EFFECT OF WARFARIN AND INTENSITY OF ANTICOAG-ULATION ON OUTCOME OF INTRACEREBRAL HEMORRHAGE

Warfarin sodium is a highly effective therapy for the prevention of thromboembolic stroke in common clinical situations, particularly in nonvalvular atrial fibrillation. However, this protective effect of anticoagulation can be offset by risk of intracerebral hemorrhage (ICH). The authors examined the determinants of ICH outcome to quantify the independent effect of warfarin. Consecutive patients aged 55 and older with supratentorial ICH, who were treated in a tertiary care hospital with a neurointensive care unit, were prospectively identified during a 7-year period, and data on hemorrhage location, clinical characteristics, and warfarin use were collected. Independent predictors of 3-month mortality were determined using multiple logistic regression analysis. Out of the 435 patients studied, 102 (23.4%) were taking warfarin at the time of ICH. For patients not taking warfarin, 3-month mortality was 25.8%, and for those taking warfarin it was 52.0%. Independent predictors of death were warfarin use (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.3-3.8), age 70 years or older (OR, 2.4; 95% CI, 1.4-4.0), and presence of diabetes mellitus (OR, 1.8; 95% CI, 1.0-3.3). Although 68.0% of all warfarin-related hemorrhages oc- curred at an international normalized ratio (INR) of 3.0 or less, it was found that increasing degrees of anticoagulation were strongly associated with increasing risk of death, compared with no warfarin use. The conclusions drawn from the study were that patients taking warfarin had a doubling in the rate of ICH mortality in a dose-dependent manner. Data suggest that careful control of the INR, already known to limit the risk of warfarin-related ICH, may also limit its severity.

Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 2004;164 (8):880-884.

DO-NOT-RESUSCITATE ORDERS IN PATIENTS HOSPITALIZED WITH ACUTE MYOCARDIAL INFARCTION
A primary cause of death in Americans is coronary heart disease. Despite increased emphasis on patient and family participation in end-of-life care, data regarding the use of do-not-resuscitate (DNR) orders in acutely ill cardiac patients remain extremely limited. The Worcester Heart Attack Study is an ongoing longitudinal investigation of 4621 residents of the Worcester, MA, metropolitan area who were hospitalized with acute myocardial infarction. The objectives of the study were to describe the use of DNR orders, treatment approaches, and hospital outcomes in patients with acute myocardial infarction. Residents of these hospitals were studied in five 1-year periods from 1991 to 1999. Investigators observed significant increases in the use of DNR orders during the study decade (from 16% in 1991 to 25% in 1999). It was found that the elderly, women, and patients with previous diabetes mellitus or stroke were more likely to have DNR orders. In addition, patients with DNR orders were significantly less likely to be treated with effective cardiac medications, even if the DNR order occurred late in the hospital stay. Less than 1% of patients were noted to have DNR orders before hospital admission. Furthermore, patients with DNR orders were significantly more likely to die during hospitalization than patients without DNR orders (44% vs 5%). Conclusions drawn from this community-wide study were that, during the past decade, there was an increased use of DNR orders in patients hospitalized with acute myocardial infarction. In addition, use of certain cardiac therapies and hospital outcomes are different between patients with and without DNR orders. The use of DNR orders in patients with acute coronary disease needs further study.

Jackson EA, Yarzebski JL, Goldberg RJ, Wheeler B, Gurwitz JH, Lessard DM, Bedell SE, Gore JM. Do-not-resuscitate orders in patients hospitalized with acute myocardial infarction: The Worcester Heart Attack Study. Arch Intern Med 2004;164(7): 776-783.

APOLIPOPROTEIN E EPSILON4 COUNT AFFECTS AGE AT ONSET OF ALZHEIMER’S DISEASE, BUT NOT LIFETIME SUSCEPTIBILITY
While the incidence of Alzheimer’s disease (AD) increases with age, little is known about the cumulative incidence of AD over a lifetime of 100 years, or its relationship to the polymorphic APOE locus that encodes apolipoprotein E. APOE is a strong genetic risk factor for AD. The Cache County Study was designed to estimate the occurrence of AD as a function of age as well as the number of APOE Epsilon4 alleles. The study also sought to investigate evidence for heterogeneity of AD risk related to APOE genotype and to other sources. This prospective longitudinal study analyzed nonparametric and parametric survival data of AD incidence of 3308 elderly residents of Cache County, Utah. The main outcome measured was the cumulative incidence of AD; in mixture models assuming susceptible and nonsusceptible individuals, the proportion of individuals not susceptible to AD at any age. Investigators found that these models estimated the 100-year lifetime incidence of AD at 72%, implying that 28% of individuals would not develop AD over any reasonable life expectancy. They observed an acceleration of AD onset in individuals with 1, or especially 2, APOE Epsilon4 alleles, but saw no meaningful difference in 100-year lifetime incidence related to number of Epsilon4 alleles. Therefore, the APOE Epsilon4 allele acts as a potent risk factor for AD by accelerating onset. However, the risk of AD appears to be heterogeneous in ways independent of APOE. For some individuals, it seems certain that they will avoid AD, even over an extended lifespan. The relative invulnerability of these individuals may reflect other genes or environmental factors that can be further investigated.

Khachaturian AS, Corcoran CD, Mayer LS, Zandi PP, Breitner JC; Cache County Study Investigators. Apolipoprotein E Epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study. Arch Gen Psychiatry 2004;61(5):518-524.