Research JAMA | Original Investigation Association Between Use of Antithrombotic Medication and Hematuria-Related Complications Christopher J. D. Wallis, MD, PhD; Tristan Juvet, MD; Yuna Lee, MD, MEd; Rano Matta, MD, MSc; Sender Herschorn, MD; Ronald Kodama, MD; Girish S. Kulkarni, MD, PhD; Raj Satkunasivam, MD, MPH; William Geerts, MD; Anne McLeod, MD; Steven A. Narod, MD; Robert K. Nam, MD, MSc Related article page 1250 IMPORTANCE Antithrombotic medications are among the most commonly prescribed Supplemental content medications. OBJECTIVE To characterize rates of hematuria-related complications among patients taking antithrombotic medications. DESIGN, SETTING, AND PARTICIPANTS Population-based, retrospective cohort study including all citizens in Ontario, Canada, aged 66 years and older between 2002 and 2014. The final follow-up date was December 31, 2014. EXPOSURES Receipt of an oral anticoagulant or antiplatelet medication. MAIN OUTCOMES AND MEASURES Hematuria-related complications, defined as emergency department visit, hospitalization, or a urologic procedure to investigate or manage gross hematuria. RESULTS Among 2 518 064 patients, 808 897 (mean [SD] age, 72.1 [6.8] years; 428 531 [53%] women) received at least 1 prescription for an antithrombotic agent over the study period. Over a median follow-up of 7.3 years, the rates of hematuria-related complications were 123.95 events per 1000 person-years among patients actively exposed to antithrombotic agents vs 80.17 events per 1000 person-years among patients not exposed to these drugs (difference, 43.8; 95% CI, 43.0-44.6; P < .001, and incidence rate ratio [IRR], 1.44; 95% CI, 1.42-1.46). The rates of complications among exposed vs unexposed patients (80.17 events/1000 person-years) were 105.78 for urologic procedures (difference, 33.5; 95% CI, 32.8-34.3; P < .001, and IRR, 1.37; 95% CI, 1.36-1.39), 11.12 for hospitalizations (difference, 5.7; 95% CI, 5.5-5.9; P < .001, and IRR, 2.03; 95% CI, 2.00-2.06), and 7.05 for emergency department visits (difference, 4.5; 95% CI, 4.3-4.7; P < .001, and IRR, 2.80; 95% CI, 2.74-2.86). Compared with patients who were unexposed to thrombotic agents, the rates of hematuria-related complications were 191.61 events per 1000 person-years (difference, 117.3; 95% CI, 112.8-121.8) for those exposed to both an anticoagulant and antiplatelet agent (IRR, 10.48; 95% CI, 8.16-13.45), 140.92 (difference, 57.7; 95% CI, 56.9-58.4) for those exposed to anticoagulants (IRR, 1.55; 95% CI, 1.52-1.59), and 110.72 (difference, 26.5; 95% CI, 25.9-27.0) for those exposed to antiplatelet agents (IRR, 1.31; 95% CI, 1.29-1.33). Patients exposed to antithrombotic agents, compared with patients not exposed to these drugs, were more likely to be diagnosed as having bladder cancer within 6 months (0.70% vs 0.38%; odds ratio, 1.85; 95% CI, 1.79-1.92). CONCLUSIONS AND RELEVANCE Among older adults in Ontario, Canada, use of antithrombotic medications, compared with nonuse of these medications, was significantly associated with higher rates of hematuria-related complications (including emergency department visits, hospitalizations, and urologic procedures to manage gross hematuria). Author Affiliations: Author affiliations are listed at the end of this article. Corresponding Author: Robert K. Nam, MD, MSc, Division of Urology, Sunnybrook Health Sciences Centre, Room MG-406, 2075 Bayview Ave, Toronto, ON M4N 3M5, Canada JAMA. 2017;318(13):1260-1271. doi:10.1001/jama.2017.13890 ([email protected]). 1260 (Reprinted) jama.com © 2017 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Antithrombotic Medication Use and Hematuria-Related Complications Original Investigation Research ntithrombotic agents are among the most com- monly prescribed medications for older adults in Key Points North America.1 Oral anticoagulants are indicated for A Question Is there an association between the use of oral primary and secondary prevention of stroke and systemic em- antithrombotic agents and hematuria-related complications? bolism, as well as treatment of venous thromboembolism.2 Findings In this cohort study that included 2 518 064 older adults Antiplatelet agents are indicated for primary and secondary in Ontario, Canada, use of antithrombotic medications, compared prevention of cardiovascular disease.3 Despite proven ben- with nonuse of these medications, was significantly associated efits, antithrombotic agents are among the medications with hematuria-related complications (including emergency most commonly associated with adverse events4 and have department visits, hospitalizations, and urologic procedures). contributed to nearly half of all adverse drug events.5 Fur- Meaning Use of antithrombotic medications was associated with ther, the rates of these adverse events are increasing.4 To date, a significant increase in rates of hematuria-related complications. published randomized clinical trials and observational stud- ies of antithrombotic agents have focused on intracranial hemorrhage, gastrointestinal bleeding, and all-cause bleed- excluded individuals who died and those who emigrated prior ing as adverse events.6,7 to the index date. We further excluded patients diagnosed as To our knowledge, a complication that has not been having a cancer (other than nonmelanomatous skin cancer) examined as the primary outcome in patients treated with prior to the index date and those with prior endoscopic uro- antithrombotic agents is hematuria. While hematuria repre- logic procedures as these are likely to significantly affect a pa- sents a less life-threatening adverse event than intracranial or tient’s likelihood of hematuria-related complications. We also gastrointestinal bleeding, it is common and involves diagnos- excluded patients older than the age of 105 years. tic evaluation including abdominal imaging and invasive From linked databases, we collected demographic testing8,9 and management. The prevalence, severity, and information including patient age at the time of each pre- risk factors for hematuria associated with the use of anti- scription, geographic location (local health integration thrombotic agents are largely unknown. To better character- networks12), sex, geographically derived socioeconomic sta- ize this association, this analysis examined rates of gross tus, rurality, and general comorbidity (Johns Hopkins aggre- hematuria-related complications including hospitalization, gate disease group13). The Johns Hopkins aggregate disease emergency department visits, and urologic interventions group has better discrimination than the Charlson score in over a 13-year period among patients who received antico- comorbidity assessment.14 agulant or antiplatelet therapy from a population-based cohort of adults aged 66 years or older in Ontario, Canada. Exposure The primary exposure was use of any oral antithrombotic agent, including anticoagulant and antiplatelet medications for which Methods the first prescription occurred during the study interval (eTable 1intheSupplement). We operationalized antithrombotic ex- We conducted a population-based, retrospective cohort study posure in an intermittent, time-varying fashion (examples of of patients aged 66 years or older in Ontario, Canada, between operationalization of this exposure are in the eFigure in the April 2002 and December 2014 using data from the Institute Supplement). Age 66 years was selected for cohort inclusion of Clinical Evaluative Sciences (ICES). In Ontario, medical care to allow for a 1-year look-back to ensure that patients were not is reimbursed by a single, government-operated health insur- exposed to antithrombotic agents prior to study entry. ance system (Ontario Health Insurance Plan). The cost of pre- On the date of filling their first prescription during the study scription medications is covered for all patients starting at age interval, patients were considered “exposed” and remained 65 years through the Ontario Drug Benefit. exposed until 14 days following the prescription end date This study was designed and conducted according to (washout period). Fifteen days following the prescription end the Strengthening the Reporting of Observational Studies date, patients were considered to be “unexposed.” When the in Epidemiology guidelines10 and Reporting of Studies Con- washout period coincided with prescription renewal, pa- ducted Using Observational Routinely-Collected Health Data tients had continuous, ongoing exposure. When patients dis- Statement.11 The Sunnybrook Health Sciences Centre Re- continued antithrombotic therapy and then restarted after dis- search Ethics Board approved this study. Individual informed continuation, a new exposure period commenced. Similarly, consent was waived owing to the anonymous, aggregated na- when patients switched medications, exposure and outcome ture of the data. time was allocated to each medication during the prescrip- tion period plus the 14-day washout period. Study Patients We identified all residents of Ontario born before 1936, who Outcomes would be aged 66 years or older during the study interval We measured counts of total hematuria-related complica- (2002-2014), based on date of birth using unique identifiers tions, which was the sum of the counts of 3 specific end points (ICES key number). The index date was defined as each per- including the occurrence of emergency department visits for son’s 66th birthday. To include only those patients actively re- gross hematuria, hospital admissions with