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AS438 - Novel Hemorrhagic Stroke Risk factors in WHI: Pilot Study

[This page is intended to provide a study summary, the sections of which are below. Please complete these sections, as applicable. The headings below are suggested headings. You can remove inapplicable sections, or add new ones relevant to your study]

Investigator Names and Contact Information

Philip Greenland [p-greenland@northwestern.edu]​

Introduction/Intent

Stroke is the second leading cause of death worldwide and a leading cause of disability ^1,2.  Intracerebral hemorrhage (ICH) is the second most common stroke subtype, accounting for up to 20% of all strokes ^1,2. Primary ICH occurs in the absence of a clear predisposing abnormality such as vascular malformation or tumor (i.e., secondary ICH). ICH typically occurs suddenly and unexpectedly --unlike ischemic stroke that is often preceded by transient ischemic attacks.  Mortality and morbidity of ICH are high ^1,2, therefore efforts to identify factors associa​ted with development of ICH are important so that better preventive approaches to ICH could be developed. 

A meta-analysis of 14 case-control and 11 cohort studies on risk factors for ICH in general populations ³ indicated that age, higher alcohol intake, hypertension, male sex, current smoking, and diabetes were significantly associated with ICH. Lower blood cholesterol and lower triglycerides are also associated with higher risk of ICH ⁴, as is warfarin use ^1,2 and aspirin use ^1,2,5.  Low and high BMI ⁶ are both also associated with higher risk of ICH.

It is important to note that risk associations for ICH can be detected many years before onset of ICH. For example, in a prospective study of 36,686 healthy Finnish people ⁷, studied for a mean of 13.7 years, adherence to a number of healthy "lifestyle factors" was associated with a graded risk of both ischemic and hemorrhagic stroke.  Also, exposures measured only once years before the ICH were found to be strongly associated with ICH events ^3,7.

Observations from the Women's Health Initiative hormone trials showed that risks of new ischemic stroke and new hemorrhagic stroke were divergent ⁸. While there were small numbers of total hemorrhagic strokes (including both subarachnoid hemorrhage and intracerebral hemorrhage) in the hormone trials, in a pooled analysis of the 2 trials of estrogen plus progestin and estrogen alone versus placebo groups, the hazard ratio (HR) for hemorrhagic stroke suggested a protective effect (HR 0.72, CI 0.47 to 1.12). Conversely, the HR for ischemic stroke was clearly increased in WHI and was one of the reasons that the trial was stopped early. The increased risk in hormone-users in the WHI trials for ischemic stroke versus the lower risk for hemorrhagic stroke suggests an overall tendency from hormone therapy favoring thrombosis rather than bleeding in menopausal hormone users. So far, there have been no additional studies in WHI that focused on ICH despite these intriguing observations from the hormone trials.

These findings from the literature show that factors present years before the onset of ICH can identify higher and lower risk individuals. A study of factors that favor bleeding or factors that tilt the balance of bleeding/clotting may be useful in clarifying precursors for ICH and suggesting potential preventive approaches.

Specific Aims

1. Immediate Aim: To measure a small group of hemostatic and hemorrhagic baseline biomarkers, in a pilot study from WHI, that could identify whether excessive fibrinolytic capacity is a potential precursor of subsequent ICH, capitalizing on the existing large cohort of older women, followed for stroke events by subtype over a period of more than 10 years, with clinical data and stored blood samples.
2. Future Aim: If the pilot study shows evidence of altered hemostasis that might be related to risk of ICH, we will plan to submit a full NIH RO1 grant application to conduct analyses in the full WHI OS sample of more than 700 cases of ICH accrued since the beginning of WHI.  As noted above, ICH research is a new area of exploration in WHI, and we believe it is highly consistent with the current role of WHI as a means of studying diseases of older women in population-based samples.