Cocaine Use and Risk of Ischemic Stroke in Young Adults
Background and Purpose—Although case reports have long identified a temporal association between cocaine use and ischemic stroke (IS), few epidemiological studies have examined the association of cocaine use with IS in young adults, by timing, route, and frequency of use.
Methods—A population-based case–control study design with 1090 cases and 1154 controls was used to investigate the relationship of cocaine use and young-onset IS. Stroke cases were between the ages of 15 and 49 years. Logistic regression analysis was used to evaluate the association between cocaine use and IS with and without adjustment for potential confounders.
Results—Ever use of cocaine was not associated with stroke with 28% of cases and 26% of controls reporting ever use. In contrast, acute cocaine use in the previous 24 hours was strongly associated with increased risk of stroke (age–sex–race adjusted odds ratio, 6.4; 95% confidence interval, 2.2–18.6). Among acute users, the smoking route had an adjusted odds ratio of 7.9 (95% confidence interval, 1.8–35.0), whereas the inhalation route had an adjusted odds ratio of 3.5 (95% confidence interval, 0.7–16.9). After additional adjustment for current alcohol, smoking use, and hypertension, the odds ratio for acute cocaine use by any route was 5.7 (95% confidence interval, 1.7–19.7). Of the 26 patients with cocaine use within 24 hours of their stroke, 14 reported use within 6 hours of their event.
Conclusions—Our data are consistent with a causal association between acute cocaine use and risk of early-onset IS.
See related article, p 909.
Cocaine is one of the most commonly abused drugs in the United States. Population-based data from the Greater Cincinnati and Northern Kentucky region indicate a 3-fold increase in cocaine use among young adults with stroke between 1993 and 2005.1 Case reports and case series2 have long suggested a link between acute cocaine use and ischemic stroke (IS) in young adults. These clinical observations have strong biological plausibility because of cocaine’s effects on the cardiovascular system. Nevertheless, few epidemiological studies have evaluated the effect of cocaine on IS risk.3–8 Although most,3–5 but not all reports6,7 have supported an association between cocaine use and IS, limitations of previous research include grouping ischemic and hemorrhagic stroke,3,6 lack of data on time of last cocaine use4–6 or route of use,3,5,6 and small numbers of cases.3,4,6,7 The goal of this report is to determine the association between cocaine use and risk of IS, with particular attention to the effects of timing and route of cocaine use, in a large population-based case–control study.
The Stroke Prevention in Young Adults Study was designed as a population-based case–control study of young-onset IS. During 3 study periods between 1992 and 2008, cases with a first-ever IS ages 15 to 49 years were identified by discharge surveillance from 59 nonfederal acute care hospitals in the greater Baltimore/Washington, DC, area and by direct referral from regional neurologists. In the initial study period, only women were recruited, the upper age limit was 44 years, and controls were in a 2:1 ratio to cases and were frequency-matched to cases by age, sex, and region of residence. Women were recruited in the second study period and men in the third study period. In the last 2 study periods, the upper age limit was 49 years, and controls were in a 1:1 ratio to cases and were additionally matched for race. Details of the study design have been previously described.8
Assessment of Cocaine Use and Other Stroke Risk Factors
To assess the use of illicit drug use, participants were asked to recall whether, before the reference date, they had ever used drugs, pills or medications, for nonmedical or recreational reasons or to get high. The name(s), route(s), and timing(s) of drug use were also collected. The reference date was defined as the date of stroke onset for cases and for controls, the date of interview (initial study period) or the day of week that the stroke occurred in the matched case (last 2 study periods). Participants were shown cards with the names, routes of use, and duration of use of various illicit drugs. To minimize potential discomfort associated with disclosing sensitive information, participants indicated their responses using codes printed on the cards, rather than naming the drug or route of use directly. In addition, participants were informed that their responses were protected by a Federal Confidentiality Certificate. A copy of the questionnaire on drug use is provided in the online-only Data Supplement. Acute cocaine use was defined as use of cocaine within 24 hours before the reference date, and current cocaine use was defined as cocaine use within 1 month (including those reporting cocaine use within 24 hours) before the reference date.
Information on traditional stroke risk factors (eg, history of hypertension, diabetes mellitus, current smoking status, and alcohol consumption) and demographic variables (eg, age, sex, and race) was collected by self-report through a standardized face-to-face interview. Current smoking status was defined as use within 1 month before the stroke or, for controls, before the reference date. Current alcohol consumption was defined as having a drink of wine, beer, or hard liquor in the year before the stroke or, for controls, before the reference date.
The study was approved by the University of Maryland at Baltimore Institutional Review Board and all participants gave informed consent.
Statistical analyses were performed using the Statistical Analysis System Software package (version 9.3; SAS Institute, Inc, Cary, NC). Cases and controls were compared for differences in means using t tests (for continuous variables) or differences in proportions by χ2 tests (for categorical variables) to obtain the unadjusted 2-sided P values. Logistic regression with case/control status as the outcome and study characteristics as predictors was used to obtain the age-, sex-, and ethnicity-adjusted P values.
Assessment of the association between cocaine use and IS was performed using a logistic regression model with case/control status as outcome and cocaine variable as the predictor after adjusting for the effect of age, sex, ethnicity, and other stroke risk factors. The odds ratio (OR) of cocaine use (eg, ever, 1–30 days, or within 24 hours) was estimated by comparing with those who had never used cocaine previously (reference group).
Kappa was calculated to estimate the agreement between self-reported current cocaine use and the results of toxicology screening from the medical record among a subset of 373 cases.
A total of 1101 adjudicated first-ever IS cases and 1154 stroke-free controls, aged 15 to 49 years old, were recruited in the study. This report is based on the 1090 cases and 1152 controls for whom cocaine information was available. Table 1 summarizes the characteristics of the study participants. The mean age was 41 years for cases and 39 years for controls. Self-reported race was primarily white or black. Cases were more likely than controls to report having a history of hypertension and diabetes mellitus and being current smokers but less likely to be current alcohol users. There was no statistical difference of self-reported history of ever use of cocaine between cases and controls (28% versus 26%, P=0.95). Figure 1 shows rates of ever use and current use of cocaine among controls, stratified by race and sex. Males had higher rates of use than females, and blacks had higher rates of use than whites.
Cocaine Use and Risk of IS
Table 2 shows the association between cocaine use and IS, stratified by timing and route of intake, adjusted for age, sex, and ethnicity. Compared with those who had never used cocaine, individuals reporting acute cocaine use within last 24 hours had a 6.4-fold (95% confidence interval [CI], 2.2–18.6) increase in the odds of IS. The sample sizes of the cocaine use groups by different routes were small, particularly for intravenous use. However, among the acute users, those who indicated smoking as the route of administration showed the strongest association with IS (OR, 7.9; 95% CI, 1.8–35.0). Among cases with acute use of cocaine within 24 hours before stroke onset, the median frequency of cocaine use in the past year was 7× per week, higher than the median frequency among all cases (1.2× per week). After excluding acute cocaine users, those who reported frequent use of cocaine (more than once per week) in the past year remained significantly associated with an increased risk of IS, although the estimated effect was markedly reduced (OR, 1.9; 95% CI, 1.1–3.3). The association between acute cocaine use and risk of IS remained statistically significant after additionally adjusting for the effect of smoking, alcohol consumption, and hypertension (OR, 5.7; 95% CI, 1.7–19.7).
The OR for acute cocaine use was higher for the initial study period where the reference date for controls was the date of the interview (% of acute users cases versus controls: 5.2% versus 0%; OR, 19.1, Fisher exact P<0.001) than that for the last 2 study periods (% of acute users in cases versus controls: 2.6% versus 0.7%; OR, 3.6, P=0.02) where reference date for controls was the same day of the week as the stroke occurrence of the matched case. Restricting the analysis to the last 2 study periods and adjusting for age, sex, and race, the association between acute cocaine use and risk of IS remained statistically significant (OR, 3.3; 95% CI, 1.1–10.1). Additional adjustment for current smoking, alcohol consumption, and hypertension did not reduce the point estimate for the association but further widened the CI with the loss of statistical significance (OR, 3.5; 95% CI, 0.9–12.6).
Table 3 shows the agreement between self-reported cocaine use within 30 days and toxicology results among a subset of cases. A total of 373 cases with stroke underwent toxicology screening at the time of hospital admission and, of these, 46 (12.3%) tested positive for cocaine use. The κ value between self-reported acute cocaine use and results from toxicology screening was 0.65 (SE 0.06), indicating moderate agreement between the 2 approaches.
Clinical Characteristics of 26 Stroke Patients With Acute Cocaine Use
Table I in the online-only Data Supplement summarizes the demographic characteristics, risk factors, and information on the cocaine exposure for the 26 IS stroke cases with self-reported acute cocaine use, grouped by probable stroke mechanism. Fifteen cases were female and 21 were black, with a mean age of 39.8 years. Stroke risk factors were present in all patients, including tobacco use, hypertension, hyperlipidemia, diabetes mellitus, and myocardial infarction. A history of tobacco use was reported in 25 cases, and 24 cases were current smokers. Twelve patients also reported concurrent use of other illicit drug within 24 hours before stroke onset, including marijuana and heroin, but none of them reported using other vasoactive drugs. Probable stroke mechanism was determined based on clinical data without consideration of cocaine exposure. Of the 26 cases, 7 had a strong cardiac source of embolism, 3 were cryptogenic strokes in multiple vascular territories, 9 were cryptogenic strokes in a single vascular territory, 6 were lacunar strokes, and 1 was a carotid dissection. The 7 cases with a strong cardiac source of embolism included 3 with poor ventricular function, 2 with endocarditis, 1 with acute myocardial infarction, and 1 with a mobile aortic mass.
Figure 2 summarizes results from the Table I in the online-only Data Supplement by showing the timing of last cocaine use for the 24 patients who reported use within 24 hours (2 cases without specific timing, in hours, were excluded). Fourteen (54%) of these 26 patients with stroke reported cocaine use within 6 hours before the onset of stroke.
Our study, including >1000 adjudicated young stroke cases, is one of the largest case–control studies to date examining the association of cocaine use and risk of IS in young adults. Compared with those who had never used cocaine, those who reported acute cocaine use before the study reference time had a 5.7-fold increase in the odds of stroke after adjusting for other stroke risk factors. Furthermore, among the 26 stroke patients with acute cocaine use, the majority reported cocaine use within 6 hours before stroke onset and the most commonly used route of drug use was smoking (crack). In contrast to acute use, use of cocaine months or years ago was not associated with increased risk of stroke.
Cocaine has multiple effects that could predispose to IS.9 At lower cocaine doses, enhanced sympathetic activity because of inhibition of catecholamine reuptake at sympathetic nerve terminals predominates, leading to hypertension and vasoconstriction. At higher doses, cocaine blocks sodium and potassium channels, leading to depressed myocardial contractility and ventricular arrhythmias. Cocaine also induces a prothrombotic state.9 Previous case series10,11 of IS among cocaine users of all ages that found atherosclerosis or small vessel disease to be the predominant cause. In contrast, we found cardiogenic stroke or cryptogenic nonlacunar stroke to be the most common IS types. This is not surprising because cardiogenic or cryptogenic nonlacunar stroke is also the most common cause in general among young-onset IS in the Baltimore–Washington region.12
In one of the earliest studies, Kaku et al3 reported an adjusted OR of 49.4 (95% CI, 6.4–379.0) for illicit drug abuse and stroke risk based on a chart review study of 214 matched young adult case–control pairs from San Francisco General Hospital. However, the analysis included illicit drugs other than cocaine, and aggregated intracerebral and subarachnoid hemorrhage with IS. Petitti et al4 reported an adjusted OR of 13.9 (95% CI, 2.8–69.4) for cocaine use in the week before the index date in 347 cases of ischemic or hemorrhagic stroke and 1,021 controls within the Kaiser Permanente Medical Care Program of California. Adjusted ORs were similar for cocaine as a paste or powder and smoked cocaine. The authors did report the OR for use of either cocaine or amphetamine as 9.6 (95% CI, 2.7–33.5) for hemorrhagic stroke and 4.5 (95% CI, 0.9–21.6) for IS. However, they did not report the specific association of cocaine use with IS. Qureshi et al7 reported that crack cocaine use, either at any time or acute use, was not associated with stroke or cerebral infarction among a small sample of 144 cases and 147 controls from Grady Memorial Hospital in Atlanta. However, this discordant result may be because of several reasons: the cocaine exposure was based on chart review, a high percentage of cases and controls had missing information on cocaine use, and the controls were hospitalized patients who may not have been representative of the nonstroke population because they had a higher prevalence of smoking and diabetes mellitus than the cases. Other studies of cocaine and stroke risk were based on administrative data sets and lacked information on the timing of cocaine use in relationship to the index stroke.5,6
Nevertheless, there are also limitations to our study. Although our study is substantially larger than previous reports, the sample size, specifically the number of cases and controls with cocaine exposure within 24 hours, was too small to address the possibility of residual confounding with measured risk factors. Although we did control for current smoking in past month and any alcohol intake in past year, we were not able to control for amount of use of these substances. This is particularly important for smoking, which is known to have a graded association with risk of stroke in young adults.13 The high prevalence of cocaine use in both cases and controls but a low absolute risk of stroke suggests the possibility that other factors may be necessary to potentiate the risk of cocaine. However, again because of sample size limitations, we were not able to examine the interaction of cocaine use with other vascular risk factors.
The most important limitation of our study relates to information bias between cases and controls about self-report of cocaine use. First, in the initial study period, controls were asked to recall drug use in the 24 hours before the study visit, and they may have been less likely to take drugs shortly before the study interview. The reference time for the cases was always the time of the stroke. This potential bias was addressed in the last 2 recruitment periods where controls were asked to recall drug use 24 hours before a reference date that is matched to the day of the week of stroke onset of the matched index case. For example, if the control was interviewed on a Wednesday and was matched to a case whose event occurred on a Saturday, the reference date for the control was the previous Saturday. When restricting our analyses to the last 2 study periods, we still see a significant, albeit smaller, association between cocaine use and stroke risk in the unadjusted model. Point estimates for the association were similar after adjusting for demographic and risk factors, although the fully adjusted model failed to achieve statistical significance. Second, study participants also may have been reluctant to share information about illegal drug activity. To maximize truthfulness of responses, we used the card approach for obtaining the sensitive information about illicit drug use and also informed subjects of the Federal Confidentiality Certificate, which means that no person, organization, or legal entity can acquire information obtained during the interview. There was substantial, but not perfect, agreement between self-report and toxicology screen results in the subset of cases that had this testing for clinical care. Although we do not have similar data for our control participants, the most persuasive argument against information bias is the fact that self-report of cocaine use at any time in the past and even in the prior 1 to 30 days was virtually identical among cases and controls. Cocaine use was associated with stroke only when exposure occurred in the most biologically relevant time period.
In summary, our data provide the strongest evidence to date that acute cocaine use within 24 hours is associated with IS in young adults. Because cocaine use may be a contributory factor in stroke risk, probing for recent cocaine use and obtaining a toxicology screen should be considered in the evaluation of stroke in young adults.
This article is dedicated to Michael A. Sloan, MD, MS, whose ideas and writings on drug abuse and stroke contributed greatly to this project.
Sources of Funding
This work was supported by the Department of Veterans Affairs, the Centers for Disease Control and Prevention, and the National Institutes of Health (R01 NS45012). Dr Cheng was supported by Department of Veterans Affairs (Career Development Award 1IK2BX001823). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the article.
Guest Editor for this article was Tatjana Rundek, MD, PhD.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.115.011417/-/DC1.
- Received September 4, 2015.
- Revision received December 7, 2015.
- Accepted January 4, 2016.
- © 2016 American Heart Association, Inc.
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