Abstract
Background and Purpose:
Allergic reactions, including anaphylaxis, can sometimes occur after intravenous thrombolysis in patients with acute ischemic stroke. However, it remains unclear whether stroke patients who receive thrombolytic agents face a higher risk of anaphylaxis than those who do not receive thrombolytics.
Methods:
We performed a retrospective cohort study using inpatient and outpatient claims between 2008-2015 from a nationally representative 5% sample of Medicare beneficiaries. We included patients who were ≥65 years old and hospitalized with acute ischemic stroke, defined by validated ICD-9-CM diagnosis codes. Our exposure was treatment with an intravenous thrombolytic agent during the index hospitalization (ICD-9-CM code 99.10). Our primary outcome was anaphylaxis, defined using an accepted ICD-9-CM code algorithm (989.5, 995.0-4, 995.6x, E905, E905.3, E905.5, or E905.8-9). A secondary outcome was anaphylactic shock (995.0 or 995.6x). Multiple logistic regression was used to evaluate the association between intravenous thrombolysis and anaphylaxis after adjustment for demographics, vascular risk factors, the Charlson comorbidity index, exposure to intravenous contrast dye, treatment with mechanical thrombectomy, and history of allergic reactions.
Results:
Among 66,989 patients with stroke, the 3,176 (4.7%) who underwent intravenous thrombolysis more often had atrial fibrillation (47.7% vs 37.4%) and more often received intravenous contrast dye (44.3% vs 21.9%) but were otherwise similar in terms of demographics and comorbidities. Anaphylaxis developed in 17 (0.54%; 95% CI, 0.31-0.86%) patients who received intravenous thrombolysis versus 45 (0.07%; 95% CI, 0.05-0.09%) who did not. After adjustment for demographics, comorbidities, contrast dye, mechanical thrombectomy, and history of allergies, there was a significant association between receipt of intravenous thrombolysis and anaphylaxis (OR, 7.8; 95% CI, 4.3-13.9). We found a similar association for anaphylactic shock.
Conclusions:
Although a rare occurrence, the risk of anaphylaxis among patients with acute ischemic stroke was significantly higher among those who received intravenous thrombolysis.
Keywords: acute stroke, anaphylaxis, therapeutic thrombolysis, risk factors, medicare, Treatment, Complications, Quality and Outcomes, Ischemic Stroke
Intravenous thrombolysis is a key treatment for acute ischemic stroke.1 Nevertheless, there are important risks which may affect the cost-benefit calculation when considering thrombolysis.2 Allergic reactions have been reported as one potentially serious side effect of intravenous thrombolysis. In large series of stroke patients, orolingual angioedema has been described as a relatively common (2.2%) reaction to intravenous thrombolysis administration.3 Anaphylaxis, which represents a more severe entity on the same spectrum of disease, has been described in case reports.4–7 The actual risk of anaphylaxis after thrombolysis remains unclear, and an independent association between thrombolysis and anaphylaxis has not been confirmed. Therefore, we performed an observational study to compare the risk of anaphylaxis in those receiving intravenous thrombolysis versus those who did not.
Methods
Study Design and Population
We conducted a retrospective cohort study using Medicare claims data.8 Available claims data from hospitals include International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis and procedure codes and dates of hospitalization, while physician claims include Current Procedural Terminology® (CPT®) codes and the dates of service. Multiple claims for a given patient can be linked via a unique beneficiary identifier code, thus allowing for a longitudinal analysis of each beneficiary’s care over time. The Weill Cornell Medical College institutional review board approved this study. Investigators can access these data by application to the Centers for Medicare and Medicaid Services.
We included beneficiaries ≥65 years of age with continuous coverage in traditional fee-for-service Medicare (both Parts A and B) for at least 1 year or until death. We selected patients hospitalized between January 1, 2009 and September 30, 2015 for acute ischemic stroke, defined by an ICD-9-CM diagnosis code algorithm previously validated to have a sensitivity of 86% and specificity of 95% when compared with medical record review.9 We included only the first documented stroke hospitalization for each patient.
Measurements
Our exposure variable was treatment with an intravenous thrombolytic agent during the index stroke hospitalization (ICD-9-CM procedure code 99.10). Our primary outcome was anaphylaxis, defined using a previously published ICD-9-CM code algorithm (989.5, 995.0-4, 995.6x, E905, E905.3, E905.5, or E905.8-9).10 Secondary outcomes were anaphylactic shock (995.0 or 995.6x), orolingual angioedema (995.1), and death. We only included outcomes which occurred during the index hospitalization for ischemic stroke.
As covariates, we ascertained mechanical thrombectomy (as a marker of stroke severity) and intravenous contrast agent injection using CPT® codes from the index hospitalization. We ascertained a history of allergic reactions (ICD-9-CM diagnoses V14.x or V15.0x) and prior receipt of an intravenous thrombolytic agent for myocardial infarction (MI) or pulmonary embolism (PE) prior to the stroke hospitalization. We used standard ICD-9-CM codes to ascertain the Charlson comorbidity index and prespecified vascular risk factors.
Statistical Analysis
We used standard descriptive statistics with exact confidence intervals (CI) to report crude rates. Baseline characteristics were compared using the t-test and the chi-squared test. Multiple logistic regression was used to evaluate the association between intravenous thrombolysis and anaphylaxis after adjustment for age, sex, race, the Charlson comorbidity index, exposure to intravenous contrast dye, treatment with mechanical thrombectomy, history of allergic reactions, and prior intravenous thrombolytic administration. The same model was used to examine the association between anaphylaxis and death. To assess a potential cross-reaction between contrast agents and intravenous thrombolysis, we checked the interaction between these two variables in our model. All statistical analyses were performed by H.K. using Stata/MP (version 14, College Station, TX). Statistical significance was set at a two-sided α = 0.05.
Results
We identified 66,989 patients with acute ischemic stroke (mean age, 79.9 ± 8 years; 58.4% female), of whom 3,176 (4.7%) received intravenous thrombolysis and 63,813 (95.3%) did not. Those patients who underwent intravenous thrombolysis more often had atrial fibrillation and more often received intravenous contrast dye (Table 1).
Table 1.
Characteristics of Medicare Beneficiaries with Ischemic Stroke, Stratified by Thrombolysis Status, 5% National Sample.
| Characteristica | Intravenous Thrombolysis (N = 3,176) | No Intravenous Thrombolysis (N = 63,813) |
|---|---|---|
| Age, mean (SD), y | 79.3 (7.9) | 79.9 (8.0) |
| Female | 1,835 (57.8) | 37,297 (58.5) |
| Race | ||
| White | 2,746 (86.5) | 53,655 (84.1) |
| Black | 281 (8.9) | 7,020 (11.0) |
| Other | 149 (4.7) | 3,138 (4.9) |
| Charlson comorbidity index, mean (SD) | 3.1 (1.6) | 3.1 (1.6) |
| History of allergies | 335 (10.6) | 6,205 (9.7) |
| Contrast dye exposure | 999 (31.5) | 6,139 (9.6) |
| Hypertension | 2,928 (92.2) | 57,674 (90.4) |
| Diabetes mellitus | 1,241 (39.1) | 26,444 (41.4) |
| Coronary heart disease | 1,429 (45.0) | 28,525 (44.7) |
| Congestive heart failure | 908 (28.6) | 17,889 (28.0) |
| Peripheral vascular disease | 613 (19.3) | 11,840 (18.6) |
| Chronic obstructive pulmonary disease | 627 (19.7) | 13,728 (21.5) |
| Chronic kidney disease | 659 (20.8) | 14,963 (23.5) |
| Atrial fibrillation/flutter | 1,516 (47.7) | 23,838 (37.4) |
| Valvular heart disease | 717 (22.6) | 13,574 (21.3) |
| Tobacco use | 524 (16.5) | 8,833 (13.8) |
| Alcohol abuse | 361 (11.4) | 6,848 (10.7) |
Abbreviations: SD, standard deviation.
Data are presented as number (%) unless otherwise specified.
Anaphylaxis was documented in 17 (0.54%; 95% CI, 0.31-0.86%) patients who received intravenous thrombolysis versus 45 (0.07%; 95% CI, 0.05-0.09%) patients who did not. After adjustment for demographics, comorbidities, contrast dye, mechanical thrombectomy, history of allergies, and prior thrombolytic administration, there was a significant association between intravenous thrombolysis and anaphylaxis (OR, 7.8; 95% CI, 4.3-13.9). We found a similar association with our secondary outcome of anaphylactic shock. We also found an association with orolingual angioedema (OR, 11.1; 95% CI, 5.6-21.7). We found no significant evidence of interaction between contrast agents and intravenous thrombolysis in relation to anaphylaxis. Similarly, a history of intravenous thrombolysis during a prior admission during the study period did not modify the association between stroke thrombolysis and anaphylaxis. Patients who developed anaphylaxis had a substantially higher risk of death (OR, 1.9; 95% CI, 1.1-3.2).
Discussion
In a large cohort of Medicare beneficiaries with ischemic stroke, those who received intravenous thrombolysis were at an 8-fold higher risk of anaphylaxis compared to those who did not, and the development of anaphylaxis was associated with a substantially higher risk of death. However, the absolute risk of anaphylaxis in patients treated with intravenous thrombolysis was 1 in 200, which appears small compared to other risks of thrombolysis, including symptomatic intracerebral hemorrhage (1 in 16)11 and orolingual angioedema (1 in 45).3
Prior case reports have supported a diagnosis of allergic anaphylaxis by reporting serum tryptase levels4 or IgE antibodies against tissue plasminogen activator5 during or closely following an anaphylactic event. A systematic review of the Food and Drug Administration’s Adverse Event Reporting System found 12 cases between 2004 and 2012 of an adverse allergic reaction directly attributable to intravenous thrombolytics.7 Of these cases, three patients experienced anaphylactic shock. In this context, our study provides novel data supporting an independent association between intravenous thrombolysis and anaphylaxis in stroke patients as well as estimates of absolute and relative risks.
Potential mechanisms underlying the association between thrombolysis and anaphylaxis are unclear. Since recombinant tissue plasminogen activator is structurally identical to the endogenous protein and has low antigenicity in humans, actual immunoglobulin-mediated anaphylaxis should be rare.12 It may be that many cases of apparent anaphylaxis after thrombolysis are systemic hypersensitivity reactions as the result of the release of vasoactive substances.13 Regardless of the mechanism, clinicians should be aware that hemodynamic or airway compromise is a potential adverse reaction of intravenous thrombolysis for stroke.
Our study has several limitations. First, we were unable to review medical records to confirm a diagnosis of anaphylaxis. We attempted to minimize misclassification by using standard definitions of anaphylaxis proposed by the National Institute of Allergy and Infectious Disease and the Food Allergy and Anaphylaxis Network.10 Given similar mechanisms, cases of angioedema may have been erroneously included as mild cases of anaphylaxis in our study. Even in that case, our findings support an independent association between intravenous thrombolysis and angioedema, which to our knowledge has not been shown previously. Second, we could not adjust for concomitant exposure to medications that may have influenced the risk of anaphylaxis, such as angiotensin-converting enzyme inhibitors, though our results did not change after adjustment for several potential confounders such as demographic characteristics, medical comorbidities, exposure to intravenous contrast dye, treatment with mechanical thrombectomy, history of allergic reactions, and prior intravenous thrombolytic administration.
Conclusions
Although a rare occurrence, anaphylaxis occurred significantly more often among stroke patients who received intravenous thrombolysis than those who did not. Our findings underscore the importance of guidelines recommending frequent cardiovascular and pulmonary evaluations immediately post thrombolysis.2
Acknowledgments:
Sources of Funding: Dr. Merkler is supported by the American Heart Association (grant 18CDA34110419) and the Leon Levy Foundation. Dr. Salehi Omran was supported by the NIH StrokeNet (grant U24NS107237). Dr. Parikh was supported by the NIH (grant NIH/NINDS T32NS07153). Dr. Murthy is supported by the NIH (grant K23NS105948). Dr. Navi is supported by the NIH (grant K23NS091395) and the Florence Gould Endowment for Discovery in Stroke. Dr. Kamel is supported by the NIH (grant R01NS097443) and the Michael Goldberg Research Fund.
Disclosures: Dr. Grotta receives grant support from Genentech in the form of study drug for the BEST-MSU trial. Dr. Kamel serves as the co-PI for the NIH-funded ARCADIA trial which receives in-kind study drug from the BMS-Pfizer Alliance and in-kind study assays from Roche Diagnostics, serves as a steering committee member of Medtronic’s Stroke AF trial (uncompensated), serves on an endpoint adjudication committee for a trial of empagliflozin for Boehringer-Ingelheim, and has served on an advisory board for Roivant Sciences related to Factor XI inhibition.
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