Evidence-Based Cardiovascular Disease Medicines' Availability in Low-Cost Generic Drug Programs in the United States : A Cross-Sectional Study.

BACKGROUND: Low-cost generic programs (LCGPs) that expand access to affordable cardiovascular disease (CVD) medicines can assist patients in achieving desired cardiovascular outcomes. It is important that LCGPs offer CVD medicines that promote evidence-based prescribing. OBJECTIVE: To evaluate LCGPs' coverage of evidence-based CVD medications using a clinical framework that examines coverage of core treatments, coverage of options with the highest-quality evidence, and the variety of medication options and strengths that create choices and allow dosing titration. DESIGN: Cross-sectional study. SETTING: Publicly available LCGPs in March and April 2023 in the United States. PARTICIPANTS: 19 LCGPs. MEASUREMENTS: Proportion of LCGPs that offered evidence-based CVD medicines within a clinical framework for 6 CVDs (atrial fibrillation, heart failure, hyperlipidemia, hypertension, post-acute coronary syndrome secondary prevention, and stable angina) according to 4 availability metrics (breadth, choice, high-quality evidence, and titratability). RESULTS: The availability of CVD medication varied by program, drug, and CVD condition. Some programs had more breadth and choice of coverage for most CVDs (H-E-B, Kroger, Mark Cuban Cost Plus Drug Company, and Walmart), whereas many had more focused coverage and others markedly limited offerings. Nearly all LCGPs offered angiotensin-converting enzyme inhibitors, ß-blockers, thiazides, and moderate-intensity statins, but availability was low for higher-cost or lower-use generics (antiplatelets and antiarrhythmics). Core pharmacotherapy coverage and choices were limited for atrial fibrillation and heart failure but widely available for hypertension and hyperlipidemia. LIMITATION: In-depth cost analysis was not investigated. CONCLUSION: Coverage of evidence-based medications for the 6 CVDs investigated varied by LCGP and condition. Because high availability of core CVD pharmacotherapy can enhance optimal disease state management, LCGPs should identify existing limitations in their coverage and continuously revise their formularies to improve the comprehensiveness of CVD medication coverage. PRIMARY FUNDING SOURCE: None.

Comparison of measures of medication adherence from pharmacy dispensing and insurer claims data.

OBJECTIVE: Medication nonadherence is linked to worsened clinical outcomes and increased costs. Existing system-level adherence interventions rely on insurer claims for patient identification and outcome measurement, yet suffer from incomplete capture and lags in data acquisition. Data from pharmacies regarding prescription filling, captured in retail dispensing, may be more efficient. DATA SOURCES: Pharmacy fill and insurer claims data. STUDY DESIGN: We compared adherence measured using pharmacy fill data to adherence using insurer claims data, expressed as proportion of days covered (PDC) over 12 months. Agreement was evaluated using correlation/validation metrics. We also explored the relationship between adherence in both sources and disease control using prediction modeling. DATA EXTRACTION METHODS: Large pragmatic trial of cardiometabolic disease in an integrated delivery network. PRINCIPAL FINDINGS: Among 1113 patients, adherence was higher in pharmacy fill (mean = 50.0%) versus claims data (mean = 47.4%), although they had moderately high correlation (R = 0.57, 95% CI: 0.53-0.61) with most patients (86.9%) being similarly classified as adherent or nonadherent. Sensitivity and specificity of pharmacy fill versus claims data were high (0.89, 95% CI: 0.86-0.91 and 0.80, 95% CI: 0.75-0.85). Pharmacy fill-based PDC predicted better disease control slightly more than claims-based PDC, although the difference was nonsignificant. CONCLUSIONS: Pharmacy fill data may be an alternative to insurer claims for adherence measurement.

Prior Authorization, Copayments, and Utilization of Sacubitril/Valsartan in Medicare and Commercial Plans in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Slow uptake of sacubitril/valsartan in patients with heart failure with reduced ejection fraction has been reported, which may negatively impact clinical outcomes. We characterized prior authorization (PA) burden, prescription copayment, and utilization of sacubitril/valsartan by insurance plan type to identify potential barriers to its use. METHODS: We conducted a national population-level, cross-sectional study using PA data from an insurance coverage website accessed in March 2019 and IQVIA National Prescription Audit data from August 2018 to July 2019. Primary outcomes were proportion of plans requiring PA, frequency of specific PA criteria, number of sacubitril/valsartan prescriptions, and copayments per insurance plan type. RESULTS: Overall, 48.1% (1394/2896) of insurance plans required PA for sacubitril/valsartan. Fewer Medicare (27.7%) than commercial (57.2%) plans required PA (P<0.001). For both plan types, the most frequently required PA criteria were ejection fraction (71.6%, 90.9%) and New York Heart Association class (60.4%, 90.8%) for Medicare and commercial plans, respectively. Copayment amounts varied by plan type, with more sacubitril/valsartan prescriptions for commercial plans not requiring a patient copayment (32.4%) compared with Medicare plans (19.3%; P<0.001). There were 814 437 sacubitril/valsartan prescriptions for Medicare and 822 292 for commercial plans dispensed from August 2018 to July 2019. Based on estimated heart failure with reduced ejection fraction populations for each plan type, 4-fold more sacubitril/valsartan prescriptions were dispensed in commercial than in Medicare plans (820 versus 215 prescriptions/1000 individuals in the heart failure with reduced ejection fraction population). The estimated proportion of heart failure with reduced ejection fraction patients prescribed sacubitril/valsartan was 3.6% (1.5%-6.8%) for Medicare and 13.7% (4.9%-31.8%) for commercial plan populations. CONCLUSIONS: Despite commercial plans having greater PA requirements than Medicare, population-adjusted use of sacubitril/valsartan was higher in commercial plans. Given that commercial plans had more prescriptions with low copayments than Medicare, copayment policies may be more influential on sacubitril/valsartan use than its PA policies. Low sacubitril/valsartan use in both plan types highlights the multifactorial nature of medication underutilization that includes factors beyond the drug policies that we evaluated.

Comparison of a new 3-item self-reported measure of adherence to medication with pharmacy claims data in patients with cardiometabolic disease.

BACKGROUND: Less than half of patients with cardiometabolic disease consistently take prescribed medications. While health insurers and some delivery organizations use claims to measure adherence, most clinicians do not have access during routine interactions. Self-reported scales exist, but their practical utility is often limited by length or cost. By contrast, the accuracy of a new 3-item self-reported measure has been demonstrated in individuals with HIV. We evaluated its concordance with claims-based adherence measures in cardiometabolic disease. METHODS: We used data from a recently-completed pragmatic trial of patients with cardiometabolic conditions. After 12 months of follow-up, intervention subjects were mailed a survey with the 3-item measure that queries about medication use in the prior 30 days. Responses were linearly transformed and averaged. Adherence was also measured in claims in month 12 and months 1-12 of the trial using proportion of days covered (PDC) metrics. We compared validation metrics for non-adherence for self-report (average <0.80) compared with claims (PDC <0.80). RESULTS: Of 459 patients returning the survey (response rate: 43.5%), 50.1% were non-adherent in claims in month 12 while 20.9% were non-adherent based on the survey. Specificity of the 3-item metric for non-adherence was high (month 12: 0.83). Sensitivity was relatively poor (month 12: 0.25). Month 12 positive and negative predictive values were 0.59 and 0.52, respectively. CONCLUSIONS: A 3-item self-reported measure has high specificity but poor sensitivity for non-adherence versus claims in cardiometabolic disease. Despite this, the tool could help target those needing adherence support, particularly in the absence of claims data.

Clinical Outcomes With Beta-Blocker Use in Patients With Recent History of Myocardial Infarction.

BACKGROUND: It is uncertain whether beta-blockers (BBs) are beneficial in contemporary stable patients with prior myocardial infarction (MI). Therefore, we sought to examine the effectiveness of BB use in this population. METHODS: We conducted a cohort study with the use of administrative databases of patients ≥ 65 years of age, alive on April 1, 2012 (index date) with a hospital discharge diagnosis of MI within the previous 3 years. The primary outcome was time to death or hospitalization for MI or angina 1 year after the index date, with inverse probability of treatment weighting. RESULTS: We included 33,811 patients with prior MI, of whom 21,440 (63.4%) were dispensed a BB. The median age was 78 years, and 56% were male. There was no difference in the 1-year hazard of death/hospitalization for MI or angina (14.8% vs 14.7%, hazard ratio 1.00, 95% confidence interval 0.94-1.07; P = 0.90) in those receiving vs not receiving BB. Similarly, there was no difference in the individual end points in composite nor in 3-year outcomes. Subgroup analysis by age, sex, MI timing, MI type, heart failure, and atrial fibrillation found no benefit. Patients with a history of revascularisation treated with BBs had a lower rate of the composite outcome compared with those without such history (P = 0.006 for interaction) at 1 year but not at 3 years. CONCLUSIONS: In this large contemporary population-based observational study of older stable patients with prior MI, BBs were not associated with a reduction in major cardiovascular events or mortality in those with MI within the previous 3 years. This study supports the need to conduct contemporary clinical trials evaluating the use of BBs after MI.

Eligibility, Clinical Outcomes, and Budget Impact of PCSK9 Inhibitor Adoption: The CANHEART PCSK9 Study.

Background The FOURIER (Further Cardiovascular Outcomes Research With PCSK9i [Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors] in Subjects With Elevated Risk) trial found a reduction in cardiovascular events in patients with atherosclerotic cardiovascular disease ( ASCVD ). Our objective was to estimate the eligibility, clinical outcomes, and budget impact of adopting PCSK 9i in a large healthcare system. Methods and Results Ontario, Canada, residents alive in 2011, aged 40 to 85 years, were eligible for inclusion. PCSK 9i eligibility was determined on the basis of FOURIER trial definition. Hazard ratios observed in the FOURIER trial were applied to assess the number of events that could be avoided. Budget impact was calculated as the difference between projected costs of treatment adoption and events avoided if PCSK 9i were used. Of the 2.4 million included individuals, 5.3% had a history of ASCVD . We estimated that 2.7% of the general population and 51.9% of the patients with ASCVD would be eligible for PCSK 9i. Adoption of PCSK 9i in all eligible patients with ASCVD was projected to reduce primary events rates by 1.8% after 3 years. Despite cost reduction of $44 million in events, PCSK 9i adoption would have a net budget impact of $1.5 billion over 3 years. Potential benefits of PCSK 9i varied widely across subgroups, with the largest absolute risk reduction estimated to be 4.3% at 3 years in peripheral artery disease. In this subgroup of 5601 patients, the budget impact of treatment adoption was $116 million. Conclusions We estimated that ≈1 in 2 patients with ASCVD would be eligible for PCSK 9i. The budget impact of adopting PCSK 9i for all patients with ASCVD is substantial. Selective adoption to high-risk patients will lessen the overall budgetary impact of PCSK 9i treatment.

Clinical Outcomes of Plavix and Generic Clopidogrel for Patients Hospitalized With an Acute Coronary Syndrome.

BACKGROUND: Clopidogrel is one of the most commonly prescribed medications because of its ability to improve clinical outcomes for a broad range of cardiovascular conditions. After patent protection expired for Plavix in 2012, many healthcare systems adopted generic clopidogrel as a strategy to reduce healthcare costs. METHODS AND RESULTS: We conducted a population-based observational study to determine whether generic clopidogrel was noninferior to Plavix. Patients who were hospitalized with an acute coronary syndrome (ACS) from 2009 to 2014 in Ontario, Canada, >65 years, survived ≥7 days after discharge, were eligible for inclusion. The primary outcome was a composite of death and recurrent ACS at 1 year. The noninferiority margin was prespecified at a relative hazard difference of 10%. Inverse propensity of treatment weighting of the propensity score was used to account for differences in baseline characteristics between the treatment groups. The effect of clopidogrel on the hazard of clinical outcomes was estimated using a Cox proportional hazards model within the propensity-weighted cohort using Plavix as a reference. Our study included 24 530 patients with ACS, 12 643 were prescribed Plavix and 11 887 were prescribed generic clopidogrel at hospital discharge. The mean age was 77 years, 57% were men, and 21% had an ST-segment-elevation myocardial infarction. At 1 year, 17.6% of patients prescribed Plavix and 17.9% of patients prescribed clopidogrel experienced the primary outcome (hazard ratio, 1.02; 95% confidence interval, 0.96-1.08; P=0.005 for noninferiority). No significant differences between rates of death, all-cause readmission, ACS, stroke or transient ischemic attack, or bleeding were observed. CONCLUSIONS: Generic clopidogrel was noninferior to Plavix with respect to the composite end point of death and recurrent hospitalization for ACS at 1 year among adults >65 years after an ACS hospitalization. Our findings support generic clopidogrel in ACS, which could lead to substantial healthcare cost savings.

The impact of drug shortages on patients with cardiovascular disease: causes, consequences, and a call to action.

Shortages of cardiovascular drugs have become increasingly common, representing an ongoing public health crisis. Given few therapeutic alternatives to many of the drugs in short supply, these shortages also pose a major challenge for cardiovascular care professionals. Although changes in the regulatory environment have led to some improvements in recent years, problems involving manufacturing processes remain the most common underlying cause. Because of the complex nature of drug shortages, sustainable solutions to prevent and mitigate them will require collaboration between regulatory agencies, drug manufacturers, and other key stakeholder groups. In this report, we describe the scope of the cardiovascular drug shortage crisis in the United States, including its underlying causes and the efforts currently being made to address it. Furthermore, we provide specific recommendations for how cardiovascular care professionals can be involved in efforts to limit the impact of drug shortages on patient care as well as policy changes aimed at preventing and mitigating them.

Potential benefit of electronic pharmacy claims data to prevent medication history errors and resultant inpatient order errors.

OBJECTIVE: We sought to assess the potential of a widely available source of electronic medication data to prevent medication history errors and resultant inpatient order errors. METHODS: We used admission medication history (AMH) data from a recent clinical trial that identified 1017 AMH errors and 419 resultant inpatient order errors among 194 hospital admissions of predominantly older adult patients on complex medication regimens. Among the subset of patients for whom we could access current Surescripts electronic pharmacy claims data (SEPCD), two pharmacists independently assessed error severity and our main outcome, which was whether SEPCD (1) was unrelated to the medication error; (2) probably would not have prevented the error; (3) might have prevented the error; or (4) probably would have prevented the error. RESULTS: Seventy patients had both AMH errors and current, accessible SEPCD. SEPCD probably would have prevented 110 (35%) of 315 AMH errors and 46 (31%) of 147 resultant inpatient order errors. When we excluded the least severe medication errors, SEPCD probably would have prevented 99 (47%) of 209 AMH errors and 37 (61%) of 61 resultant inpatient order errors. SEPCD probably would have prevented at least one AMH error in 42 (60%) of 70 patients. CONCLUSION: When current SEPCD was available for older adult patients on complex medication regimens, it had substantial potential to prevent AMH errors and resultant inpatient order errors, with greater potential to prevent more severe errors. Further study is needed to measure the benefit of SEPCD in actual use at hospital admission.

Effect of electronic prescribing with formulary decision support on medication tier, copayments, and adherence.

BACKGROUND: Medication non-adherence is prevalent. We assessed the effect of electronic prescribing (e-prescribing) with formulary decision support on preferred formulary tier usage, copayment, and concomitant adherence. METHODS: We retrospectively analyzed 14,682 initial pharmaceutical claims for angiotensin receptor blocker and inhaled steroid medications among 14,410 patients of 2189 primary care physicians (PCPs) who were offered e-prescribing with formulary decision support, including 297 PCPs who adopted it. Formulary decision support was initially non-interruptive, such that formulary tier symbols were displayed adjacent to medication names. Subsequently, interruptive formulary decision support alerts also interrupted e-prescribing when preferred-tier alternatives were available. A difference in differences design was used to compare the pre-post differences in medication tier for each new prescription attributed to non-adopters, low user (<30% usage rate), and high user PCPs (>30% usage rate). Second, we modeled the effect of formulary tier on prescription copayment. Last, we modeled the effect of copayment on adherence (proportion of days covered) to each new medication. RESULTS: Compared with non-adopters, high users of e-prescribing were more likely to prescribe preferred-tier medications (vs. non-preferred tier) when both non-interruptive and interruptive formulary decision support were in place (OR 1.9 [95% CI 1.0-3.4], p = 0.04), but no more likely to prescribe preferred-tier when only non-interruptive formulary decision support was in place (p = 0.90). Preferred-tier claims had only slightly lower mean monthly copayments than non-preferred tier claims (angiotensin receptor blocker: $10.60 versus $11.81, inhaled steroid: $14.86 versus $16.42, p < 0.0001). Medication possession ratio was 8% lower for each $1.00 increase in monthly copayment to the one quarter power (p < 0.0001). However, we detected no significant direct association between formulary decision support usage and adherence. CONCLUSION: Interruptive formulary decision support shifted prescribing toward preferred tiers, but these medications were only minimally less expensive in the studied patient population. In this context, formulary decision support did not significantly increase adherence. To impact cost-related non-adherence, formulary decision support will likely need to be paired with complementary drug benefit design. Formulary decision support should be studied further, with particular attention to its effect on adherence in the setting of different benefit designs.

Trends in use of ezetimibe after the ENHANCE trial, 2007 through 2010.

IMPORTANCE: Results from the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, announced in January 2008, demonstrated that ezetimibe use lowered cholesterol levels but did not slow the progression of atherosclerosis. OBJECTIVE: To examine the association of this announcement with national patterns of ezetimibe prescribing, including medication initiation and discontinuation, as well as predictors of use. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of a national sample of adults 18 years or older who were continuously enrolled in plans of a large US pharmacy benefit manager from 2007 to 2010. MAIN OUTCOMES AND MEASURES: Lipid-lowering therapy prescription claims were categorized as ezetimibe-containing treatments or any other lipid-lowering agent. Initiation was defined as an ezetimibe claim without another in the prior 180 days; discontinuation, as an ezetimibe claim without another in the subsequent 180 days. RESULTS: From 2007 to 2010, 29.1% of the 10,597,296 continuously eligible adults obtained at least 1 lipid-lowering agent prescription. Among these adults, 17.8% were prescribed ezetimibe and 95.3% another lipid-lowering agent, predominantly statins. Ezetimibe use peaked in January 2008, when 2.5% of all adults were ezetimibe users, but declined to 1.8% by December 2010. The ENHANCE trial announcement was associated with a nonsignificant 0.16% fewer monthly ezetimibe users (P = .11) but a significant 0.14% more monthly monotherapy users and 0.30% fewer users of ezetimibe concomitant with other lipid-lowering agents (both P = .01). The ENHANCE trial was also associated with 0.44% fewer monthly ezetimibe initiations (P = .002) and 10.4% more monthly ezetimibe discontinuations (P < .001), particularly of ezetimibe monotherapy for both. More than half of adults who initiated ezetimibe use did so without first being prescribed another lipid-lowering agent, both before (50%-60%) and after (60%-70%) the trial. Those aged 50 to 64 years and those living in the East South Central US Census division were both more likely to initiate and less likely to discontinue ezetimibe after the ENHANCE trial. CONCLUSIONS AND RELEVANCE: After announcement of the results of the ENHANCE trial, nearly 2% of all continuously enrolled adult beneficiaries within a large US pharmacy benefit manager used ezetimibe, although ezetimibe initiations declined and discontinuations increased.

Impact of drug policy on regional trends in ezetimibe use.

BACKGROUND: Ezetimibe use has steadily increased in Canada during the past decade even in the absence of evidence demonstrating a beneficial effect on clinical outcomes. Among the 4 most populated provinces in Canada, there is a gradient in the restrictiveness of ezetimibe in public-funded formularies (most to least strict: British Columbia, Alberta, Quebec, and Ontario). The effect of formulary policy on the use of ezetimibe over time is unknown. METHODS AND RESULTS: We conducted a population-level cohort study using Intercontinental Marketing Services Health Canada's data from June 2003 to December 2012 to examine ezetimibe use in these 4 provinces to better understand the association between use and formulary restrictiveness. We found regional variations in the patterns of ezetimibe use. From June 2003 to December 2012, British Columbia (most restrictive) had the lowest monthly increasing rate from $261 to $21 926 ($190/100 000 population/mo), whereas Ontario (least restrictive) had the most rapid monthly increase from $223 to $74 030 ($ 647/100 000 population/mo), and Quebec from $130 to $59 690 ($522/100 000 population/mo) and Alberta from $356 to $ 37 604 ($327/100 000 population/mo) were intermediate (P<0.001). CONCLUSIONS: Ezetimibe use remains common, increasing during the past decade. Use steadily increased in provinces with the most lenient formularies. In contrast, use was lower, plateauing since 2008 in British Columbia and Alberta, which have more restrictive formularies. The gradient in ezetimibe use was related to variability in restrictiveness of the provincial formularies, illustrating the potential of a policy response gradient that may be used to more effectively manage medication use.

The pharmacist role in predicting and improving medication adherence in heart failure patients.

BACKGROUND: Heart failure is one of the most common reasons for hospital admissions in patients aged 65 years and older, with an estimated 1 million hospitalizations annually. In 2010, health care expenditures for heart failure were estimated to be $32 billion. Nonadherence to medications and lifestyle contributes to hospital admissions in up to one-third of patients. Efforts to reduce readmissions are of critical importance. Pharmacist involvement in the management of heart failure patients has been shown to reduce heart failure hospitalizations, with trends towards a reduction in mortality. Literature is scarce on instruments that clinicians can use to identify patients at risk for medication nonadherence. OBJECTIVES: To (a) describe factors that predict medication adherence for patients with heart failure, (b) evaluate the impact and value of pharmacist interventions on adherence and outcomes, and (c) assess tools to predict medication nonadherence in heart failure patients. METHODS: From inception to September 2013, a search was conducted in the databases MEDLINE, PubMed, CINAHL, and The Cochrane Library to identify relevant studies for 3 separate searches, identifying predictors of medication adherence in heart failure patients, pharmacist involvement to impact medication adherence, and tools to predict medication nonadherence in this population. RESULTS: Many significant predictors of both medication adherence and nonadherence have been identified in heart failure patients. Studies evaluating the effect of pharmacist involvement in the management of heart failure demonstrated improvements in medication adherence that dissipated once the intervention was withdrawn. The Morisky Medication Adherence Scale and the Merck Adherence Estimator are simple and practical tools that may be useful for identifying nonadherence in heart failure patients. CONCLUSIONS: Clinicians should be cognizant of factors that may affect medication adherence in heart failure patients and be aware of instruments available to predict the risk for medication nonadherence. Pharmacist interventions should be part of a multidisciplinary system of care initiated at discharge that involve personal contact and are continued indefinitely in order to sustain these benefits.

Impact of the ENHANCE trial on the use of ezetimibe in the United States and Canada.

BACKGROUND: We previously found that the use of ezetimibe increased rapidly with different patterns between the United States (US) and Canada prior to the landmark Ezetimibe and Simvastatin in Hypercholesterolemia Enhance Atherosclerosis Regression (ENHANCE) trial, which was reported in January 2008, and failed to show that the drug slowed the progression of atherosclerosis. What is not known is how practice in the 2 countries changed after the ENHANCE trial. We examined ezetimibe use trends in the US and Canada before and after the reporting of the ENHANCE trial. METHODS: We conducted a population-based, retrospective, time-series analysis using the data collected by IMS Health in the US and CompuScript in Canada from January 1, 2002, to December 31, 2009. The main outcome measure was monthly number of prescriptions for ezetimibe-containing products. RESULTS: The monthly number of ezetimibe prescriptions/100,000 population rose from 6 to 1,082 in the US from November 2002 to January 2008, then significantly declined to 572/100,000 population by December 2009 after the release of the ENHANCE trial, a decrease of 47.1% (P < .001). In contrast, in Canada, use continuously rose from 2 to 495/100,000 population from June 2003 to December 2009 (P = .2). United States expenditures totaled $2.24 billion in 2009. CONCLUSIONS: Ezetimibe remains commonly used in both the US and Canada. Ezetimibe use has decreased in the US post-ENHANCE, whereas use has gradually but steadily increased in Canada. The diverging patterns of ezetimibe use in the US and Canada require further investigation, as they reveal that a common evidence base is eliciting very different utilization patterns in neighboring countries.

When choosing statin therapy: the case for generics.

The development of "Top 5" lists across specialties and at regular intervals can help to remind physicians that optimal care is often possible at a lower cost. For purposes of cardiovascular risk reduction, generic statins, or their brand equivalents if priced similarly, remain the appropriate choice for dyslipidemic patients initiating statin therapy. In this article, we review the evidence supporting the choice of generic statins.