Published Online: August 20, 2014
Andrew M. Goldsweig, MD; Kimberly J. Reid, MS; Kensey Gosch, MS; Fengming Tang, MS; Margaret C. Fang, MD, MPH; Thomas M. Maddox, MD, MSc; Paul S. Chan, MD, MSc; David J. Cohen, MD, MSc; and Jersey Chen, MD, MPH
CHARISMA was a landmark randomized clinical trial that failed to demonstrate a benefit of dual antiplatelet therapy (DAPT) over aspirin alone for preventing cardiovascular events. However, subgroup analyses of the trial found fewer major adverse cardiovascular events (MACEs) for patients with established cardiovascular disease but more MACEs for patients with multiple risk factors without established cardiovascular disease. Our objective was to examine DAPT use in contemporary clinical practice after publication of CHARISMA results.
Retrospective analysis of a large clinical registry of outpatient cardiovascular visits to over 1000 physicians that collected data on patient clinical history, symptoms, vital signs, and medications.
Clinical characteristics and prescription rates of aspirin and clopidogrel were compared for patients with established cardiovascular disease and for patients with only multiple cardiovascular risk factors. Prescription of DAPT by calendar quarter was evaluated from 2008 to 2011 using multivariable Poisson regression models.
Of 167,839 patients with established cardiovascular disease, 20.5% were prescribed both aspirin and clopidogrel. Of 20,478 patients with multiple risk factors but no known cardiovascular disease, 3.5% were prescribed both aspirin and clopidogrel. Across 14 calendar quarters, prescription rates of DAPT did not change significantly for patients with established CVD but decreased for patients with multiple risk factors with an incidence rate ratio of 0.77.
Use of DAPT is modest in patients with established cardiovascular disease, for whom the CHARISMA trial suggested decreased MACEs, and prescription rates have remained stable over time. Use of DAPT in patients with multiple risk factors only, for whom CHARISMA suggested that DAPT may lead to increased MACE, was low and decreased over time.
Am J Manag Care. 2014;20(8):659-665
An examination of contemporary use of dual antiplatelet therapy provides insight as to how physicians appear to have responded to subgroup analyses from a landmark randomized clinical trial.
Dual antiplatelet therapy with aspirin and clopidogrel was prescribed in 20.5% of patients with established cardiovascular disease, a subgroup for whom a decrease in cardiovascular events was found.
Among patients with multiple risk factors only, for whom dual antiplatelet therapy was associated with increased cardiovascular events in subgroup analyses, 3.5% of patients were prescribed aspirin and clopidogrel.
Adding clopidogrel to aspirin has well-established benefits in settings of acute coronary syndrome (ACS)1,2 and percutaneous coronary intervention (PCI).3,4 However, the role of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel for secondary prevention of major adverse cardiovascular events (MACEs) in patients with chronic cardiovascular disease (CVD) in other settings remains controversial. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial5 failed to demonstrate a benefit of DAPT in preventing MACEs in its overall study population, which consisted of both patients with established CVD and patients with multiple cardiovascular risk factors but without established CVD. However, a pre-specified subgroup analysis of CHARISMA demonstrated divergent results for the 2 study subgroups with decreased MACEs in patients with established CVD but significantly higher risk of death (both all-cause and cardiovascular) for patients with multiple risk factors.5 Additional subgroup studies have reported that DAPT may confer benefit for specific cohorts within CHARISMA such as patients with prior myocardial infarction (MI), ischemic stroke, or symptomatic peripheral arterial disease (PAD),6 or those exclusively with PAD.7 Editorial commentators have generally discounted the subgroup analyses and recommended against the use of DAPT in patients with either established CVD or multiple cardiovascular risk factors.8,9 However, it is not clear how clinicians have applied the evidence from CHARISMA and its subgroup analyses to clinical prescription of DAPT. Accordingly, we analyzed data from a large registry of cardiovascular outpatient visits to examine prescription rates for DAPT among patients with characteristics similar to those in the CHARISMA trial.
We used data from PINNACLE (Practice INNovation And CLinical Excellence),10,11 a prospective registry administered by the American College of Cardiology National Cardiovascular Data Registry (ACC-NCDR). PINNACLE is the first national, office-based cardiac quality improvement registry in the United States, containing data on more than 2 million patient encounters submitted by more than 1000 participating physicians to date. Detailed information regarding the registry data collection has been published.11 Briefly, physician practices collected longitudinal patient data including clinical history, symptoms, vital signs, and medications, either by paper forms or through electronic medical records, and regularly submitted them to PINNACLE. Selected data elements for this study include patient demographics (age, sex, race), cardiovascular risk factors (diabetes, hypertension, hyperlipidemia), prior cardiovascular procedures (percutaneous coronary intervention [PCI], coronary artery bypass surgery [CABG]), selected physical examination findings (systolic blood pressure), medications, and insurance status. Data quality was routinely monitored by Saint Luke’s Mid America Heart Institute, the primary analytic center for the PINNACLE program.
We identified PINNACLE subjects meeting the inclusion criteria of the CHARISMA trial, both patients with established CVD and those with only multiple cardiovascular risk factors.5 A total of 682,348 patients treated in 31 outpatient sites in PINNACLE were identified from April 2008 to September 2011; all were 45 years or older, as in the CHARISMA population. We selected the first outpatient record for each patient to avoid double counting. Because current clinical guidelines recommend DAPT for up to 12 months after PCI with stent implantation,12 patients who underwent PCI within the year prior to the outpatient encounter (n = 61,193) were excluded from the study cohort. Subjects with acute myocardial infarction (AMI) within the year prior to the index outpatient visit (n =45,460) were also excluded as, DAPT is also indicated for these patients.1 In addition, because DAPT has been demonstrated to reduce stroke in patients with atrial fibrillation (AF) who are not candidates for warfarin anticoagulation,13 patients with AF were excluded (n = 108,905). Patients prescribed warfarin for other indications (n = 22,621) were also excluded, similar to the CHARISMA trial. Of the remaining 435,795 patients, we excluded an additional 247,478 patients who did not meet the CHARISMA trial definitions of either established CVD or multiple cardiovascular risk factors without known CVD, resulting in a final cohort size of 188,317. Patients were categorized as having established CVD if they had a history of coronary artery disease (CAD; stable or unstable angina or previous MI), transient ischemic attack (TIA), stroke, PAD, or CABG. Similarly, patients were classified into the multiple cardiovascular risk factor group if they had 1 major risk factor (diabetes mellitus) and 2 of the following minor risk factors: systolic blood pressure ≥150 mm Hg despite medical therapy (beta-blocker, calcium channel blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or diuretic), hyperlipidemia, current smoking, and aged ≥65 years for males or ≥70 years for females; or no major risk factor and 3 minor risk factors. As PINNACLE did not capture all the cardiovascular risk factors available in CHARISMA, the group definitions for our study were subsets of those in CHARISMA. Specifically, our study was not able to determine whether patients had the following major risk factors assessed in CHARISMA: diabetic nephropathy, ankle-brachial index <0.9, carotid stenosis ≥70%, or carotid plaque by intimamedia thickness.
Analyses were conducted separately for the established CVD group and the multiple risk factor group. We calculated the proportion of patients prescribed antiplatelet medications: aspirin (A) only, clopidogrel (C) only, A+C, or neither A nor C. We compared differences in demographic and clinical characteristics across the 4 antiplatelet regimens using analysis of variance for continuous variables (age) and X2 test for categorical variables. We then developed multivariable Poisson regression models to examine the number of antiplatelet medication prescriptions by calendar quarter, adjusting for age, sex, cardiovascular risk factors, and insurance status. From these models, we calculated adjusted incidence rate ratios (IRRs) for each antiplatelet medication regimen from the second calendar quarter of 2008 (Q2 2008) to the third calendar quarter of 2011 (Q3 2011) using the initial calendar quarter as a baseline. For the adjusted models, approximately 7.7% of patients were excluded due to missing data, predominately insurance status. All statistical analyses were conducted using SAS 9.2 software (SAS Institute, Cary, North Carolina) and R (www.r-project.org).
We identified a total of 188,317 patients meeting our modified CHARISMA classification criteria: 167,839 patients with established CVD and 20,478 patients with multiple cardiovascular risk factors. Patients in the established CVD group were slightly younger than those in the multiple cardiovascular risk factor group (aged 68.5 years vs 71.7 years, P <.001). Patients in the established CVD group were predominately male (59.3%), while patients in the multiple risk factor group were predominately female (55.1%). A history of CAD was the most common reason (89.8%) for classification into the established CVD group; cerebrovascular disease (TIA or stroke) and PAD were less common reasons at 14.0% and 16.1%, respectively. Hyperlipidemia (93.6%) and hypertension (91.7%) were the most common cardiovascular risk factors. By design, no patients in the multiple risk factor group had known CVD, similar to the CHARISMA trial. Small differences in distribution across health insurance type were observed between the 2 groups, but consistent with national trends,15 private insurance was the most common health insurance for both the established CVD and multiple risk factors groups, followed by fee-for-service Medicare (Table 1).
Patients with established CVD were more likely than those with multiple cardiovascular risk factors to be prescribed aspirin only (57.6% vs 56.5%, P = .006), more likely to be treated with clopidogrel only (4.3% vs 2.2%, P <.001), and more likely to be treated with A+C (20.5% vs 3.5%, P <.001) (Table 1). Overall prescription rates of any antiplatelet therapy (aspirin, clopidogrel, or A+C) were 82.4% in the established CVD group and 62.2% in the multiple risk factor group. In established CVD patients prescribed A+C, the most common CVD diagnoses were previous myocardial infarction (29.5%), peripheral arterial disease (23.9%), and coronary artery disease (21.6%) (Table 2).
For the established CVD group, unadjusted prescription rates of A+C decreased slightly during the study period from 20.3% in Q2 2008 to 20.2% in Q3 2011 (P for trend = .002) (Table 3). A decline in the prescription of aspirin only was observed from 60.0% in Q2 2008 to 53.9% in Q3 2011 in the established CVD group (P for trend <.001). A+C use also decreased slightly in the multiple risk factor group (4.3% in Q2 2008 to 1.5% in Q3 2011, P for trend <.001) (Table 3). The use of aspirin alone increased insignificantly during the study period (55.4% to 60.9%, P-fortrend = .967) in this group.
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