Evaluation of Aspirin and Statin Therapy Use and Adherence in Patients With Premature Atherosclerotic Cardiovascular Disease

This cross-sectional study evaluates the pattern of aspirin use and statin use and adherence in US veterans with premature atherosclerotic cardiovascular disease.


Introduction
Substantial advancements in prevention of atherosclerotic cardiovascular disease (ASCVD) have led to substantial improvements in adverse cardiovascular events and associated mortality. [1][2][3] Despite the improvements, the incidence of ASCVD has increased in younger patients. 4 This trend is prevalent across all 3 domains of ASCVD: ischemic heart disease (IHD), ischemic cerebrovascular disease (ICVD), and peripheral arterial disease (PAD). [5][6][7][8][9][10] Furthermore, patients with premature ASCVD experience similar rates of all-cause and cardiovascular mortality compared with older adults. [11][12][13][14] The use of aspirin and high-intensity statin for secondary prevention of ASCVD is well established and endorsed by multisociety guidelines. [15][16][17][18] A strong association between nonadherence with these secondary prevention measures and increased cardiovascular mortality has also been well demonstrated. 19,20 Whether the similarity in rates of cardiovascular mortality between older patients with ASCVD and younger patients with premature ASCVD is attributable to less aggressive implementation of and adherence with secondary prevention strategies among younger adults remains unknown because it has not been studied. Although a previous investigation evaluated statin use in younger patients, the study was limited to 1 domain of ASCVD (IHD). 21 Hence, a thorough assessment of statin use across the entire spectrum of patients with premature ASCVD is unavailable. Data on statin adherence and the use of aspirin in this population are also scarce.
The primary objective of this cross-sectional study was to evaluate aspirin use, statin use, and statin adherence in patients with premature ASCVD vs in patients with nonpremature ASCVD. We also investigated similar outcomes among patients with extremely premature ASCVD because these individuals are at risk for a higher accrued lifetime morbidity and health care financial burden.

Methods
The study protocol was approved, and informed consent was waived by the institutional review board at Baylor College of Medicine. The data obtained for this study did not involve interaction with any patients and did not include any individually identifiable information. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. 22 Using the US Department of Veterans Affairs (VA) clinical and administrative data sets, we We analyzed patients enrolled in the nationwide Veterans With Premature Atherosclerosis (VITAL) registry, which was created from the large cohort of adults with ASCVD. 28 In accordance with national cardiovascular guidelines, premature ASCVD was defined as the first ASCVD event occurring before age 55 years for men and before age 65 years for women. 29 These adults with premature ASCVD were included in the VITAL registry. Nonpremature ASCVD was defined as the first ASCVD event occurring at age 55 years or older for men or age 65 years or older for women. Furthermore, extremely premature ASCVD was defined as the first ASCVD event occurring before age 40 years.
Patients with nonpremature and extremely premature ASCVD were also included in this study. Aside from patients with missing date of birth or sex data, patients with limited life expectancy, as indicated by a history of metastatic cancer in the past 5 years or receipt of hospice care in the past 12 months, were excluded from the analyses. 30 Clinical data sources in the VA system were used to identify patient age, sex, race/ethnicity, and body mass index (calculated as weight in kilograms divided by height in meters squared). Medical history of hypertension, diabetes, myocardial infarction, IHD, ICVD, and PAD was ascertained from

International Classification of Diseases, Ninth Revision, Clinical Modification and Current Procedural
Terminology codes. The VA data sets included baseline levels of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, triglycerides, lipoprotein A, and apolipoprotein B. The Diagnosis Cost Group (DCG) relative risk score, a well-established and validated surrogate marker of the overall illness burden, was also calculated. 31,32 A DCG relative risk score of 1 signified an average illness burden; a score above 1, a higher-than-average illness burden; and a score below 1, a lowerthan-average illness burden. We also identified various facility-level and clinician-level variables, including receipt of care from a physician vs an advanced practice practitioner (nurse practitioner or physician assistant), a teaching vs nonteaching facility, and an urban vs a rural facility; median number of PCP visits in the 12 months before the index PCP visit; and percentage of patients receiving cardiological and PCP services in the 12 months before the index PCP visit. We ascertained the median number of days from the first ASCVD event to the index PCP visit, nonaspirin antiplatelet use, and anticoagulant use among this cohort.
The primary outcomes in this study were aspirin use, any statin use, high-intensity statin use, and statin adherence, which were ascertained from the VA pharmacy data. The term use referred to an existing prescription for the said medication within 100 days before or 14 days after the index PCP visit. The prescribed statin drugs included atorvastatin, rosuvastatin, pravastatin, fluvastatin, lovastatin, simvastatin, and pitavastatin. In accordance with the national cholesterol guidelines, 33 high-intensity statin was defined as atorvastatin, 40 mg or more, or rosuvastatin, 20 mg or more. We included both aspirin and statin therapy that were prescribed outside the VA health care system if proper notations were made in the VA primary care encounter. Adherence to statin therapy was assessed by the proportion of days covered (PDC), a well-established and validated method that has been documented previously. 32,34 The PDC was calculated by dividing the number of days with (covered by) a certain statin prescription refill by the total number of days within that period. 35 The PDC calculations accounted for changes in statin doses or type of statin and early refills. If statin dose was changed, we assumed pill splitting or doubling to match the new dose from the previous supply.
If the statin type was changed, we assumed the remaining supply of the previous statin was discarded in favor of the new statin. We also accounted for stockpiling by assuming that early refills were not consumed until the previous supply was finished. Based on data from previous studies on medication adherence, 36 patients were deemed to be adherent to statin therapy if the PDC was 0.8 or higher. We measured the PDC both as a categorical variable (Ն0.8 or <0.8) and as a continuous variable. The term adherence referred to the filling or refilling of prescriptions by the patients. continuous variables were analyzed with an unpaired, 2-tailed t test. Two-sided P < .05 was used to indicate statistical significance.
Use of aspirin, any statin, and high-intensity statin and statin adherence were evaluated across patients with premature ASCVD and nonpremature ASCVD. Subsequently, we created multivariable hierarchical logistic and linear regression models to study the association between premature ASCVD and aspirin use, any statin use, high-intensity statin use, and statin adherence. Identical analytical methods were used to study patients with extremely premature ASCVD. The referent category included patients with nonpremature ASCVD.
All analyses were adjusted for sex, race/ethnicity, type of ASCVD, history of obesity, hypertension, diabetes, DCG relative risk score, median number of days from first ASCVD event to index PCP visit, and facility-and clinician-level covariates. The regression models for aspirin use were adjusted for nonaspirin antiplatelet use and anticoagulant use. Generalized linear latent and mixed models adjusted the regression models for facility-level clustering of patients. Analyses were performed with SAS, version 9.1.3 (SAS Institute Inc) and Stata, version 14 (StataCorp LLC) from November 1, 2019, to January 1, 2020.

Results
A total of 1 248 158 patients with ASCVD were identified after excluding patients with missing date of birth or sex data (n = 95), with limited life expectancy (n = 28 316), or with missing DCG relative risk score variable (n = 129). After age-based exclusion was applied, a total of 135 703 patients ( (Figure). The presence of extremely premature ASCVD was also associated with a 56% lower likelihood of statin adherence (OR, 0.44; 95% CI, 0.41-0.47).

Discussion
This study demonstrated that patients with premature ASCVD or extremely premature ASCVD were less likely to receive aspirin and any statin therapy than patients with nonpremature ASCVD. Patients with premature ASCVD were more likely to receive guideline-concordant high-intensity statin, whereas those with extremely premature ASCVD were less likely to receive this medication.
Furthermore, this study showed that all patients, regardless of their age of ASCVD onset, had suboptimal use of these secondary prevention medications. Presence of premature or extremely premature ASCVD was independently associated with lower statin adherence. Such differences between groups were evident despite patients with premature or extremely premature ASCVD having a higher frequency of outpatient encounters with PCPs and cardiovascular specialists than patients with nonpremature ASCVD.
These results present evidence of the existing knowledge gap regarding aspirin and statin use for secondary prevention among patients with premature ASCVD. The rationale behind the observed disparities in prescription patterns is likely multifactorial. Although accurate, the prevailing emphasis on older age as a leading risk factor of ASCVD 37-39 may create the misperception that younger age has protective properties against ASCVD. Furthermore, as observed in this study, the prevalence of metabolic risk factors, such as hypertension and diabetes, was often lower among patients with premature or extremely premature ASCVD. Therefore, it may be hypothesized that in such patients, nontraditional and nonmetabolic risk factors (eg, hereditary thrombophilia, inflammatory disorders) may instead be more prevalent. 40,41 The treatment of nontraditional and nonmetabolic conditions may supersede the secondary prevention of ASCVD. In patients with premature ASCVD, the occurrence of the index ASCVD event at a younger age may be incorrectly perceived as an isolated episode rather than as the true risk for recurrent adverse cardiovascular events.
Therapeutic inertia, which is defined as the lack of initiation or intensification of clinically indicated treatment, 42,43 may also be an important factor in these observed differences. The  Adjusted odds ratios (ORs) represent independent odds of medication use or medication adherence among patients with either premature ASCVD or extremely premature ASCVD compared with patients with nonpremature ASCVD. The true OR has a 95% certainty of falling between the specified CI range. PDC indicates the proportion of days covered. a Aspirin use regression models were adjusted for nonaspirin antiplatelet use and anticoagulant use in addition to sex, race/ethnicity, ischemic heart disease (IHD), obesity (body mass index [BMI] Ն30 [calculated as weight in kilograms divided by height in meters squared]), hypertension, diabetes, clinician type (physician vs advanced practice practitioner [APP]), teaching vs nonteaching facility, urban vs rural facility, number of cardiology visits 12 months before the index primary care physician (PCP) visit, median number of PCP visits 12 months before the index PCP visit, median number of days from first ASCVD event to the index PCP visit, and Diagnostic Cost Group (DCG) relative risk score (marker of the overall illness burden of the patient). b Adjusted for sex, race/ethnicity, IHD, obesity (BMI Ն30), hypertension, diabetes, clinician type (physician vs APP), teaching vs nonteaching facility, urban vs rural facility, number of cardiology visits 12 months before the index PCP visit, median number of PCP visits 12 months before the index PCP visit, median number of days from first ASCVD event to the index PCP visit, and DCG relative risk score. The presence of premature or extremely premature ASCVD was also associated with lower statin adherence. This finding is consistent with the finding in a recent investigation that individuals younger than 55 years were less likely to be statin adherent after a myocardial infarction. 44 Younger patients with premature or extremely premature ASCVD may exhibit unrealistic optimism bias 45,46 and lack the necessary understanding of their disease process to foster optimal statin adherence.
Similarly, an overall higher functional status after the index ASCVD event may be misinterpreted by patients as indicating their reduced need for statin therapy. Although clinical evidence of statinassociated adverse effects based on patient age is lacking, 47 the perceived statin-associated adverse effects among the premature ASCVD population may be another factor in statin discontinuation and lower adherence rates. As previously reported, social determinants, such as health literacy and social support, may be associated with medication adherence. 48 Hence, in the present study, the suboptimal adherence observed among patients with premature or extremely premature ASCVD may be attributed in part to socioeconomic factors. Statin misinformation or misconceptions because of a greater reliance on social media-based or non-clinician-based resources and a comparative lack of experience in long-term medication management 49 may contribute to lower rates of statin adherence in patients, especially in those with premature ASCVD.
To our knowledge, this study was the first to assess the nationwide disparities in aspirin use, statin use, and statin adherence among US veterans with premature or extremely premature ASCVD.
The findings revealed the extent of underuse of and suboptimal adherence to secondary prevention medications in this younger but at-risk population despite adequate clinical encounters with PCPs and cardiovascular specialists. Suboptimal secondary preventive measures in patients with premature ASCVD may be associated with a higher accrued lifetime morbidity risk and financial burden on the health care system. Hence, it is imperative for investigators and health care policy advisors to recognize the presence and implications of the disparities in medication use and adherence. Future efforts are needed to provide clinician and patient education to discredit misperceptions, conduct qualitative and outcomes research into premature ASCVD, and implement research findings. In addition, evidence-based strategies, such as motivational interviewing and the Screening, Brief Intervention and Referral to Treatment approach, may be adopted by clinicians to partially overcome some of the socioeconomic barriers to medication use and adherence.

Limitations
This study has some limitations. Because of the inherent constraints of clinical data sets and the observational design of the study, we were unable to ascertain and adjust for additional confounders, such as health literacy of patients, the presence of polypharmacy, and the presence of statinassociated adverse effects or aspirin allergy. We were unable to integrate data from non-VA pharmacies to identify additional medication filled outside of the VA system, including over-thecounter aspirin use. Although the VA health care system serves a preponderance of older patients with nonpremature ASCVD, the number of younger and female patients with premature ASCVD included in the VITAL registry remained substantially large given the national scope of the data set.
The generalizability of the findings to other non-VA facilities may be imperfect. Abbreviations: ASCVD, atherosclerotic cardiovascular disease; OR, odds ratio; PDC, proportion of days covered. a Patients with extremely premature ASCVD were those who experienced their first ASCVD event before age 40 years.
b Patients with nonpremature ASCVD were those who experienced their first ASCVD event at age 55 years or older for men and age 65 years or older for women.
c Adjusted for sex, race/ethnicity, obesity (body mass index Ն30 [calculated as weight in kilograms divided by height in meters squared]), hypertension, diabetes, type of ASCVD (ischemic heart disease vs peripheral arterial disease vs ischemic cerebrovascular disease), clinician type (physician vs advanced practice practitioner), teaching vs nonteaching facility, urban vs rural facility, number of cardiology visits 12 months before index primary care physician (PCP) visit, median number of PCP visits 12 months before index PCP visit, median number of days from first ASCVD event to the index PCP visit, and Diagnostic Cost Group relative risk score. d Regression model for aspirin use was adjusted for nonaspirin platelet use and anticoagulant use in addition to all of the aforementioned covariates.