Acute Cardiovascular Events after Herpes Zoster: A Self-Controlled Case Series Analysis in Vaccinated and Unvaccinated Older Residents of the United States

Background: Herpes zoster is common and can have serious consequences. Additionally, emerging data suggest an increased risk of acute cardiovascular events following herpes zoster. However, to our knowledge, existing association studies compare outcomes between individuals and are therefore vulnerable to between-person confounding. In this study, we used a within-person study design to quantify any short-term increased risk of acute cardiovascular events (stroke and myocardial infarction [MI]) after zoster and to assess whether zoster vaccination modifies this association. Methods and Findings: The self-controlled case series method was used to estimate rates of stroke and acute MI in defined periods after herpes zoster compared to other time periods, within individuals. Participants were fully eligible Medicare beneficiaries aged ≥65 y with a herpes zoster diagnosis and either an ischemic stroke (n = 42,954) or MI (n = 24,237) between 1 January 2006 and 31 December 2011. Age-adjusted incidence ratios (IRs) for stroke and MI during predefined periods up to 12 mo after zoster relative to unexposed time periods were calculated using conditional Poisson regression. We observed a marked increase in the rate of acute cardiovascular events in the first week after zoster diagnosis: a 2.4-fold increased ischemic stroke rate (IR 2.37, 95% CI 2.17–2.59) and a 1.7-fold increased MI rate (IR 1.68, 95% CI 1.47–1.92), followed by a gradual resolution over 6 mo. Zoster vaccination did not appear to modify the association with MI (interaction p-value = 0.44). We also found no evidence for a difference in the IR for ischemic stroke between vaccinated (IR 1.14, 95% CI 0.75–1.74) and unvaccinated (IR 1.78, 95% CI 1.68–1.88) individuals during the first 4 wk after zoster diagnosis (interaction p-value = 0.28). The relatively few vaccinated individuals limited the study’s power to assess the role of vaccination. Conclusions: Stroke and MI rates are transiently increased after exposure to herpes zoster. We found no evidence for a role of zoster vaccination in these associations. These findings enhance our understanding of the temporality and magnitude of the association between zoster and acute cardiovascular events. Using U.S. Medicare data, Caroline Minassian and colleagues test for associations between shingles and subsequent myocardial infarction or stroke.Background: Chickenpox, which is caused by the varicella zoster virus, is a common childhood infectious disease. Although recovery from chickenpox is usually quick, the varicella zoster virus can persist throughout life inside the nervous system. The dormant virus causes no symptoms, but if it becomes activated, it causes herpes zoster (also known as shingles or zoster), a painful skin rash. Anyone who has had chickenpox can develop zoster, but the condition is most common and most severe in elderly people—half of zoster episodes occur in people aged more than 60 years. Early signs of zoster include burning or shooting pain, tingling, and itching. Blister-like sores, which last 1–14 days, then develop on one side of the face or on one side of the body in a horizontal band. The pain of zoster, which can be debilitating, can continue for years after the rash disappears—a condition called post-herpetic neuralgia, which greatly reduces the quality of life. There is no cure for zoster, but vaccination can prevent the condition or lessen its effects, and early treatment with antivirals may prevent lingering pain by inhibiting viral replication. Why Was This Study Done?: Association studies suggest that people have an increased risk of an acute cardiovascular event—a stroke or a myocardial infarction (MI; heart attack)—in the weeks and months following a zoster episode. However, these studies mainly compared the incidence of stroke and MI (the number of strokes and MIs in a given time period) among people who had had zoster with the incidence among people who had not had zoster and were therefore vulnerable to between-person confounding. That is, rather than zoster increasing a person’s risk of MI or stroke, people who had had zoster may have shared another unknown characteristic (confounder) that was responsible for their increased risk of MI and stroke. Here, the researchers investigate whether there is an increased risk of acute cardiovascular events after zoster using a self-controlled case series study design. Specifically, they compare the incidence of MI and ischemic stroke in a population of individuals during a period of time before and more than a year after the individuals had zoster with the incidence of MI and ischemic stroke in the same individuals during the weeks and months right after they were diagnosed with zoster. Because each case is his/her own control, between-person confounding is avoided. What Did the Researchers Do and Find?: The researchers identified 42,954 Medicare beneficiaries aged ≥65 years who had had a zoster diagnosis and an ischemic stroke and 24,237 beneficiaries who had had a zoster diagnosis and an MI during a five-year period (Medicare is a US government health insurance plan that mainly covers the healthcare costs of elderly individuals; an ischemic stroke occurs when a blood clot blocks the brain’s blood supply). They then calculated age-adjusted incidence ratios for stroke and MI during predefined periods up to 12 months after a diagnosis of zoster relative to the time period before and more than a year after a diagnosis of zoster (the “baseline” period). Compared to the baseline period, there was a 2.4-fold increased rate of ischemic stroke and a 1.7-fold increased rate of MI in the first week after zoster. The increased rate of acute cardiovascular events reduced gradually over the six months following zoster. There was no evidence that MI or ischemic stroke incidence ratios differed between individuals who had been vaccinated against zoster (but still contracted the disease) and those who had not been vaccinated. What Do These Findings Mean?: These findings suggest that zoster is associated with transiently increased rates of ischemic stroke and MI. Zoster vaccination—which reduces zoster incidence by half and can reduce zoster symptoms—was not found to modify the associations between zoster and ischemic stroke or MI. However, this second finding needs confirmation: the study had limited power to detect an effect of vaccination on ischemic stroke or MI following zoster, given the small number of participants who were vaccinated and then developed zoster despite being vaccinated. Another potential study limitation is residual confounding. Although the self-controlled case series design controls for time-fixed confounders, time-varying factors such as major life events or stress may still play a role in the association. Thus, an episode of zoster may cause stress, which could then lead to an increased risk of MI or stroke. Importantly, however, these findings enhance our understanding of the magnitude and timing of the association between zoster and acute cardiovascular events and provide information that might help to prevent such events in older individuals. Additional Information: This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001919.