Author + information
- Ravi S. Hira, MD†∗ (, )
- Kevin Kennedy, MS‡,
- Hani Jneid, MD§,†,
- Mahboob Alam, MD†,
- Sukhdeep S. Basra, MD, MPH†,
- Laura A. Petersen, MD, MPH§,‖,¶,
- Christie M. Ballantyne, MD†,
- Vijay Nambi, MD, PhD§,†,
- Paul S. Chan, MD, MSc‡ and
- Salim S. Virani, MD, PhD§,†,‖
- †Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas
- ‡Mid America Heart Institute, Saint Luke's Hospital, Kansas City, Missouri
- §Michael E. DeBakey VA Medical Center, Houston, Texas
- ‖Health Policy, Quality and Informatics Program, Michael E. DeBakey Veteran Affairs Medical Center Health Services Research and Development Center for Innovations, Houston, Texas
- ¶Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas
- ↵∗Baylor College of Medicine, 6620 Main Street, Suite 11D, Houston, Texas 77030
To the Editor:
Prasugrel significantly decreased cardiovascular death, myocardial infarction (MI), and stroke compared with clopidogrel in TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel—Thrombolysis in Myocardial Infarction 38) (1). However, prasugrel use was associated with increased bleeding in patients with a history of previous stroke or transient ischemic attack (TIA) and was not associated with benefit in those ≥75 years of age. The prasugrel package insert (2) includes a black box warning for patients with previous stroke/TIA and also recommends against its use in patients aged ≥75 years due to an increased risk of fatal intracranial bleeding and uncertain benefit, except in high-risk situations (age ≥75 years with history of diabetes or a previous MI). The current American College of Cardiology Foundation/American Heart Association guidelines for patients with ST-segment elevation myocardial infarction and unstable angina/non–ST-segment elevation myocardial infarction (3,4) assign a Class I recommendation for prasugrel use at the time of percutaneous coronary intervention (PCI) and a Class III (harm) recommendation for its use in patients with history of TIA or stroke.
In the present study, we examined the frequency and practice-level variation in inappropriate and nonrecommended prasugrel prescribing in a national registry. PINNACLE is a national, prospective, quality improvement registry. Site participation is voluntary, with data collected at the point of care for all outpatients with coronary artery disease, heart failure, atrial ﬁbrillation, and hypertension. Periodic edit checks are conducted on all records before submission to the Centers for Medicare & Medicaid Services. We evaluated patients receiving prasugrel from 123 practices between July 1, 2009 (after U.S. Food and Drug Administration approval), and June 13, 2013. Prasugrel use in patients with a documented history of previous stroke or TIA was defined as inappropriate. Nonrecommended treatment was defined as prasugrel use in patients ≥75 years of age without diabetes or a previous MI.
To evaluate the frequency of inappropriate or nonrecommended prasugrel prescribing, we used the number of patients receiving inappropriate (or nonrecommended) prasugrel as the numerator and all patients receiving prasugrel as the denominator in our assessments. We further examined the extent of practice-level variation in inappropriate or nonrecommended prasugrel prescribing by constructing multivariable hierarchical regression models to determine the median rate ratio (MRR), which quantifies the likelihood that 2 randomly chosen practices would differ in treating “identical” patients. Covariates in our model were: sex, provider type (physician versus nurse practitioner), hypertension, dyslipidemia, atrial ﬁbrillation, unstable angina, heart failure, and tobacco use. We also examined prasugrel use in patients receiving concomitant aspirin and warfarin because the efficacy and safety of prasugrel (as a third agent) has not been evaluated in this subgroup.
We identified 27,533 patients receiving prasugrel; 3,824 patients (13.9%) had an inappropriate indication and 1,210 patients (4.4%) had a nonrecommended indication. When comparing patients receiving prasugrel for an inappropriate indication versus those receiving it appropriately, there were no differences in age or sex. Patients in the appropriate indication group had higher rates of private insurance and treatment by a physician provider; patients in the inappropriate indication group had a higher prevalence of comorbidities such as diabetes, hypertension, dyslipidemia, atrial ﬁbrillation, heart failure, peripheral artery disease, and coronary arterial bypass graft surgery.
The percentage of patients in individual practices receiving prasugrel inappropriately ranged from 0% to 90% (median: 4.4% [interquartile range: 2% to 10%]). MRR was 2.89 (95% confidence interval: 2.75 to 3.03), indicating significant practice-level variation (Fig. 1). This finding suggests that between 2 “identical” patients treated at 2 randomly chosen practices, 1 patient was 189% more likely to receive prasugrel inappropriately. Nonrecommended prasugrel prescribing ranged from 0% to 19.8% (median: 2.6% [interquartile range: 1.5% to 4.1%]); the MRR was 2.29 (95% confidence interval: 2.05 to 2.51). A total of 4,248 (15.4%) patients received triple therapy with aspirin, warfarin, and prasugrel. Among them, 319 received prasugrel inappropriately and 677 received prasugrel for a nonrecommended indication.
In our study, 18.3% of patients were receiving prasugrel for an inappropriate or a nonrecommended indication. A previous study from Michigan found that among patients receiving prasugrel, 6% to 10% had ≥1 contraindication to prasugrel (5). They reported higher rates of bleeding and vascular complications in these patients, with no difference in ischemic outcomes. Our analyses indicate a higher rate of inappropriate prasugrel prescribing from a nationally representative cohort, with significant practice-level variation in both inappropriate and nonrecommended prasugrel prescribing. In addition, 15.4% of patients were receiving concomitant aspirin and warfarin with prasugrel. It is possible that triple therapy with prasugrel in this group, even when appropriate, may lead to increased rates of major bleeding and offset any anti-ischemic benefit of prasugrel.
Our study has several limitations. Previous TIA/stroke and prasugrel use were self-reported. Prasugrel use without prior acute coronary syndromes or PCI should be considered off-label; however, this information could not be reliably extracted because data about MI and PCI were available for only 12 months prior to a patient's visit. Practices participating in PINNACLE may be motivated for quality improvement and, therefore, inappropriate and nonrecommended rates may be higher in nonparticipating practices. Data on the contraindications to clopidogrel, reason for choosing prasugrel instead of clopidogrel, dosage of prasugrel pertaining to patients weighing <60 kg, results of platelet function studies, and ischemic and bleeding outcomes are not collected in the PINNACLE registry, and analyses pertaining to these variables, therefore, could not be performed.
Almost 1 in 5 patients receiving prasugrel had an inappropriate or nonrecommended indication with significant practice-level variation. Our ﬁndings suggest opportunities to improve evidence-based prasugrel prescribing.
Please note: Dr. Alam has been a member of the advisory board for AstraZeneca. Dr. Petersen has received grant/research support from the National Institutes of Health (R01 HL0791731) and the Houston VA HSR&D Center of Excellence (HFP9O-020). Dr. Ballantyne has received grant/research support (all significant [>$10,000] and all paid to institution, not individual) from Abbott, Amarin, Amgen, Eli Lilly, GlaxoSmithKline, Genentech, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi-Synthelabo, the National Institutes of Health, and the American Heart Association; she has also served as a consultant for Abbott, Aegerion, Amarin, Amgen, Arena, Cerenis, Esperion, Genentech, Genzyme, Kowa, Merck, Novartis, Pfizer, Resverlogix, Regeneron, Roche, and Sanofi-Synthelabo; and on the speakers' bureau for Abbott. Dr. Nambi was a national monitor for a study sponsored by Anthera Inc.; a co-investigator on a provisional patent filed by Baylor College of Medicine, Roche Diagnostics, on the use of biomarkers in heart failure prediction; and involved in a research collaboration with GE and Tomtec. Dr. Virani has received grant/research support in the form of a Department of Veterans Affairs Health Services Research and Development Career Development Award (09-028) and an American Diabetes Association Clinical Science and Epidemiology Award (1-14-CE-44). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs.
- American College of Cardiology Foundation
- ↵(2013) Prasugrel [package insert] (Eli Lilly and Company, Indianapolis, IN).
- O'Gara P.T.,
- Kushner F.G.,
- Ascheim D.D.,
- et al.
- Jneid H.,
- Anderson J.L.,
- Wright R.S.,
- et al.
- Sandhu A.,
- Seth M.,
- Dixon S.,
- et al.