Cerebrovascular Disease Incidence, Characteristics, and Outcomes in Patients Initiating Dialysis: The Choices for Healthy Outcomes in Caring for ESRD (CHOICE) Study

Results 

Approximately two-thirds of eligible patients were enrolled in CHOICE from participating dialysis units. Eligible patients enrolled were similar to eligible, but unenrolled, patients with regard to age, sex, dialysis modality, albumin level, and blood pressure. Baseline characteristics of the 1,041 CHOICE participants are listed in Table 1. Age, sex, race, and dialysis modality distributions were similar to those of the 1997 US dialysis population, as described previously.16 During a median follow-up of 2.7 years (range, 0.1 to 9.5 years), 165 patients experienced an incident cerebrovascular event after dialysis therapy initiation; 27% of these patients had cerebrovascular disease before dialysis therapy initiation (19% prior stroke). Those with cerebrovascular events during the study were more likely to be older, be men, have lower diastolic blood pressure, and have a history of diabetes mellitus, prior cerebrovascular disease, or prior peripheral vascular disease at baseline than those without subsequent cerebrovascular events. Other common risk factors, such as systolic blood pressure, presence of arrhythmias, presence of left ventricular hypertrophy, and cholesterol level, were not statistically significantly different between the 2 groups. In multivariate Cox proportional hazards regression analysis accounting for the competing risk of death, age, race, ICED score, previous diabetes mellitus, and previous cerebrovascular disease were significantly associated with increased risk of cerebrovascular disease events (Table 2). Results were similar between models that included or excluded CEA as a cerebrovascular event.

Table 1. Baseline Characteristics of 1,041 Incident Dialysis Patients

	Characteristic	All Patients (N = 1,041)	Patients Without Cerebrovascular Event (n = 876)	Patients With Cerebrovascular Event (n = 165)	P
	Age (y)	58±15	57±15	62±13	<0.001
	Men	564(54)	490(56)	74(45)	0.006
	Race				0.9
	White	695(67)	585(67)	110(67)
	Black	295(28)	249(28)	46(28)
	Other	51(5)	42(5)	9(5)
	Systolic blood pressure (mm Hg) (n = 944)	149±19	148±19	150±18	0.3
	Diastolic blood pressure (mm Hg) (n = 944)	79±10	79±11	76±9	<0.001
	Modality: hemodialysis	767(74)	637(73)	130(79)	0.1
	Tobacco use: current or former (n = 977)	592(61)	498(60)	94(62)	0.8
	Comorbid conditions
	Diabetes mellitus	561(54)	447(51)	114(69)	<0.001
	Cerebrovascular disease	176(17)	132(15)	44(27)	0.001
	Coronary heart disease	457(44)	382(44)	75(45)	0.7
	Peripheral vascular disease	270(26)	216(25)	54(33)	0.03
	Left ventricular hypertrophy	259(24)	213(24)	46(28)	0.4
	Arrhythmia	308(30)	258(30)	50(30)	0.9
	Valvular disorder	189(18)	153(18)	36(22)	0.2
	Congestive heart failure	466(46)	383(45)	83(51)	0.2
	Index of Coexistent Disease score	1.94±0.81	1.92±0.82	2.04±0.77	0.08
	Total cholesterol (mg/dL) (n = 999)	189±48	188±49	193±45	0.1
	Low-density lipoprotein cholesterol (mg/dL) (n = 872)	104±40	104±40	107±41	0.3
	High-density lipoprotein cholesterol (mg/dL) (n = 867)	44±17	43±17	45±16	0.4
	Triglycerides (mg/dL) (n = 916)	206±129	203±129	217±131	0.2
	Albumin (mg/dL)	3.62±0.37	3.63±0.38	3.59±0.36	0.2
	Corrected calcium-phosphate product (mg2/dL2)	48.9±12.6	49.0±12.8	48.3±12.0	0.7
	Hematocrit (%)	32.5±4.1	32.5±4.1	32.3±3.8	0.6

Note: Values expressed as mean±SD or number(percent). Less than 5% missing unless otherwise noted. P values by using Fisher exact test or Mann-Whitney rank sum test. Conversion factors for units: total, low-, and high-density lipoprotein cholesterol in mg/dL to mmol/L, ×0.02586; triglycerides in mg/dL to mmol/L, ×0.01129; albumin in g/dL to g/L, ×10; calcium-phosphorus product in mg2/dL2 to mmol2/L2, ×0.08056355.

Table 2. Association of Risk Factors With Cerebrovascular Disease Events Among CHOICE Participants

	Risk Factor	HR (95% CI) of Stroke Without CEA (n = 147)	HR (95% CI) of Stroke or CEA (n = 165)
	Age (/10 y)	1.26(1.19-1.34)⁎	1.26(1.19-1.34)⁎
	Sex
	Men	Reference	Reference
	Women	1.04(0.90-1.21)	1.04(0.90-1.21)
	Race
	White	Reference	Reference
	Black	0.64(0.54-0.77)⁎	0.64(0.53-0.76)⁎
	Other	0.68(0.50-0.91)†	0.69(0.51-0.94)†
	Modality
	Hemodialysis	Reference	Reference
	Peritoneal dialysis	1.12(0.93-1.35)	1.14(0.95-1.36)
	Comorbid conditions
	Diabetes mellitus	1.32(1.13-1.54)⁎	1.35(1.16-1.57)⁎
	Cerebrovascular disease	1.20(0.99-1.46)	1.23(1.02-1.49)†
	Index of Coexistent Disease score
	0 or 1	Reference	Reference
	2	1.40(1.18-1.65)†	1.35(1.14-1.59)†
	3	1.68(1.39-2.03)⁎	1.64(1.36-1.98)⁎

Note: Multivariate adjustment accounting for the competing risk of death from causes other than stroke. Abbreviations: CEA, carotid endarterectomy; CHOICE, Choices for Healthy Outcomes in Caring for End-Stage Renal Disease; CI, confidence interval; HR, hazard ratio.

⁎ P < 0.001. † P < 0.05.

Figure 1 shows the characterization of cerebrovascular events. From the 165 patients who experienced an incident event during the study, there were 35 additional repeated events in 29 patients because patients could experience multiple separate events during the course of the study. One hundred sixteen (58%) of these 200 events were ascertained by means of chart adjudication (95 ischemic strokes, 10 hemorrhagic strokes, and 11 CEAs) with 68% agreement from USRDS or HCFA records and 13% from the combination of DCI and comorbidity records. Seventy-seven (39%) events were assigned by using USRDS or HCFA records (8% agreement with the combination of DCI and comorbidity records), and 7 (4%) events were assigned solely by using the combination of DCI and comorbidity records. Fourteen of 105 abstracted stroke events were recurrent strokes.

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Figure 1. Cerebrovascular event classification in 1,041 incident dialysis patients. The number of each cerebrovascular event, including recurrent events, is shown. Event types were determined from International Classification of Diseases, Ninth Revision codes and chart abstraction. Ischemic stroke subtypes were defined using the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification system by 2 abstractors. *Of 165 patients, 35 had repeated events. †No statistically significant differences from nonabstracted patients with regard to demographics, comorbid conditions, or baseline laboratory results. Abbreviations: CEA, carotid endarterectomy; USRDS, US Renal Data System.

The majority of the 200 total cerebrovascular events were ischemic strokes. Of the 95 (62%) ischemic strokes available for chart abstraction, the largest proportion of events was cardioembolic in origin at 28%, although other ischemic stroke subtypes also were common. Of 11 CEAs available for chart abstraction, 55% were preceded by symptoms of stroke or transient ischemic attack, whereas the rest were performed for intraluminal stenosis that was greater than 60%, but asymptomatic. Median stenosis measured by using ultrasonography or angiography was 90% (range, 70% to 99%). The subset of patients with available medical charts for chart abstraction did not differ significantly by demographics, clinical characteristics, or comorbid conditions compared with patients without available medical records (data not shown).

Figure 2 shows the cumulative incidence of first cerebrovascular event type accounting for the competing risk of nonstroke death. Twenty-one percent of patients experienced a cerebrovascular event by the end of the study, with 15% of patients experiencing an ischemic stroke; 3%, a hemorrhagic stroke; and 3%, a CEA. The overall incidence rate of cerebrovascular events was 4.9 events/100 person-years (95% confidence interval, 4.2 to 5.7 events/100 person-years). Although the incidence rate for cerebrovascular events was greatest in the first 2 years after dialysis therapy initiation at 21.0 events/100 person-years, the majority of incident cerebrovascular events occurred after being on dialysis therapy for more than 2 years. Ischemic stroke accounted for the majority of events at all times. The incidence across time was similar for CEA and hemorrhagic stroke.

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Figure 2. Cumulative incidence of cerebrovascular events in incident dialysis patients accounts for the competing risk of death from causes other than stroke. Abbreviation: CEA, carotid endarterectomy.

Nineteen of 176 strokes (10%) occurred in the setting of hospitalization for acute myocardial infarction (8) and/or a cardiovascular disease procedure (3 coronary artery bypass surgeries, 1 percutaneous transluminal coronary angioplasty, 4 nontraumatic amputations, 2 peripheral bypass surgeries, and 2 CEAs). For the 90 abstracted strokes that occurred in hemodialysis patients, 10 occurred during the dialysis session, 17 occurred on the same day as the dialysis procedure, 35 occurred on a nondialysis day, and 28 occurred at a remote indeterminate time from the last dialysis.

Table 3 lists presentation and follow-up characteristics of strokes in CHOICE. Overall, the time from stroke symptom onset to presentation was long (median, 8.5 hours; 25th and 75th percentiles, 1 and 42), but shortest for cardioembolic and hemorrhagic causes of stroke (median times, 2.5 hours). Stroke from multiple causes and small-vessel occlusion had the longest times to presentation (median, 13 and 18 hours, respectively). Median hospital stay for all events was 6 days. Stroke from small-vessel occlusion and hemorrhagic stroke had the shortest lengths of stay at a median of 3.5 days, whereas strokes from cardioembolism and large-artery atherosclerosis had the longest lengths of stay at 9 and 10.5 days, respectively. Thirty-five percent of all events were fatal, 28% of ischemic strokes were fatal, and 90% of hemorrhagic strokes were fatal. Overall, 56% of patients who experienced a stroke were able to be discharged to home or acute rehabilitation, with the best recovery seen in those with small-vessel occlusion (78% discharge rate). However, only 10% of patients with hemorrhagic stroke were able to be discharged to home or acute rehabilitation. Baseline dialysis modality was not associated with significant differences in stroke etiologic subtype (P = 0.6), time from symptom onset to presentation (P = 0.09), length of hospital stay (P = 0.2), or discharge location (P = 0.5).

Table 3. Stroke Presentation and Follow-up Characteristics in Incident Dialysis Patients

		Median Time From Symptoms to Presentation (h)	Median Hospital Stay (d)	Case-Fatality (%)	Successful Recovery (% discharged to home or acute rehabilitation)
	Stroke overall (n = 105)	8.5(1,42)	6(3,13)	35	56
	Ischemic stroke (n = 95)	11(1,48)	7(4,13)	28	54
	Large artery	7.5(3,13)	10.5(5,14)	29	56
	Cardioembolism	2.5(1,16)	9(6,17)	36	54
	Small-vessel occlusion	18(6,48)	3.5(3,7)	17	78
	Multiple causes	13(1,72)	7(4,15)	41	41
	Other/undetermined	4(1,48)	6(3,13)	19	70
	Hemorrhagic stroke (n = 10)	2.5(1,19)	3.5(1,9)	90	10

Note: Values in parentheses are 25th, 75th percentiles. Data from strokes that were chart abstracted.

Discussion 

In this national prospective cohort study of patients initiating dialysis therapy for end-stage renal disease, cerebrovascular events, including fatal and nonfatal clinical stroke and CEA, occurred 10 times more frequently than in the general population,8, 17 with an incidence rate of 4.9 events/100 person-years. The majority of events were related to ischemic stroke, with cardioembolic stroke the most common form of ischemic stroke in dialysis patients. To our knowledge, this is 1 of the first studies to classify ischemic stroke in dialysis patients into etiologic subtypes based on TOAST criteria.12 This allows us to potentially alter our stroke prevention strategies from those used in the general population. We found that dialysis patients with stroke present late after symptom onset, leaving little room for early interventions. Dialysis patients also have high fatality and low recovery rates. Dialysis patients and their families may need better education about stroke warning signs and symptoms and encouragement to bring these symptoms to their providers' attention quickly.

We found that ischemic stroke was more common than hemorrhagic stroke in our national US dialysis cohort. This is consistent with a prior study relying on national administrative data.2 Few other studies have characterized stroke types, except for a Japanese cohort of 151 patients, in whom hemorrhagic stroke was the most common type of stroke.18 Causes of hemorrhagic stroke may differ from ischemic stroke in patients on long-term dialysis therapy and thus acquired risk factors could account for this later hemorrhagic stroke risk. Reasons could include excess vascular calcification and stiffness,19, 20 leading to worsening hypertension. This, combined with use of anticoagulation on dialysis therapy, could increase hemorrhagic stroke.

For ischemic stroke, cardioembolism was the most common subtype, although all ischemic stroke subtypes were well represented. In addition to preventing vascular calcification and arterial stiffness, treatment of underlying cardiac disease at dialysis therapy initiation may mitigate future stroke risk in this high-risk population. The use of aspirin in dialysis patients has been associated with a reduced risk of stroke, but the overall strength of this association was modest, as noted in the international Dialysis Outcomes and Practice Patterns Study (DOPPS).21 Baseline cardioembolism risk factors in our study, such as arrhythmias, left ventricular hypertrophy, valvular disease, and congestive heart failure, were not significantly different between individuals who experienced a cerebrovascular event versus those who did not in our cohort, suggesting that these aspects may not be correctly identified in dialysis patients. Measurement of cardiac function by means of echocardiography has been suggested for all patients initiating dialysis therapy22 because of its more accurate assessment than physical examination and chest radiography in identifying cardiac dysfunction and valvular disease. Furthermore, arrhythmias are common in dialysis patients, and early recognition and treatment of these arrhythmias may also reduce the risk of stroke. Use of other prevention measures, such as statins, was not associated with decreased risk of stroke in prevalent diabetic hemodialysis patients in the Die Deutsche Diabetes Dialyse (4D) study.23 Whether similar findings hold for incident dialysis patients is unclear.

Median time to presentation was more than 8 hours, much longer than that observed in a systematic review of the literature on all strokes,24 signifying symptoms of stroke may be missed by providers and/or patients. This is especially problematic because patients on hemodialysis therapy have regular access to the health care system. With this delay in presentation, any benefit from earlier interventions in this population, such as thrombolytic use,25 may not be practiced, thus worsening mortality and morbidity after stroke. Improved education about symptoms of transient ischemic attack or stroke, such as numbness, weakness, confusion, or difficulty speaking, should be given to dialysis patients and their families. One might suspect that stroke is more common during or immediately after a dialysis session because of changes in cerebral blood flow.6 In a study by Toyoda et al,18 34% of ischemic brain infarcts occurred within 30 minutes of the dialysis procedure. Thirty percent of abstracted strokes in this study occurred either during the dialysis session or several hours later, although this timing was not statistically different from events that occurred on a nondialysis day. A larger study may need to be undertaken to observe any temporal trends.26

Outcomes after stroke, especially hemorrhagic stroke, were poor, with a high case-fatality and low successful recovery rate. Based on this study, for every 100 dialysis patients who have a stroke, 35 will die within 30 days and only 56 of the 100 patients will be able to go home or to an acute rehabilitation facility. Although this low successful recovery rate is similar to that found in an earlier single-center cohort of prevalent hemodialysis patients followed up in New York,27 it is inferior to the 10% adjusted stroke case-fatality rate seen in the Atherosclerosis Risk in Communities (ARIC) cohort28 and the 20% of patients requiring institutional care in the general population.28 This likely reflects the comorbid conditions that our patients on dialysis therapy accumulated before they experienced a stroke. The overall length of hospital stay surprisingly was similar to that observed in the general population by using the National Hospital Discharge Survey.29 This implies that practice patterns of poststroke care, including evaluation, management, and disposition, may be similar across populations.

As a national prospective cohort study with characteristics similar to the 1997 US dialysis population, results of this study may be generalizable to the population of patients initiating dialysis therapy. The follow-up of up to 9.5 years in this study also allowed for evaluation of changing stroke causes over time on dialysis therapy. Our ability to have such lengthy follow-up with well-described characteristics and events is a unique aspect of this study.

This study has some limitations that deserve mention. We had a relatively small number of cerebrovascular events, which limited our ability to evaluate specific risk factors for stroke subtypes. We also did not have medical records for all stroke events to classify stroke; however, the subset of the population with medical records of the stroke event did not differ from those with no medical record. In cases in which a chart was not available, use of administrative data might not necessarily reflect an admission for an acute cerebrovascular event. In addition, CEA potentially could involve referral bias and thus may not represent an acute event; however, CEA events that we were able to abstract involved symptomatic disease or significant intraluminal stenosis, suggesting that these events were indicative of clinically meaningful cerebrovascular disease.

We conclude that cerebrovascular events are common in patients initiating dialysis therapy. Dialysis-related risk factors for all types of cerebrovascular events may differ by the type of event and timing of event after dialysis therapy initiation. This classification of cerebrovascular event types may help focus our efforts to better treat and prevent recurrence of stroke, thereby improving the prognosis of dialysis patients. Additional studies to understand the pathophysiological characteristics, prevention, and treatment of cerebrovascular disease in patients with end-stage renal disease need to focus on subclinical disease, including cognitive function,30 cerebral white matter changes,31 and subclinical strokes,3 as well as imaging techniques with magnetic resonance imaging to earlier identify cerebrovascular disease.