Association of multiple ischemic strokes with mortality in incident hemodialysis patients: an application of multistate model to determine transition probabilities in a retrospective observational cohort

In this study, we examined recurrent strokes in patients receiving chronic dialysis. In patients who had experienced a first stroke on dialysis, we sought to determine what factors were associated with subsequent strokes and to assess the relative hazard for death of a subsequent stroke compared to an initial one. Since patients with an initial stroke can remain alive without a subsequent stroke, experience a subsequent stroke, or die after either of a first or subsequent stroke, we reasoned that a multistate model was a suitable approach to investigate these questions. Our principal findings were that females had a substantially increased risk of subsequent stroke compared to males; that African-Americans had greater survival after a first new stroke than Caucasians; that the likelihood of experiencing a second stroke, compared to remaining alive after a first new stroke or dying, increases rapidly over the first 6 months but later diminishes; and that a subsequent stroke markedly decreases survival probability and tends to be associated with increased risk of mortality relative to a first new stroke.

The issue of subsequent or multiple stokes has not been well-addressed in the dialysis literature; indeed, data is somewhat sparse even in the nondialysis population [19]. While a substantial body of work has been compiled regarding stroke in dialysis patients [3–10, 20–23], the relative effects of subsequent strokes appears not to have been specifically studied. The overall number of subsequent strokes as relatively low, perhaps because of the high mortality associated with an index stroke [10]. However, with prevalent dialysis patients living substantially longer, on average, than was the case just a few years ago [2], this issue of recurrent stroke may take on increasing importance, especially since stroke is strongly related to increasing age [24].

That females on dialysis were substantially more likely to experience a subsequent ischemic stroke than males has not, to our knowledge, been specifically reported. However, insights can be garnered from other work in both the dialysis and non-dialysis patients populations. While some studies have suggested that there is no difference in HR for stroke between males and females [3, 6], we have previously found females to be at higher risk of ischemic stroke. Additionally, Power et al. reported the HR for stroke among females to be approximately 1.25 [8], while Seliger et al. found females to be more likely to experience a stroke in univariate (HR 1.33), but not multivariable analyses [5]. Recently, the important role that sex differences might play in stroke has received increased scrutiny. An analysis by Paulus et al. [25] suggested that sex differences appear to be important in risk of ischemic stroke and in post-stroke survival in the general population. While they found that females had a reduced risk of mortality after an ischemic stroke, we observed no such differences (although females had an increased risk of incurring a subsequent ischemic stroke). It may be that epidemiological findings in the general population, such as those relating to sex, may not be generalizeable to the HD population, as the latter have both quantitative and qualitative differences in stroke risk factors compared to the former.

Another major demographic finding concerned race. Compared to African-Americans, Caucasians were more likely to die following a first new ischemic stroke. The issue of survival on dialysis is a complex one, with recent work suggesting that, at least among older individuals (who also comprise those most likely to experience major cardiovascular events such as stroke), African-Americans had better survival than Caucasians [26]. The improved survival of racial minorities has also been demonstrated in other HD populations, such as that of the UK [27–29]. Racial differences in stroke incidence may also be related to previous disease burden, since Seliger et al. reported that differential stroke risk by race interacts with the presence of previous cardiovascular disease [5]. If true, this suggests that there are complexities in stroke epidemiology by race in dialysis patients. Our findings seem to indicate that African-Americans may survive strokes that Caucasians do not. Whether this might be due to biological differences, phenotypic differences in stroke by race, stroke treatment, or other factors is unknown. More broadly, this phenomenon may be operative for other cardiovascular events such as myocardial infarctions or complications of peripheral vascular disease; if so, the greater ability of black, as opposed to white, HD patients to weather catastrophic cardiovascular events may be a reason for greater longevity in black, as compared to white, HD patients.

Subsequent ischemic strokes demonstrated a noteworthy temporal pattern. Multistate models have the advantage of permitting risks to “compete” against each other by generating relative transition probabilities at varying times. This permits inferences to be made about important clinical questions, such as whether a subsequent stroke changes the risk of progression to death compared to having only one stroke. We found that the transition probability to a subsequent ischemic stroke increased over time (particularly during the first 6 months after an initial stroke), peaked at 12 months, and then declined. Within the framework of the multistate model, this later decline is likely the result of an increasing probability of transitioning to death. However, our findings suggest that, among those who do survive, risk of subsequent stroke may ultimately begin to decline as time from initial stroke increases.

We were initially uncertain as to the relative effect on mortality of a subsequent, as compared to a first new, ischemic stroke. While the survival plots demonstrated, as would be expected, that a subsequent stroke has a marked effect of decreasing survival (an effect which increased proportionately as time from the initial stroke elapsed), this does not directly address the issue of relative risk of mortality of first, as compared to subsequent, strokes. We did find a signal that a subsequent stroke may confer a greater risk of mortality compared to the first by???70 %. However, the odds ratio narrowly missed the traditional threshold of statistical significance, likely due to relatively modest number of subsequent strokes, thus definitive conclusions con not be drawn.

These findings must be appreciated within the context of an apparent paradox suggested by the HRs of??1 for patients with a history of stroke (within, or even before, the first 90 days of dialysis initiation) associated with the transition of ischemic stroke to death. This unexpected finding may be the result of competition with death during the first critical 90 days after dialysis initiation: since the sickest patients are likely the ones who die soonest, only the healthiest or most resilient are likely to survive the first 90 days to become observable. Because death is, in effect, an outcome “competing” with a stroke, a stroke within the first 90 days of dialysis (or even before dialysis initiation) appears, upon superficial examination, to be “protective” for the transition from stroke to death.