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Patients with acute myocardial infarction (AMI) and non-obstructive coronary artery disease (nonobCAD) may be perceived to be at lower risk for cardiac events, relative to those with obstructive CAD (obCAD), and thus less likely to receive optimal preventive medications in the year following AMI. We aimed to determine if AMI patients with nonobCAD, compared to obCAD, received lower rates of prevention medications in the year following AMI.
We compared optimal prevention medication use at hospital discharge, 1, 6, and 12 months after hospitalization. Optimal medication use was defined as the receipt of all prevention medications for which that patient was eligible (e.g. aspirin, clopidogrel, statins, beta-blockers and ACEI/ARBs). We used multivariable logistic regression analyses to determine the association between nonobCAD to medication use and adjusted for potential confounders. 3630 AMI patients were studied, of which 200 (5.2%) had nonobCAD. Fewer nonobCAD patients received optimal medication use compared to obCAD patients at discharge (31% v. 65%, p<0.001), driven primarily by lower rates of clopidogrel use (40.5% v. 83.3%, p < 0.001). After adjustment for percutaneous coronary intervention (PCI), differences in medication use were similar at discharge and 1 year after hospitalization. Stratified analyses by receipt of PCI suggested patients confined to medical management had less optimal medication use, regardless of their CAD burden.
Lower rates of unadjusted optimal medication use were seen in nonobCAD patients, driven by low clopidogrel use among medically managed patients, suggesting improvement efforts should focus on these patients.
Non-obstructive coronary artery disease (CAD), defined as a coronary artery stenosis 20% or greater but less than 50% in the left main coronary artery or a stenosis 20% or greater but less than 70% in any other epicardial coronary artery, occurs in 5–10% of acute myocardial infarction (AMI) patients.1–3 While patients with non-obstructive CAD have lower rates of recurrent cardiovascular events than those with obstructive CAD,4 they still have a 2.2% 30-day risk of death or recurrent myocardial infarction,1 which places them at substantially higher risk than those without known CAD. In addition, one study demonstrated that non-obstructive CAD patients had a 3.6% higher absolute risk of 1-year mortality compared to a matched population of obstructive CAD patients.3
Dual antiplatelet therapy demonstrated improvement in cardiovascular outcomes in the Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators (CURE) trial.5 Thus, secondary prevention measures for AMI patients and the use of dual-antiplatelet therapy have been well established in clinical practice guidelines since 2002.6 Importantly, these guidelines apply equally to patients with non-obstructive and obstructive CAD alike, and require long-term adherence for maximum cardiac risk reduction.7–9 However, the presence of non-obstructive CAD may inadvertently diminish the importance of these measures in both providers’ and patients’ minds, diminishing focus on secondary prevention at and after discharge.10 If such gaps are present, this may represent an important opportunity for improvement, not only at hospital discharge, but also for subsequent efforts at secondary prevention after acute MI.
In this study, we compared longitudinal secondary prevention medication use between patients with non-obstructive and obstructive CAD after AMI. We hypothesized that non-obstructive CAD would be associated with lower rates of secondary prevention medication use, both at hospital discharge and in the subsequent year.
We studied AMI patients in the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients’ Health Status (TRIUMPH) Prospective Multicenter Registry. Between April 2005 and December 2008, AMI patients from 24 US hospitals were enrolled in the registry. Study design, patient selection and protocol for longitudinal care and outcomes assessment have been previously described.11 Patients were considered for registry enrollment if their initial AMI presentation was to any of the 24 participating institutions or were transferred within the first 24 hours of presentation to a participating institution. Registry inclusion criteria consisted of patient age ≥18 years, World Health Organization Type 1 myocardial infarction, elevated troponin level, and clinical evidence of ischemia (prolonged ischemic signs and symptoms, electrocardiographic ST changes in ≥ 2 consecutive leads). All patients included in the study had a coronary angiogram during their index AMI hospitalization. The institutional review board of each facility approved the enrollment process and protocol. All patients provided informed consent.
Baseline data collection occurred within 24 to 72 hours of admission. Subjects’ demographics (e.g. age, sex, race), socioeconomic information, and medical history (e.g. smoking status, prior history of CAD, medication use prior to hospitalization) were collected by interview and chart abstraction. Patients’ hospital course (e.g. in-hospital treatment, complications, adverse events), discharge medications, and medication contraindications were also collected via chart abstraction. Subsequent patient interviews occurred at 1, 6 and 12 months after hospitalization. Medication use was documented by having the patients collect all of their current medications and read them to the interviewer.
Consistent with prior studies and generally agreed upon definitions, non-obstructive CAD was defined as a coronary artery stenosis 20% or greater but less than 50% in the left main coronary artery or a stenosis 20% or greater but less than 70% in any other epicardial coronary artery.12, 13 Coronary arteries without evidence of disease, luminal irregularities only, or stenosis < 20% were excluded from the study cohort. Obstructive CAD type was defined as any stenosis in the left main coronary artery ≥ 50% or any stenosis in any other coronary artery ≥ 70%.
Our primary independent variable was non-obstructive or obstructive CAD. Our primary dependent variable was optimal secondary prevention medication use at hospital discharge and 1, 6, and 12 months after the index AMI. Consistent with AMI clinical practice guidelines, secondary prevention medications included aspirin, clopidogrel, statins, beta-blockers, and angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB).10 Optimal, or “defect-free” medication use, as defined by Joint Commission criteria, is the receipt of all secondary prevention medications for which that patient was eligible.14 For example, if a patient had a contraindication to or had no indication for ACEI/ARB medication use (i.e. the patient did not have left ventricular systolic ejection fraction less than 40%, diabetes, hypertension or chronic renal disease), but was eligible and received the other four secondary prevention medications, then that patient would be considered to have optimal medication use.
Characteristics of patients with non-obstructive and obstructive CAD were compared using t-tests for continuous variables and chi-square tests for categorical variables.
We assessed unadjusted rates of optimal medication use and individual medication use in patients with non-obstructive CAD and obstructive CAD at hospital discharge and 1, 6, and 12 months after hospitalization and compared them using chi-square tests. To assess the independent association between degree of CAD obstruction and medication use over time, we employed a repeated measures multivariable model. Covariates for the model were chosen based on prior studies and clinical knowledge of potential confounders between CAD degree of obstruction and medication use. These included demographics (age, sex, race, insurance), clinical history (body mass index, smoking, hypertension, diabetes mellitus, coronary artery disease, chronic kidney disease, depression, left ventricular ejection fraction less than 40%), medications at arrival (aspirin, ACEI/ARB, statin, beta blockers and clopidogrel), in-hospital complications (bleeding, renal failure), percutaneous coronary intervention (PCI) during index hospitalization and warfarin use at discharge.15 We also evaluated for a differential effect of time on the degree of CAD obstruction and medication use relationship using interaction terms in the repeated measures. Hospital site was specified as a random effect to account for clustering of patients within hospitals. Because the proportion of patients with optimal medication use was greater than 10%, we estimated relative rates using Poisson regression modeling, rather than odds ratios, to avoid overestimation of effect sizes.
Review of the initial data suggested that patient receipt of PCI significantly modified the degree of CAD obstruction and medication use relationship. Accordingly, we conducted an analysis stratifying the cohorts by receipt of PCI and comparing patient characteristics by degree of CAD obstruction. We then repeated our analyses of unadjusted optimal and individual medication use rates by degree of CAD obstruction, both at discharge and one year after index event. A small number of non-obstructive CAD patients underwent PCI (n=29), likely for ruptured, but non-occlusive plaque. Because of these low numbers, we were unable to specify multivariable models for the stratified analysis. In addition, 33.5% of AMI patients who did not undergo PCI underwent coronary artery bypass grafting (CABG) as part of their AMI management. Because the management of CABG patients may have been different than the management of AMI patients who received no revascularization, we conducted a sensitivity analysis excluding CABG patients to determine if there were differences in medication rates by CAD degree in those patients who were truly “medically managed”.
A p-value of < 0.05 was considered statistically significant. Data analyses were performed using SAS 9.3. The study was reviewed and approved by the Colorado Multiple Institutional Review Board.
Demographics and clinical characteristics of our study cohort are shown in Table 1. There were 3830 AMI patients in our study cohort, of which 200 (5.2%) patients had non-obstructive CAD. Patients with non-obstructive CAD were significantly more likely to be female (52.5% v. 30.5%, p <0.001), non-white (55.5% v. 27.9%, p < 0.001), and to have presented with non-ST elevation myocardial infarction (82.5% v. 51.1%, p <0.001). However, both groups had similar rates of cardiovascular risk factors such as hypertension and diabetes.
At hospital discharge, non-obstructive CAD patients had lower unadjusted rates of optimal medication use compared to obstructive CAD patients (31.0% v. 64.8%, p < 0.001) (Figure 1). Analysis of individual medication use at discharge demonstrated that non-obstructive CAD patients had lower unadjusted rates of clopidogrel (40.5% v. 83.3%, p < 0.001), beta-blocker (87.8% v. 94.8%, p < 0.001), and ACEI/ARB (73.3% v. 79.9%, p=0.027) use compared to obstructive CAD patients (Figure 1). Unadjusted rates of aspirin (94.3% v. 96.5%, p=0.114) and statin (87.8% v. 90.7%, p=0.168) use were similar between the two groups.
After multivariable adjustment for potential confounders, the differences in optimal medication use rates at discharge between non-obstructive and obstructive CAD patients were similar (rate ratio 0.96, CI 0.83–1.12) (Table 2). Among individual medications, the rates of clopidogrel and beta-blocker use in non-obstructive CAD patients remained lower than obstructive CAD after adjustment (clopidogrel rate ratio 0.85, CI 0.77–0.94; beta-blocker rate ratio 0.92, CI 0.89–0.96), but rates of aspirin (rate ratio 1.02, CI 0.99–1.05), statin (rate ratio 0.99, CI 0.94–1.03), and ACEI/ARB (rate ratio 1.08, CI 0.99–1.17) use were similar between groups at discharge (Table 2).
Over the year following AMI hospitalization, non-obstructive CAD patients had significantly lower unadjusted rates of optimal medication use compared to obstructive CAD patients (Figure 2). Lower unadjusted rates of use for all individual medications among non-obstructive CAD patients were also seen at all time points in the year following the index AMI. The only exceptions to this pattern were statin use at 1 month, ACEI/ARB use at 1 month, and beta-blocker use at 12 months. After multivariable adjustment, non-obstructive CAD patients adjusted rate of optimal medication use during the year following AMI compared to obstructive CAD patients was not significantly different (rate ratio 0.96, CI 0.83–1.12) (Table 2).
Among individual medications, non-obstructive CAD patients had lower adjusted rates of beta-blocker use at all time points after AMI hospitalization, compared to obstructive CAD patients (rate ratio 0.92, CI 0.89–0.96). Non-obstructive CAD patients also had lower adjusted rates of aspirin use at 1 month (rate ratio 0.91, CI 0.84–0.99) and 12 months (rate ratio 0.90, CI 0.83–0.99), compared to obstructive CAD patients. Adjusted rates of all other medications were not significantly different between groups at each time point. The adjusted rate of clopidogrel differed slightly at each time point, but was still overall not significantly different between CAD obstruction groups (Table 2).
In secondary analyses, we stratified the study cohort by receipt of PCI. 2797 (73.0%) AMI patients underwent PCI, and 1033 (27.0%) did not. Patients who underwent PCI were younger, more often white, and had lower rates of both cardiac and non-cardiac co-morbidities (Table 3). Among those patients who underwent PCI, non-obstructive and obstructive CAD patients had similar unadjusted rates of optimal medication use at discharge (75.9% v. 77.0%, p = 0.89) (Figure 3). Among individual medications, non-obstructive and obstructive CAD patients had similar unadjusted rates of medication use at discharge, including clopidogrel (89.7% v. 97.3%, p=0.05) (Figure 3). However, among patients who did not undergo PCI, rates of optimal medication were markedly lower than those patients undergoing PCI. For example, unadjusted rates of optimal medication use (23.4% v. 25.8%, p =0.52) were similar but strikingly lower for both obstructive and non-obstructive CAD. Among individual medications, aspirin, clopidogrel, and statin rates were similar between non-obstructive and obstructive CAD patients not undergoing PCI, while beta-blockers were less frequent in non-obstructive CAD patients (86.3% v. 93,7, p = 0.001) and ACEI/ARBs were more frequent in non-obstructive CAD (78.4% v. 68.4%, p = 0.02).
In the year following AMI hospitalization, patients with non-obstructive and obstructive CAD who underwent PCI had similar unadjusted rates of optimal and individual medication use at 1, 6, and 12 months (Figure 4). Among those patients who did not undergo PCI, non-obstructive CAD patients, in general, had similar unadjusted rates of optimal and individual medication use at 1, 6, and 12 months (Figure 4). The only exceptions to this pattern were aspirin use at 1 month and 12 months, statin use at 6 months and 12 months, beta-blocker use at 1 and 6 months, and ACEI/ARB use at 12 months (Figure 4). Our sensitivity analysis excluding patients who underwent CABG, rather than PCI, did not materially affect these results.
In this multi-center study, AMI patients with non-obstructive CAD had lower unadjusted rates of optimal secondary prevention medication use, both at hospital discharge and in the subsequent year, compared to those with obstructive CAD. In addition, rates of medication use in both groups declined significantly over the year following AMI. Importantly, our analysis suggests that this gap, rather than being associated with non-obstructive CAD per se, was predominantly due to lower rates of clopidogrel use among so-called “medically managed” AMI patients. These findings suggest that quality improvement initiatives should particularly focus on improving medication use in the year following AMI for medically managed AMI patients.
Consistent with prior studies, our unadjusted analyses show that secondary prevention medication use in AMI patients with non-obstructive CAD is lower than in those with obstructive CAD at hospital discharge. De Ferrari et al described individual medication use from a pooled analysis of non-ST elevation myocardial infarction clinical trials and found that patients with non-obstructive CAD had a lower proportion of patients taking the indicated medications during their index hospitalization.1 Similarly, using data from the National Cardiovascular Data Registry, our group found that patients with non-obstructive CAD were less likely to receive secondary prevention medication prescription at hospital discharge compared to patients with obstructive CAD.16
Our study expands on this prior work in several important ways. One, it is the first study, to our knowledge, to demonstrate that non-obstructive CAD AMI patients have continued gaps in optimal secondary prevention medication use in the year following their AMI. Second, our analyses found that this gap was fully explained by differences in management strategy between medically treated patients and those receiving PCI; those who did not receive PCI were much less likely to receive guideline-recommended dual antiplatelet therapy. Finally, it adds to the accumulating evidence that all AMI patients, regardless of CAD degree, had significant and concerning decreases in optimal medication use during the year following AMI.17, 18
This study has several important implications. First, rather than identifying non-obstructive CAD as a driver of sub-optimal secondary prevention, our results suggest that medically managed patients, or those patients who do not receive PCI as part of their AMI management, are the ones at risk for sub-optimal care due to low rates of P2Y12 inhibitor prescription. The much higher proportion of patients who undergo PCI receive high rates of secondary prevention prescription at discharge, regardless of CAD degree of obstruction, may indicate that the standardized processes that are part of many hospitals’ current quality improvement initiatives for patients receiving PCI have been successful. However, these measures may have inadvertently neglected medically managed AMI patients. The CURE trial demonstrated that the benefit of P2Y12 inhibitors, in addition to aspirin, was equally beneficial in revascularized and non-revascularized patients alike.5 Accordingly, current AMI guidelines since 2002 call for the use of dual antiplatelet therapy with P2Y12 inhibitors and aspirin in all patients with AMI for a minimum of 12 months, irrespective of CAD obstruction or receipt of PCI.19 Similar gaps in P2Y12 inhibitor use in medically managed AMI patients have been seen in other populations,20 and our current findings in the TRIUMPH registry further underscore the need for improvement.
Another major implication of our findings is the need to improve longitudinal medication use among all AMI patients. Decreased rates of optimal secondary prevention medication use in AMI patients over time is a well-studied phenomenon,21–24 and our study further highlights the issue and calls for the need to address it. Although a variety of programs, such as full coverage prescription of preventive medications or multidisciplinary collaborative care focusing on medication adherence, have been developed to address long-term adherence to prevention medications in AMI patients,25–27 more work remains to be done. Future quality improvement efforts to improve discharge and longitudinal medication use need to be implemented for all patients presenting with AMI, regardless of the degree of CAD obstruction or whether or not patients receive PCI.
This study was a multi-center registry reflecting contemporary cardiovascular disease prevention practices. Data obtained from the registry included extensive clinical, patient-level data that was collected prospectively (including adjudicated outcomes and medication contraindications), thus improving the fidelity of our analyses. However, the results should also be viewed in the setting of several limitations. First, relative to the size of our cohort, only 5.2% of the patients had non-obstructive CAD, decreasing the power of the effect size. However, our most significant finding, that management strategy affected medication use, was adequately powered and showed significant reduction in medication use in patients who were medically treated only. Second, medication use data in the year following AMI was self-reported, which could lend itself to bias. However, self-report has been validated as a reasonable proxy for medication adherence,28, 29 and patients were asked to report their medication use by reading from their pill bottles, rather than simply relying on memory. Third, this registry only includes patients sustaining an AMI in 2005 through 2008, and changes may have occurred in secondary prevention medication use since this time. Lastly, among patients who presented with non-obstructive CAD, 14.5% received PCI (versus 76.3% of patients with obstructive CAD). Although, by guidelines, this group should not have received PCI, we speculate these patients may represent those with intermediate-level lesions that had plaque rupture characteristics warranting intervention.
In conclusion, AMI patients with non-obstructive CAD had lower rates of optimal secondary prevention medication use, primarily driven by lower clopidogrel use, during the year following their hospitalization. Adjusted analyses suggest that this gap was predominantly due to lower rates of clopidogrel use among all medically managed AMI patients, non-obstructive and obstructive CAD alike, rather than non-obstructive CAD patients in particular. Accordingly, quality improvement efforts should focus on optimizing clopidogrel prescription, particularly among medically managed AMI patients.
Sources of funding: The TRIUMPH Registry received funding support from the National Heart, Lung, and Blood Institute (P50 HL077113).
All authors have no further disclosures.