Trajectories of P2Y12 inhibitor adherence in patients with acute coronary syndromes.

PURPOSE: P2Y12 inhibitors (P2Y12i) reduce cardiac events after acute coronary syndromes (ACS). However, suboptimal P2Y12i adherence persists. We aimed to examine P2Y12i non-adherence using group-based trajectory methods and to identify adherence predictors. METHODS: We conducted a population-based, retrospective cohort study using administrative data in Ontario, Canada of patients ≥65 years admitted for ACS between April 2014 and March 2018 with a P2Y12i dispensed within 7 days of discharge. We used group-based trajectory models to characterize longitudinal 1-year adherence patterns. Predictors associated with each adherence trajectory were identified by multinomial logistic regression. RESULTS: We included 11 917 patients using clopidogrel and 9763 using ticagrelor, aged [mean ± SD]: 77.33 ± 8.31/73.59 ± 6.79 years; men: 56.2%/65.4%, respectively. We identified 3 longitudinal adherence trajectories, that differed by agent: 75% of clopidogrel and 68% of ticagrelor patients showed a consistently adherent trajectory, while 13%/17% were gradually, and 12%/15% were rapidly non-adherent, respectively (p < 0.001). Differing baseline characteristics in each cohort were associated with observed adherence trajectories. Concomitant atrial fibrillation and prior bleeding history were associated with non-adherence among clopidogrel users. Among ticagrelor users, women and older persons were more likely to be rapidly non-adherent, adherence declining steeply starting 1 month post-ACS. CONCLUSIONS: We identified distinct adherence trajectories for clopidogrel and ticagrelor post-ACS, with 3 out of 4 clopidogrel patients but only 2 out of 3 ticagrelor patients in the consistently adherent trajectory. Intensive interventions targeted to the period of steep adherence decline post-ACS, particularly for women and older persons initiating ticagrelor, and patients with atrial fibrillation on clopidogrel should be considered and investigated further.

Association between immune checkpoint inhibitor-induced myocarditis and concomitant use of thiazide diuretics.

Although an association has been reported between diuretics and myocarditis, it is unclear whether the risk of immune checkpoint inhibitor (ICI)-induced myocarditis is affected by concomitant diuretics. Thus, the aim of this work was to evaluate the impact of concomitant diuretics on ICI-induced myocarditis. This cross-sectional study used disproportionality analysis and a pharmacovigilance database to assess the risk of myocarditis with various diuretics in patients receiving ICIs via the analysis of data entered into the VigiBase database through December 2022. Multiple logistic regression analysis was performed to identify risk factors for myocarditis in patients who received ICIs. A total of 90 611 patients who received ICIs, including 975 cases of myocarditis, were included as the eligible dataset. A disproportionality in myocarditis was observed for loop diuretic use (reporting odds ratio 1.47, 95% confidence interval [CI] 1.02-2.04, P = .03) and thiazide use (reporting odds ratio 1.76, 95% CI 1.20-2.50, P < .01) in patients who received ICIs. The results of the multiple logistic regression analysis showed that the use of thiazides (odds ratio 1.67, 95% CI 1.15-2.34, P < .01) was associated with an increased risk of myocarditis in patients who received ICIs. Our findings may help to predict the risk of myocarditis in patients receiving ICIs.

Prescribing patterns and factors associated with sodium-glucose cotransporter-2 inhibitor prescribing in patients with diabetes mellitus and atherosclerotic cardiovascular disease.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are cardioprotective agents in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease (CVD). Since little is known about their uptake in atherosclerotic CVD, we examined SGLT2 inhibitor prescribing trends and identified potential disparities in prescribing patterns. METHODS: We conducted an observational study using linked population-based health data in Ontario, Canada, from April 2016 to March 2020 of patients aged 65 years or older with concomitant type 2 diabetes and atherosclerotic CVD. To examine prevalent prescribing of SGLT2 inhibitors (canagliflozin, dapagliflozin and empagliflozin), we constructed 4 cross-sectional yearly cohorts from Apr. 1 to Mar. 31 (2016/17, 2017/18, 2018/19 and 2019/20). We estimated prevalent SGLT2 inhibitor prescribing by year and by subgroups, and identified factors associated with SGTL2 inhibitor prescribing using multivariable logistic regression. RESULTS: There were 208 303 patients in our overall cohort (median age 74.0 yr [interquartile range 68.0-80.0 yr], 132 196 [63.5%] male). Although SGLT2 inhibitor prescribing increased over time, from 7.0% to 20.1%, statin prescribing was initially 10-fold higher and later threefold higher than SGLT2 inhibitor prescribing. In 2019/20, SGLT2 inhibitor prescribing was roughly 50% lower among those aged 75 years or older than among those younger than 75 years (12.9% v. 28.3%, p < 0.001) and in women than in men (15.3% v. 22.9%, p < 0.001). Age 75 years or older, female sex, history of heart failure and kidney disease, and low income were independent factors of lower SGLT2 inhibitor prescribing. Among physician specialists, visits to endocrinologists and family physicians were stronger factors of SGLT2 inhibitor prescribing than cardiologist visits. INTERPRETATION: We found that 1 in 5 patients with diabetes and atherosclerotic CVD were prescribed SGLT2 inhibitors in 2019/20, whereas statins were prescribed for 4 of every 5 patients. Although SGLT2 inhibitor prescribing increased over the study period, disparities in adoption by age, sex, socioeconomic status, comorbidities and physician specialty remained.

Hospital-Level Variation in Ticagrelor Use in Patients With Acute Coronary Syndrome.

Background Despite improved outcomes associated with ticagrelor compared with clopidogrel in acute coronary syndrome (ACS), many studies have demonstrated slow adoption of ticagrelor in the United States because of its increased cost. Less is known about how ticagrelor is adopted when there is no added cost consideration. Our objectives were to determine patterns of use of ticagrelor, hospital-level adoption of ticagrelor use, and factors associated with its use after ACS in a publicly funded health care system. Methods and Results We conducted a population-based cohort study including patients (≥65 years) hospitalized with their first ACS from April 2014 to March 2018 in Ontario, Canada. We determined temporal trends in ticagrelor use and hospital-level adoption of its use post-ACS discharge. Using hierarchical regression models, we identified significant predictors of ticagrelor use. There were 23 962 patients with ACS (mean age 76.3 years, 59.7% men) hospitalized in 156 hospitals. Overall ticagrelor use increased from 32.6% in 2014/2015 to 51.8% in 2017/2018. There was substantial variation in ticagrelor use post-ACS across hospitals, with hospital-specific prescribing rates ranging from 0% to 83.6%. Lower odds of ticagrelor use was associated with advanced age and the presence of comorbidities. Besides patient factors, being admitted to a rurally located hospital more than halved the odds of being prescribed ticagrelor (odds ratio [OR], 0.49; 95% CI, 0.32-0.77). Being managed by a cardiologist during the index ACS hospitalization was associated with higher odds of having a ticagrelor prescription after ACS (OR, 2.80; 95% CI, 2.36-3.33). Conclusions Ticagrelor use rates varied substantially across hospitals and were strongly associated with physician and hospital factors independent of patient characteristics.

Health Disparities in Pharmacy Practice Within the Community: Let's Brainstorm for Solutions.

Health disparity is defined as a type of health difference that is closely linked with social, economic and/or environmental disadvantage. Over the past two decades, major efforts have been undertaken to mitigate health disparities and promote health equity in the United States. Within pharmacy practice, health disparities have also been identified to play a role in influencing pharmacists' practice across various clinical settings. However, well-characterized solutions to address such disparities, particularly within pharmacy practice, are lacking in the literature. Recognizing that a significant amount of work will be necessary to reduce or eliminate health disparities, the University of California, Irvine (UCI) School of Pharmacy and Pharmaceutical Sciences held a webinar in June 2021 to explore pertinent issues related to this topic. During the session, participants were given the opportunity to propose and discuss innovative solutions to overcome health disparities in pharmacy practice. The goal of this perspective article is to distill the essence of the presentations and discussions from this interactive session, and to synthesize ideas for practical solutions that can be translated to practice to address this public health problem.

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.

National Trends in the Use of Sacubitril/Valsartan.

BACKGROUND: Better understanding of recent sacubitril/valsartan prescription patterns may help identify factors that influence its use. The aim of the study was to characterize sacubitril/valsartan use and dosage patterns nationally. METHODS AND RESULTS: We conducted a population-level cohort study using IQVIA Inc. National Prescription Audit™ data in the United States from August 2016 to July 2019. Over 3 years, there was a 5.6-fold increase in the number of sacubitril/valsartan prescriptions dispensed per month, totaling 3.3 million prescriptions. For the most recent year, this extrapolates to a best-case scenario of 13.8% of patients with heart failure with reduced ejection fraction using sacubitril/valsartan, representing at most one-half of those eligible for sacubitril/valsartan use. During the most recent year, 48.7% of dispensed prescriptions were for the lowest strength (24/26 mg) and only 20.6% for the target strength (97/103 mg). A greater proportion of the target strength was used in younger patients (< 65years: 24.6%; ≥ 85: 11.1%; P<0.0001). Cardiologists prescribed 59.0% of all dispensed prescriptions, and noncardiologists showed a greater increase (7.5-fold vs 4.9-fold; P<0.0001) over time. CONCLUSIONS: Recent use of sacubitril/valsartan has increased greatly in the United States; however, a substantial proportion of eligible patients with heart failure with reduced ejection fraction did not receive treatment, and only 1 in 5 prescriptions dispensed were for the target strength. Further exploration of barriers to the use of sacubitril/valsartan and dosing uptitration and their clinical implications warrant further evaluation.

Contribution of ATP-Mediated Positive Feedback to Sympathetic Nerve-Induced Positive Inotropy in Guinea Pig Ventricular Myocardium.

The functional role of ATP released from sympathetic nerve terminals was examined in isolated guinea pig ventricular papillary muscles. The contractile force of papillary muscles was increased by field electrical stimulation of sympathetic nerve endings. This increase was attenuated by pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) or suramin, blockers of the P2X receptor, and was abolished by propranolol and prazosin. PPADS, suramin, and ATP affected neither the basal contractile force nor the positive inotropic effect of noradrenaline. These results provide functional evidence that ATP released from sympathetic nerve terminals enhances noradrenaline release and contributes to sympathetic nerve-induced inotropy.

Real-World Adherence and Persistence to Direct Oral Anticoagulants in Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis.

BACKGROUND: Stroke reduction with direct oral anticoagulants (DOACs) in atrial fibrillation (AF) is dependent on adherence and persistence in the real-world setting. Individual study estimates of DOAC adherence/persistence rates have been discordant. Our aims were to characterize real-world observational evidence for DOAC adherence/persistence and evaluate associated clinical outcomes in patients with AF. METHODS AND RESULTS: PubMed, EMBASE, and CINAHL were searched from inception to June 2018. Observational studies that reported real-world DOAC adherence/persistence in patients with AF were included. Study quality was assessed using the Newcastle-Ottawa Scale. Meta-analyses for pooled estimates were performed using DerSimonian and Laird random-effects models. Outcomes included DOAC mean proportion of days covered or medication possession ratio, proportion of good adherence (proportion of days covered/medication possession ratio ≥80%), persistence, DOAC versus vitamin K antagonists persistence, and clinical outcomes associated with nonadherence/nonpersistence. Forty-eight observational studies with 594 784 unique patients with AF (59% male; mean age 71 years) were included. The overall pooled mean proportion of days covered/medication possession ratio was 77% (95% CI, 75%-80%), proportion of patients with good adherence was 66% (95% CI, 63%-70%), and proportion persistent was 69% (95% CI, 65%-72%). The pooled proportion of patients with good adherence was 71% (95% CI, 64%-78%) for apixaban, 60% (95% CI, 52%-68%) for dabigatran, and 70% (95% CI, 64%-75%) for rivaroxaban. Similar patterns were found for pooled persistence by agent. The pooled persistence was higher with DOACs than vitamin K antagonists (odds ratio, 1.44 [95% CI, 1.12-.86]). DOAC nonadherence was associated with an increased risk of stroke (hazard ratio, 1.39 [95% CI, 1.06-1.81]). CONCLUSIONS: Suboptimal adherence and persistence to DOACs was common in patients with AF, with 1 in 3 patients adhering to their DOAC <80% of the time, which was associated with poor clinical outcomes in nonadherent patients. Although it is convenient that DOACs do not require laboratory monitoring, greater effort in monitoring for and interventions to prevent nonadherence may be necessary to optimize stroke prevention. Increased clinician awareness of DOAC nonadherence may help identify at-risk patients.

Cross-cultural Comparison of Pharmacy Students' Attitudes, Knowledge, Practice, and Barriers Regarding Evidence-based Medicine.

Objective. To explore cultural influences on US and Japanese pharmacy students' evidence-based medicine (EBM) attitudes, knowledge, and behavior. Methods. A cross-sectional study was conducted using a self-administered survey. Senior students in one pharmacy school in the United States and two pharmacy schools in Japan were invited to complete a 33-item survey instrument. Results. Students in both countries reported having positive attitudes and understanding of EBM concepts. In their self-evaluation, American students rated their current EBM practice, EBM skills, and access to EBM resources higher than Japanese students rated themselves in these areas. The most common barriers to EBM for American students were lack of time (84.5%), lack of statistical knowledge (63.9%), and lack of critical appraisal skills (53.1%). The most common barriers to EBM for Japanese students were lack of training (92.6%), lack of clinical knowledge (90.4%), and lack of opportunity (88.8%). Conclusion. Although barriers to implementing EBM and confidence levels in using EBM differed between US and Japanese pharmacy students, both cohorts recognized EBM as an important skillset for the pharmacy profession. Culturally specific approaches to teaching EBM to pharmacy students are needed to improve EBM use in practice.