CLINICAL EPIDEMIOLOGY www.jasn.org Stroke and the “Stroke Belt” in Dialysis: Contribution of Patient Characteristics to Ischemic Stroke Rate and Its Geographic Variation † ‡ James B. Wetmore,* Edward F. Ellerbeck, Jonathan D. Mahnken,§ Milind A. Phadnis,§ | Sally K. Rigler, ¶ John A. Spertus,** Xinhua Zhou,§ Purna Mukhopadhyay,§ and †‡ Theresa I. Shireman *Department of Medicine, Division of Nephrology and Hypertension, † The Kidney Institute, ‡Department of Preventive Medicine and Public Health, §Department of Biostatistics, |Department of Medicine, and ¶The Landon Center on Aging, University of Kansas School of Medicine, Kansas City, Kansas, and **St. Luke’s Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, Missouri ABSTRACT Geographic variation in stroke rates is well established in the general population, with higher rates in the South than in other areas of the United States. ESRD is a potent risk factor for stroke, but whether regional variations in stroke risk exist among dialysis patients is unknown. Medicare claims from 2000 to 2005 were used to ascertain ischemic stroke events in a large cohort of 265,685 incident dialysis patients. A Poisson generalized linear mixed model was generated to determine factors associated with stroke and to ascertain state-by-state geographic variability in stroke rates by generating observed-to-expected (O/E) adjusted rate ratios for stroke. Older age, female sex, African American race and Hispanic ethnicity, unemployed status, diabetes, hypertension, history of stroke, and permanent atrial fibrillation were positively associated with ischemic stroke, whereas body mass index .30 kg/m2 was inversely associated with stroke (P,0.001 for each). After full multivariable adjustment, the three states with O/E rate ratios .1.0 were all in the South: North Carolina, Mississippi, and Oklahoma. Regional efforts to increase primary prevention in the “stroke belt” or to better educate dialysis patients on the signs of stroke so that they may promptly seek care may improve stroke care and outcomes in dialysis patients. J Am Soc Nephrol 24: 2053–2061, 2013. doi: 10.1681/ASN.2012111077 Stroke is a catastrophic health event and a leading patients across the United States have consistent cause of disability. It represents a particularly heavy access to insurance and frequent contact with health burden for the long-term dialysis population, in care providers, who routinely measure their BP, whom stroke rates are substantially higher than in irrespective of geographic location. Second, the the general population.1 In the general population, nature of vascular disease differs between dialysis there is substantial geographic variability in stroke and nondialysis patients, so different pathophysio- rates, with the southeastern United States having logic mechanisms may be operative in the two long been recognized as a “stroke belt” of higher populations.5 Third, dialysis patients fundamentally stroke mortality rates.2–4 However, whether a stroke belt of increased ischemic stroke incidence exists in dialysis patients has not been formally Received November 12, 2012. Accepted July 8, 2013. studied. Published online ahead of print. Publication date available at Althoughone might suspect that the same factors www.jasn.org. contributing to ischemic stroke risk in the general Correspondence: Dr. James B. Wetmore, Division of Nephrol- population also apply to dialysis patients, there are ogy, Hennepin County Medical Center, 701 Park Avenue, Min- several reasons to posit that this might not be the neapolis, MN 55415. Email: james.wetmore@hcmed.org case. First, unlike the general population, dialysis Copyright © 2013 by the American Society of Nephrology J Am Soc Nephrol 24: 2053–2061, 2013 ISSN : 1046-6673/2412-2053 2053 CLINICAL EPIDEMIOLOGY www.jasn.org represent a “survivor cohort” relative to individuals with (pre- sex, African American race and Hispanic ethnicity, and being dialysis) CKD and its attendant cardiovascular disorders, sug- unemployed at the time of dialysis initiation were associated gesting that epidemiologic trends evident in one population with ischemic stroke (P,0.0001 for all). A body mass index might not be found in the other.6 Accordingly, it is uncertain of $30 kg/m2 was associated with a significantly lower rate of whether there is substantial geographic variation in stroke risk ischemic strokes. In terms of comorbid conditions, perma- among dialysis patients and what factors might, in part, explain nent atrial fibrillation (AF) (treated as a time-dependent vari- such a finding. able), diabetes, hypertension, and history of a cerebrovascular To address this gap in knowledge, we constructed a large accident were also associated with ischemic stroke (P,0.0001). cohort of incident dialysis patients to determine whether State of residence was also associated with ischemic stroke in- ischemic stroke rates vary by geography and how differences in dependent of other factors, as described below. stroke rates might be explained by patient characteristics. We reasoned that uncovering the existence of geographic variabil- Geographic Factors Associated with Stroke ity in the stroke rates of dialysis patients might provide Figure 2 and Table 3 demonstrate geographic variation in is- direction for focused health care efforts in regions at elevated chemic stroke rates under various modeling strategies. Figure risk, such as screening new dialysis patients for symptoms that 2A shows observed-to-expected (O/E) ratios after adjustment might be referable to old strokes, lowering the threshold for only for age; Figure 2B, after adjustment for age and sex; Figure investigating cerebrovascular disease, or educating dialysis 2C, after adjustment for age, sex, and race; and Figure 2D, after patients on the importance of seeking immediate care for full adjustment for factors listed Table 2. Figure 2A demon- stroke-type symptoms. strates that stroke rates are highest predominantly in the southern and southeastern United States, although the rate is also high in Indiana; eight states had O/E ratios significantly RESULTS above unity, seven of which were in the South. After additional adjustment for sex (Figure 2B), all seven of the states with the Cohort Characteristics rates significantly .1.0 were in the South, and after further Figure 1 shows the construction of the Medicare-eligible co- adjustment for race (Figure 2C), five of six states were in the hort. There were a total of 265,685 Medicare-eligible individ- South. After full adjustment (Figure 2D), three states re- uals who initiated dialysis between January 1, 2000, and mained, all of which are in the South: The O/E ratio for North October 2, 2005, and survived at least 90 days before our final Carolina was 1.15 (99% confidence interal [CI], 1.04 to 1.27); date of December 31, 2005. for Oklahoma, 1.16 (99% CI, 1.01 to 1.34); and for Missis- The characteristics of the Medicare-eligible cohort are sippi, 1.18 (99% CI, 1.03 to 1.34). Table 3 demonstrates the shown in Table 1. Mean age 6 SD was 64.7615 years; 52.9% of same phenomenon, facilitating comparison between states as the patients were male; and whites made up the largest group the various modeling strategies were undertaken; it shows that at 54.9%, followed by African Americans at 30.0%. Diabetes, the effect of state is modified by more thorough statistical at 47.1%, was the leading cause of ESRD. In terms of comorbid adjustment. Of note, employment rate in the eight states conditions, 84.4% of patients had hypertension, 33.2% had with O/E ratios .1wassignificantly, but modestly, lower heart failure, and 10.3% had a history of a cerebrovascular than in the remaining states (4.2% versus 5.0%; P,0.0001). accident upon dialysis initiation. More than 93% were under- In the unadjusted model, only New Mexico had an O/E ratio going in-center hemodialysis. The cohort was followed for a ,1 (0.74 [99% CI, 0.58 to 0.95]) while in the fully adjusted mean of 2.0 years. Bivariate analyses between individuals who model, only New York had an O/E ratio ,1 (0.90 [99% CI, did and did not have strokes during the observation period 0.82 to 0.98]), demonstrating that, overall, variation .1.0 was revealed significant differences (P,0.01) for all covariates far more common than variation ,1.0. examined with the exception of hemoglobin (P=0.05). Sensitivity Analyses Stroke Events To assess the rigor of our analysis, we performed multiple Of 265,685 individuals, 13,073 (4.9%) experienced at least one sensitivity analyses. First, we performed identical modeling stroke. Total ischemic stroke events numbered 14,240: Of save elimination of the adapted Liu comorbidity index; final individuals with a stroke, 91.9% had one stroke, 7.3% had two, results were identical, with North Carolina, Mississippi, and and 0.8% had three or more. Total follow-up time was 431,049 Oklahoma again being the only states with O/E ratios for patient-years, resulting in a rate of 33 ischemic strokes per 1000 ischemic stroke significantly .1.0. Next, we used a more sen- patient-years. Stroke ratesweregenerallyquite stable over time, sitive definition for ischemic strokes in which an additional as shown in Supplemental Table 1. 20% of strokes were included. Five (Alabama, Mississippi, North Carolina, Oklahoma, South Carolina) of the seven Person-Level Factors Associated with Stroke (New Jersey, Indiana) states with O/E ratios significantly After multivariable adjustment, factors independently associ- .1.0 were in the South; the same general trend of progressive ated with ischemic stroke are shown Table 2. Older age, female attenuation with greater adjustment was observed, starting 2054 Journal of the American Society of Nephrology J Am Soc Nephrol 24: 2053–2061, 2013 www.jasn.org CLINICAL EPIDEMIOLOGY differences in patient characteristics could account for such variability. After adjust- ment for age alone (as the single most important factor associated with stroke), there was a distinct clustering of ischemic strokes in southern states, suggesting the presence of a “stroke belt” in long-term di- alysis patients (of the states with increased risk, only Indiana was not in the South).