THE SOONER THERE IS A TREATMENT, THE BETTER

Stroke is the third leading cause of death in the United States and the second leading cause of death in the world.¹ Primary intracerebral hemorrhage (ICH), or spontaneous nontraumatic bleeding into the brain parenchyma, constitutes 10-15% of strokes in the United States, affecting approximately 65,000 people each year.^2,3 However, this disease carries a mortality rate of 30-50%, which is the highest mortality rate of any stroke subset.⁴ Incidence rates for ICH around the world vary from 20-55 per 100,000 people,^5,6 but the problem is expected to become worse. As the population ages, the incidence is likely to increase, as ICH occurs in up to 222 per 100,000 patients older than 80 years.⁵

People of racial and ethnic minority bear a disproportionate burden of this disease. While white patients suffer a death rate of 13.2 per 100,000 people per year, the rate is nearly twice as high in black persons (22.5/100,000) and Asian persons (20/100,000).⁷ Currently, more than 25 percent of the US population is composed of racial and ethnic minority populations and, by 2050, that percentage should nearly double.⁸ Therefore, the incidence and impact of this disease may well continue to grow.

The underlying pathophysiology of ICH is complex, involving both mass effect from the hematoma and a series of reactions in the involved tissue that contribute to neuronal damage.⁹ As the neurologic damage caused appears to be proportional to the volume of blood that extravasates from the ruptured vessel, mass effect itself is likely the major contributor.^10,11 ICH was once thought to be a brief event that lasted seconds to minutes; however, current data suggest that 25-50% of patients experience ongoing bleeding following presentation, particularly if they are anticoagulated.^11,12 This expansion is associated with worse neurologic outcome and increased mortality and highlights the tremendous opportunity for intervention even after the disease has occurred. Developing interventions that decrease the risk of expansion will, likely, reduce the severe morbidity and mortality of ICH.

Societal costs associated with ICH are quite significant. In a recent analysis, in-hospital costs associated with an incidence of ICH were $15,256, with patient charges of $34,014.¹³ In cases of surviving patients, the costs were even higher, at $17,442. In an analysis of 1-year health care costs following ICH, survivors incurred initial hospitalization costs of $28,360 and first-year postdischarge costs of $16,035. Of the survivors, 8% had repeat hospitalizations and 41% required inpatient skilled nursing, rehabilitation, or both.¹⁴ For comparison with a different health care system, a German study found that the cost of treatment amounted to €8,920 for hospital stay and rehabilitation and €4,598 for 1-year costs after discharge. These cost estimates do not even take into account the impact of lost work force, which was then estimated at a further €5,537 for surviving patients.⁴

Traditionally, the prognosis for ICH is considered so poor that do-not-resuscitate (DNR) orders are often placed early. However, clinical care is withdrawn from patients in a relatively variable manner that is independent of predicted outcome based upon clinical variables.^15,16 Different hospitals and different provider teams withdraw clinical care at different rates, and these differences correlate with differences in institutional mortality for ICH. Therefore, some of the high mortality associated with ICH can be attributed to pessimism on the part of health care providers; again, this highlights the critical need to bring better therapies to the bedside.

Oral anticoagulation is another factor that contributes to the increasing incidence of ICH. As the population continues to age, the number of indications for long-term anticoagulation keep increasing.¹⁷ While anticoagulation is a major risk factor for development of ICH,¹⁸ this is not a sign that too many patients are anticoagulated.² On the contrary, it appears that not enough patients are receiving appropriate anticoagulation therapy to prevent ischemic stroke.¹⁹ The fear of major bleeding events, such as ICH, contributes to significant underuse of anticoagulation therapy.²⁰ This again highlights the need for improving therapy for ICH. Reduced morbidity and mortality due to ICH may make health care providers more willing to provide appropriate anticoagulation, which will, in turn, reduce the burden of ischemic stroke.

A workshop from the National Institutes of Health (NIH) highlighted the lack of proven therapies in ICH,²¹ and no medication approved by the US Food and Drug Administration (FDA) is currently available. Some promising areas of research are ongoing; providing care in a neuroscience-focused unit may improve outcomes,^22,23 and a phase II trial of a hemostatic agent showed significant promise.²⁴ These results are exciting but await confirmation in larger trials. The overall conclusion of this NIH workshop was the urgent need to develop new therapies and improve clinical management.

Overall, ICH is a devastating disease that causes significant morbidity, mortality, and health care expenditures. No FDA-approved therapies are currently available, and demographic trends suggest that the incidence of this disease is likely to rise over time. The poor outcome associated with this disease causes significant pessimism among health care providers, which results in underuse of appropriate anticoagulation therapy in the general population and, possibly, early withdrawal of therapy in patients with ICH. Improved therapies are urgently needed, and the sooner they become available, the better.

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