Medication Surveillance CER

This study will perform safety surveillance for antiplatelet and anticoagulant agents in two pairs of cohorts:

  1. Patients who are receiving antiplatelet therapy:
    1. Cohort 1 - with clopidogrel
    2. Cohort 2 - with prasugrel
  2. Patients who are receiving anticoagulant therapy:
    1. Cohort 3 - with warfarin
      1. Cohort 3a – warfarin dose based on genetic testing
      2. Cohort 3b – did not receive genetic testing
    2. Cohort 4 – with dabigatran

Initial sites will be in three different sites, providing diverse populations: UCSD Medical Center in California, Partners Healthcare System in Massachusetts, and the VA Tennessee Valley Healthcare System.  These sites will be augmented as the network expands.

For comparison purposes, safety outcomes (bleeding events) will be compared between relatively old vs. new antiplatelet agents (clopidogrel vs. prasugrel) and old vs. new anticoagulant agents (warfarin vs. dabigatran).  The data shared across institutions will be the results of analysis performed locally on each site’s data.

 


Significance

 
Studying the effectiveness of new medications marketed in the US is a complex task complicated by rapid diffusion of medications into previously unstudied populations, incomplete information regarding existing medical conditions and concomitant medications, and the lack of a systematic approach to measure effectiveness across different health care settings.  In addition, the absence of a scalable network to perform near real-time data collection and a feedback system to close the loop with health care providers severely limits the scope and improvement of many current evaluations.

We will use risk-adjusted propensity-score matched concurrent control cases to compare the effectiveness of each new medication to its established counterpart.  The methods used for data cleaning, imputation and transformation, the risk-adjustment models, the methods used for their evaluation, and the results of the comparison will be posted to the network to allow validation in other sites and extensions for use in other studies.

 


Background

 
Clopidogrel and prasugrel, (approved for marketing in the US in 2009), will be evaluated in the population of patients who present with acute coronary syndrome and undergo percutaneous coronary interventional (PCI) procedures with insertion of drug-eluting stents.  Separately, warfarin and dabigatran will be studied in patients diagnosed for either new onset atrial fibrillation (AF) or venous thromboembolic conditions.  The medications are selected based on the high prevalence of the underlying conditions for which they are prescribed, as well as for the lack of existing clinical evidence of the “real world” safety of the newer agents in each class (prasugrel and dabigatran).


Clopidogrel vs. Prasugrel
Clopidogrel is indicated for treatment and management of acute coronary syndrome (ACS), recent myocardial infarction, recent stroke, and established peripheral arterial disease.  It is a prodrug that irreversibly inhibits platelet activation and aggregation through binding of its active metabolite to platelet P2Y12 receptor (Wiviott SD et al. 2005).  Prasugrel, a unique thienopyridine platelet inhibitor was approved for use in the US in October 2009.  The agent has been studied extensively and has been shown to significantly reduce the risk of ischemic complications for patients presenting with acute coronary syndromes who undergo PCI.  However, this benefit is associated with an increased risk of both major and minor bleeding as compared with clopidogrel, the standard thienopyridine used in the US following PCI (Wiviott SD et al. 2005; 2008).

 

Warfarin vs. Dabigatran
Warfarin has been shown to substantially reduce the risk of embolic stroke in patients with AF.  Similarly, chronic anticoagulation with warfarin reduces the risk of recurrent venous thromboembolism such as deep vein thrombosis or pulmonary embolism.  However, warfarin has a narrow therapeutic window, with dosing tailored for each patient.  It also requires frequent (typically weekly to monthly) blood tests to assure that the patient is effectively anticoagulated without being at substantially increased risk for bleeding (Schulman S et al. 2009).  Due to the complexity of maintaining a safe and effective dosing regimen for warfarin, numerous alternative anticoagulant medications have been the subject of intensive clinical investigation in recent years (Samama MM et al. 2009).  One such new agent, dabigatran, an oral direct thrombin inhibitor, is extremely promising in its potential as a replacement for warfarin.  Dabigatran is administered at a fixed dose, without a need for adjustment for age or renal function, and importantly, without the need for blood test monitoring for dose adjustment.  In recent clinical trials for patients with AF and venous thromboembolism, dabigatran has been shown to have similar efficacy in the prevention of thrombosis and embolization with equivalent risks of major bleeding, but with lower rates of non-severe bleeding as compared to warfarin (Schulman S et al. 2009).