Evaluation of the Risk of Venous Thromboembolism After Gardasil Vaccination: Mini-Sentinel Medical Product Assessment.

摘要

Gardasil is a quadrivalent vaccine indicated for the prevention of anogenital cancers, genital warts, and precancerous or dysplastic lesions caused by infection with human papillomavirus (HPV) types 6, 11, 16, and 18. Gardasil is routinely recommended for females and males aged 11–12 years in a three dose series (0, 2, and 6 months) but can be administered as young as age 9 years; catch-up vaccination is recommended for females aged 13–26 years and males aged 13-21 years who have not been previously vaccinated.1 FDA approved Gardasil in June 2006 based on 12 randomized controlled studies involving approximately 21,000 males and females aged 9–26 years in support of its safety and efficacy.2 In these clinical studies, injection site reactions were found to be higher among Gardasil-vaccinated persons than placebo recipients.3,4 However, rates of systemic reactions, new onset medical conditions, serious adverse events, and deaths following vaccination were comparable between vaccine and placebo recipients. No safety issues were identified in prelicensure studies of Gardasil. Postlicensure surveillance identified disproportional reporting of venous thromboembolism (VTE) after Gardasil vaccination. An analysis of the first 2.5 years of passive surveillance in the Vaccine Adverse Events Reporting System (VAERS) found that VTE was reported more frequently than expected compared with other vaccines.5 The median age of reported VTE cases was 20 years (range 15–39 years) and the median onset interval was 23 days (range 0–306 days). However, 90% of the reported cases had at least one preexisting risk factor for VTE, suggesting that confounding may explain a substantial proportion of the cases. Disproportional reporting alone, in a passive surveillance system, is not sufficient to demonstrate a causal relationship between VTE and Gardasil. To supplement passive surveillance, the Vaccine Safety Datalink (VSD) monitored 600,558 Gardasil doses administered to females aged 9–26 years for the first 3 years after licensure (August 2006 to October 2009). During this period, VSD monitored 8 outcomes using rapid cycle analyses, and no safety signals were detected based upon predefined criteria.6,7 However, a statistically non-significant relative risk of 1.98 for VTE (defined using ICD-9 codes 415.1x and 453.x) after Gardasil administration in females aged 9–17 years was found compared with a historical comparison group of females of the same age. Eight VTE cases in females aged 9–17 years were electronically identified 1–42 days postvaccination; 5 of these cases were chart-confirmed, 2 were instances of miscoding, and 1 was ruled out after diagnostic testing. The VTE diagnosis in 4 of the 5 confirmed cases occurred within 1-7 days after vaccination; the fifth occurred on Day 32. All 5 cases had at least one known risk factor—hormonal contraceptive use, coagulation disorders, smoking, obesity, or prolonged hospitalization. No elevated risk was detected after Gardasil vaccination among adult females aged 18–26 years. In December 2010, this information was presented to the FDA Pediatric Advisory Committee as part of a routine safety review.8 The committee recommended that additional surveillance studies be conducted to further evaluate the risk of VTE following Gardasil vaccination. This report describes the methods and results of examining the risk of VTE after Gardasil vaccination in the Post-licensure Rapid Immunization Safety Monitoring (PRISM) program.