate has and will continue to increase. For patients and providers, the competing risks of recurrent ICH and thrombotic events such as ischemic stroke have led to great consternation (7). In this population, the mortality rate is particularly high, given that each of two cardiovascular conditions (ICH and atrial fibrillation) increase with age. For several decades, prior decision analyses and observational studies have yielded varying results, leading to significant practice variation for whether to initiate or resume anticoagulation. In routine non-ICH populations with atrial fibrillation, anticoagulation is under prescribed, in part because causing a hemorrhage may be perceived as “active” harm while the more common ischemic stroke is a “passive” harm. In an ICH population, in the context of a prior brain hemorrhage, the limbic weight of this dilemma takes even greater prominence.

To date, until recently, there have been no randomized clinical trial data to provide the community with high quality information. Prior studies suggesting that anticoagulation may be associated with improved outcomes are likely highly susceptible to confounding by indication. Still, independent cohorts seem to suggest that even high-risk patients with cerebral amyloid angiopathy may benefit. In recent years, newer oral anticoagulants have an improved safety and efficacy profile in broad populations, and so the stage has been set for multiple randomized controlled trials in ICH survivors with atrial fibrillation. The first trials to report, SoStart and APACHE-AF, show that the dilemma is real. Exposure to anticoagulation showed increased bleeding and reduced thrombotic events but both trials were underpowered to make any definitive claims on these endpoints. Finally, while left atrial appendage closure is a seemingly attractive treatment option since many feel that long term anticoagulation may be avoided, but to date few ICH patients have been enrolled in previous trials. This treatment option is currently being investigated in ongoing trials in ICH populations.

Use of Lipid Lowering Drugs after ICH

Hyperlipidemia is common in ICH patients and is a risk factor for ischemic cardiovascular events. While intensive statin therapy is of ten recommended to reduce ischemic cardiovascular events, there is considerable uncertainty and lack of consensus regarding the optimal strategy for managing hyperlipidemia after ICH because only a handful of ICH survivors were enrolled in previous randomized controlled trials of various lipid-lowering therapies including stains’ trials. In this focused updated, Shomanesh and selim review existing literature to outline the competing risks of increased propensity for ICH and benefits of reducing ischemic events of lipid lowering treatments in ICH population. They suggest a treatment paradigm based (8) on available data, but appropriately note that data from dedicated randomized trials are needed to build the necessary evidence to guide optimal lipid-lowering strategy in patients with a history of ICH.

Conclusions

We hope that this focused update will raise awareness of the heightened risk of future ischemic and hemorrhagic vascular events among ICH survivors and highlight best practices and current knowledge and evidence gaps for secondary prevention in this vulnerable population. While this focused update does not explicitly address the role of antiplatelet drugs, as well imaging predictors of future stroke risk, both topics will be covered in future issues. We emphasize the need for more coordination and collaboration between primary care providers, neurologists, and cardiologists caring for these patients; and endorse the participation of patients in ongoing randomized controlled secondary prevention ICH trials whenever possible to derive the necessary evidence to guide future preventive strategies.

Non-standard Abbreviations and Acronyms

ICH

Intracerebral Hemorrhage