Modifiable statin characteristics associated with potential statin-related prescribing cascades.

STUDY OBJECTIVE: Clinicians may prescribe new medications (marker drug) to treat statin-related (index drug) adverse events, constituting a prescribing cascade. We aimed to identify modifiable statin characteristics (intensity and individual statin agents) associated with lower risk of prescribing cascades to inform clinical decisions in the presence of statin-related adverse events. DESIGN: A secondary analysis based on our previous work, a high-throughput sequence symmetry analysis screening for potential statin-related prescribing cascades. DATA SOURCE: MarketScan Commercial and Medicare Supplemental Insurance claims databases between 2005 and 2019. PATIENTS: Adults who initiated a statin between 2007 and 2018, and who were continuously enrolled in the same healthcare plan for at least 720 days before and 360 days after statin initiation. INTERVENTION: Among the previously identified 57 potential prescribing cascades, 42 statin-marker class dyad with a sample size of ≥ 500 were assessed in this study. MEASUREMENTS: We measured patients' baseline characteristics within -360 days of statin initiation and reported by modifiable statin characteristics. We also performed logistic regression and reported the adjusted odds ratios (aOR) with 95% confidence intervals (CI) of modifiable statin characteristics after adjusting for baseline characteristics. MAIN RESULTS: We identified 1,307,867 statin initiators who met the study criteria (21% elderly, 52% female). Compared with patients initiating low-intensity statins, those initiating moderate- or high-intensity statins had significantly greater odds to develop 29 (69%) prescribing cascades, including antidiabetic drugs such as dipeptidyl peptidase 4 (DPP-4) inhibitors (aOR 1.22; 95% CI, 1.11-1.35) and glucagon-like peptide-1 (GLP-1) analogs (aOR 1.31; 95% CI, 1.16-1.47), and opioids (aOR 1.18; 95% CI, 1.13-1.23). Individual statin agent selection also had a differential effect on 34 (81%) of the prescribing cascades. For example, compared with simvastatin initiators, the probability of initiating osmotically acting laxatives was significantly higher for lovastatin initiators (aOR 1.09; 95% CI, 1.03-1.15) and significantly lower in atorvastatin initiators (aOR 0.92; 95% CI, 0.89-0.94). CONCLUSION: Compared with low-intensity statins, high-intensity statins are associated with increased risk in many potential prescribing cascades, while the choice of individual statin agents affects the risk of prescribing cascades bidirectionally.

High-throughput screening for prescribing cascades among real world statin initiators.

PURPOSE: Statins are among the most prevalent medications prescribed and associated with adverse events that may prompt additional treatment (i.e., a prescribing cascade). No comprehensive assessment of statin-related prescribing cascades has been performed to our knowledge. METHODS: We utilized sequence symmetry analysis to iteratively screen prescribing sequences of all therapeutic classes ("marker" classes) based on Level 4 Anatomical Therapeutic Chemical codes among adult statin initiators, using IBM Marketscan commercial and Medicare supplemental claims databases (2005-2019). Order of initiation and secular trend-adjusted sequence ratios were calculated for each statin-marker class dyad, among marker class initiators ±90 days of statin initiation. Among signals classified as prescribing cascades, we calculated naturalistic number needed to harm (NNTH) within 1 year as the inverse of the excess risk among exposed. RESULTS: We identified 2 265 519 statin initiators (mean ± SD age, 56.4 ± 12.0 years; 48.7% women; 7.5% with cardiovascular disease). Simvastatin (34.4% of statin initiators) and atorvastatin (33.9%) were the most commonly initiated statins. We identified 160 significant statin-marker class dyad signals, of which 35.6% (n = 57) were classified as potential prescribing cascades. Of the top 25 strongest signals (lowest NNTH), 12 were classified as potential prescribing cascades, including osmotically acting laxatives (NNTH, 44, 95% CI 43-46), opioids + non-opioid combination analgesics (81, 95% CI 74-91), and first-generation cephalosporins (204, 95% CI 175-246). CONCLUSIONS: Using high-throughput sequence symmetry analysis screening, we identified previously known prescribing cascades as well as potentially new prescribing cascades based on known and unknown statin-related adverse events.

Initial Antihypertensive Regimens in Newly Treated Patients: Real World Evidence From the OneFlorida+ Clinical Research Network.

Background Knowledge of real-world antihypertensive use is limited to prevalent hypertension, limiting our understanding of how treatment evolves and its contribution to persistently poor blood pressure control. We sought to characterize antihypertensive initiation among new users. Methods and Results Using Medicaid and Medicare data from the OneFlorida+ Clinical Research Consortium, we identified new users of ≥1 first-line antihypertensives (angiotensin-converting enzyme inhibitor, calcium channel blocker, angiotensin receptor blocker, thiazide diuretic, or ß-blocker) between 2013 and 2021 among adults with diagnosed hypertension, and no antihypertensive fill during the prior 12 months. We evaluated initial antihypertensive regimens by class and drug overall and across study years and examined variation in antihypertensive initiation across demographics (sex, race, and ethnicity) and comorbidity (chronic kidney disease, diabetes, and atherosclerotic cardiovascular disease). We identified 143 054 patients initiating 188 995 antihypertensives (75% monotherapy; 25% combination therapy), with mean age 59 years and 57% of whom were women. The most commonly initiated antihypertensive class overall was angiotensin-converting enzyme inhibitors (39%) followed by ß-blockers (31%), calcium channel blockers (24%), thiazides (19%), and angiotensin receptor blockers (11%). With the exception of ß-blockers, a single drug accounted for ≥75% of use of each class. ß-blocker use decreased (35%-26%), and calcium channel blocker use increased (24%-28%) over the study period, while initiation of most other classes remained relatively stable. We also observed significant differences in antihypertensive selection across demographic and comorbidity strata. Conclusions These findings indicate that substantial variation exists in initial antihypertensive prescribing, and there remain significant gaps between current guideline recommendations and real-world implementation in early hypertension care.

Comparative Safety and Effectiveness of Aldosterone Antagonists Versus Beta-Blockers as Fourth Agents in Patients With Apparent Resistant Hypertension.

BACKGROUND: Limited evidence exists regarding long-term effectiveness and safety of aldosterone antagonists (AAs) versus beta blockers (BBs) as fourth-line antihypertensive agents in patients with resistant hypertension (RH). We evaluated the comparative effectiveness and safety of aldosterone AA versus BB. METHODS: We conducted a real-world retrospective cohort study using IBM MarketScan commercial claims and Medicare Supplemental claims (2007-2019). Patients with RH entered the cohort (ie, index date) when they newly initiated either AA or BB. The effectiveness outcome was major adverse cardiovascular events. Safety outcomes were hyperkalemia, gynecomastia, and kidney function deterioration. Potential confounding was addressed by adjustment for baseline characteristics via stabilized inverse probability of treatment weighting (SIPTW) based on propensity scores. Cox proportional hazards regression with SIPTWs were used to estimate adjusted hazard ratio (aHR) and 95% CI comparing risk for outcomes between AA and BB groups. RESULTS: We identified 80 598 patients with RH (mean age: 61 years, 51% males), of which 6626 initiated AA and 73 972 initiated BB as the fourth antihypertensive agent. Among patients with RH, initiation of AA as a fourth-line antihypertensive agent did not significantly reduce major adverse cardiovascular event risk relative to BB initiation (aHR, 0.77 [95% CI, 0.50-1.19]) but did substantially increase the risk of hyperkalemia (aHR, 3.86 [95% CI, 2.78-5.34]), gynecomastia (aHR, 9.51 [95% CI, 5.69-15.89]), and kidney function deterioration (aHR, 1.63 [95% CI, 1.34-1.99]). CONCLUSIONS: Long-term clinical trials powered to assess major adverse cardiovascular events are necessary to understand the risk-benefit trade-off of AA as fourth-line therapy for RH.

Medicare Bundled Payment Policy on Anemia Care, Major Adverse Cardiovascular Events, and Mortality among Adults Undergoing Hemodialysis.

BACKGROUND AND OBJECTIVES: In 2011, the Centers for Medicare & Medicaid Services implemented bundling of all services for patients receiving dialysis, including erythropoietin-stimulating agents use, and the Food and Drug Administration recommended conservative erythropoietin-stimulating agent dosing. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective cohort study investigated anemia care and clinical outcomes before and after the Centers for Medicare & Medicaid Services bundled payment and the revised Food and Drug Administration-recommended erythropoietin-stimulating agent labeling for Medicare-insured adults receiving hemodialysis using data from the United States Renal Data System from January 1, 2006 to December 31, 2016. Clinical outcomes included major adverse cardiovascular event (stroke, acute myocardial infarction, and all-cause mortality), cardiovascular mortality, and heart failure. Measurements were compared between prepolicy (2006-2010) and postpolicy (2012-2016) implementation using interrupted time series and Cox proportional hazards regression models. RESULTS: Of 481,564 patients, erythropoietin-stimulating agent use immediately decreased by 84.8 per 1000 persons (P<0.001), with a significant decrease in the slope of the trend line (both P=0.001). Blood transfusion use rapidly increased by 8.34 per 1000 persons in April 2012 and then gradually decreased (both P=0.001). The percentage of patients with hemoglobin >11 g/dl decreased from 68% in January 2006 to 28% in December 2016, whereas those with hemoglobin <9 g/dl increased from 5% to 9%. Overall major adverse cardiovascular event (adjusted hazard ratio, 0.95; 95% confidence interval, 0.94 to 0.96), stroke (adjusted hazard ratio, 0.83; 95% confidence interval, 0.80 to 0.86), all-cause mortality (adjusted hazard ratio, 0.87; 95% confidence interval, 0.86 to 0.89), cardiovascular mortality (adjusted hazard ratio, 0.81; 95% confidence interval, 0.79 to 0.83), and heart failure (adjusted hazard ratio, 0.86; 95% confidence interval, 0.84 to 0.88) risks were lower. Acute myocardial infarction risk (adjusted hazard ratio, 1.04; 95% confidence interval, 1.01 to 1.06) was higher after policies changed. CONCLUSIONS: The Medicare reimbursement policy and Food and Drug Administration-recommended erythropoietin-stimulating agent dosing changes were associated with lower erythropoietin-stimulating agent use and lower hemoglobin levels. These changes in anemia care were associated with lower risks of major adverse cardiovascular event, stroke, mortality, and heart failure but higher risk of acute myocardial infarction among adults receiving hemodialysis.

Assessment of Vascular Dysfunction in Patients Without Obstructive Coronary Artery Disease: Why, How, and When.

Ischemic heart disease secondary to coronary vascular dysfunction causes angina and impairs quality of life and prognosis. About one-half of patients with symptoms and signs of ischemia turn out not to have obstructive coronary artery disease, and coronary vascular dysfunction may be relevant. Adjunctive tests of coronary vasomotion include guidewire-based techniques with adenosine and reactivity testing, typically by intracoronary infusion of acetylcholine. The CorMicA (Coronary Microvascular Angina) trial provided evidence that routine management guided by an interventional diagnostic procedure and stratified therapy improves angina and quality of life in patients with angina but no obstructive coronary artery disease. In this paper, the COVADIS study group provide a comprehensive review of why, how, and when coronary vascular dysfunction should be assessed invasively. They discuss the rationale through a shared understanding of vascular pathophysiology and clinical evidence. They propose a consensus approach to how an interventional diagnostic procedure is performed with focus on practical aspects. Finally, the authors discuss the clinical scenarios in patients with stable and acute coronary syndromes in which measurement of coronary vascular function may be helpful for patient care.

Novel Self-Report Tool for Cardiovascular Risk Assessment.

Background The currently used atherosclerotic cardiovascular disease risk calculator relies on several measured variables and does not incorporate some well-established risk factors such as family history of premature myocardial infarction and other nontraditional risk factors. Our study aimed to develop and validate a simple risk score to predict 10-year risk of incident cardiovascular events using patient-reported information. Methods and Results Using data from the Atherosclerosis Risk in Communities cohort, we identified adults with no previous history of cardiovascular disease and randomly divided the cohort into "development" (70%) and "validation" (30%) subgroups. Adjusted Cox regression modeling was used to develop a prediction model. The predictive performance of the new risk score was compared with the score derived from the atherosclerotic cardiovascular disease risk calculator. A total of 9285 individuals met the inclusion criteria. During follow-up (median 8.93 years), a total of 694 (7.47%) incident cardiovascular events occurred. The following 6 factors were included: male sex, age, current smoking, diabetes mellitus, hypertension, and family history of premature myocardial infarction. The C-statistic was 0.72 in the validation cohort with good calibration. The area under the curve for the simple risk score was comparable to the atherosclerotic cardiovascular disease risk score. Conclusions The novel simple risk score is an easy-to-use tool to predict cardiovascular events in adults from self-reported information without need for laboratory or physical examination data. This risk score included 6-items and had comparable predictive performance to the guideline recommended atherosclerotic cardiovascular disease risk score but relies solely on self-reported information.

Mechanisms and diagnostic evaluation of persistent or recurrent angina following percutaneous coronary revascularization.

Persistence or recurrence of angina after a percutaneous coronary intervention (PCI) may affect about 20-40% of patients during short-medium-term follow-up. This appears to be true even when PCI is 'optimized' using physiology-guided approaches and drug-eluting stents. Importantly, persistent or recurrent angina post-PCI is associated with a significant economic burden. Healthcare costs may be almost two-fold higher among patients with persistent or recurrent angina post-PCI vs. those who become symptom-free. However, practice guideline recommendations regarding the management of patients with angina post-PCI are unclear. Gaps in evidence into the mechanisms of post-PCI angina are relevant, and more research seems warranted. The purpose of this document is to review potential mechanisms for the persistence or recurrence of angina post-PCI, propose a practical diagnostic algorithm, and summarize current knowledge gaps.

Prevalence, Causes, and Predictors of 30-Day Readmissions Following Hospitalization With Acute Myocardial Infarction Complicated By Cardiogenic Shock: Findings From the 2013-2014 National Readmissions Database.

BACKGROUND: Prior studies have shown that survivors of acute myocardial infarction (AMI) complicated by cardiogenic shock are likely to have increased risk of readmissions in the early post-discharge period. However, the contemporary prevalence, reasons, and predictors of 30-day readmissions are not well known. METHODS AND RESULTS: Hospitalizations for a primary diagnosis of AMI complicated by cardiogenic shock, and discharged alive, were identified in the 2013 and 2014 Nationwide Readmissions Databases. Prevalence and reasons for 30-day unplanned readmissions were investigated. A hierarchical logistic regression model was used to identify independent predictors of 30-day readmissions. Among 1 116 933 patient hospitalizations with AMI, 39 807 (3.6%) had cardiogenic shock and were discharged alive. Their 30-day readmission rate was 18.6%, with a median time for readmission 10 days post discharge. Predictors of readmission included: non-ST-segment elevation myocardial infarction, female sex, low-income status, nonprivate insurance, chronic renal failure, long-term ventricular assist device or intra-aortic balloon placement, and tachyarrhythmia. The majority of readmissions were attributable to cardiac-related causes (52%); heart failure being the most frequent cardiac cause (39% of all cardiac causes). Noncardiac-related readmissions included infections (14.9%), bleeding (5.3%), and respiratory causes (4.9%). The median cost per readmission was $9473 US dollars ($5037-20 199). CONCLUSIONS: Among survivors of AMI complicated by cardiogenic shock who were discharged from hospital, almost 1 in 5 are readmitted at 30 days, mainly because of cardiac reasons such as heart failure and new AMI. The risk of readmission was associated with certain baseline patient/hospital characteristics.

Quality and Equitable Health Care Gaps for Women: Attributions to Sex Differences in Cardiovascular Medicine.

The present review synthesizes evidence and discusses issues related to health care quality and equity for women, including minority population subgroups. The principle of "sameness" or women and men receiving equitable, high-quality care is a near-term target, but optimal population health cannot be achieved without consideration of the unique, gendered structural determinants of health and the development of unique care pathways optimized for women. The aim of this review is to promote enhanced awareness, develop critical thinking in sex and gender science, and identify strategic pathways to improve the cardiovascular health of women. Delineation of the components of high-quality health care, including a women-specific research agenda, remains a vital part of strategic planning to improve the lives of women at risk for or living with cardiovascular disease.

Use of bio-informatics assessment schema (BIAS) to improve diagnosis and prognosis of myocardial perfusion data: results from the NHLBI-sponsored women's ischemia syndrome evaluation (WISE).

BACKGROUND: We introduce an algorithmic approach to optimize diagnostic and prognostic value of gated cardiac single photon emission computed tomography (SPECT) and magnetic resonance (MR) myocardial perfusion imaging (MPI) modalities in women with suspected myocardial ischemia. The novel approach: bio-informatics assessment schema (BIAS) forms a mathematical model utilizing MPI data and cardiac metrics generated by one modality to predict the MPI status of another modality. The model identifies cardiac features that either enhance or mask the image-based evidence of ischemia. For each patient, the BIAS model value is used to set an appropriate threshold for the detection of ischemia. METHODS: Women (n=130), with symptoms and signs of suspected myocardial ischemia, underwent MPI assessment for regional perfusion defects using two different modalities: gated SPECT and MR. To determine perfusion status, MR data were evaluated qualitatively (MRIQL) and semi-quantitatively (MRISQ) while SPECT data were evaluated using conventional clinical criteria. Evaluators were masked to results of the alternate modality. These MPI status readings were designated "original". Two regression models designated "BIAS" models were generated to model MPI status obtained with one modality (e.g., MRI) compared with a second modality (e.g., SPECT), but importantly, the BIAS models did not include the primary Original MPI reading of the predicting modality. Instead, the BIAS models included auxiliary measurements like left ventricular chamber volumes and myocardial wall thickness. For each modality, the BIAS model was used to set a progressive threshold for interpretation of MPI status. Women were then followed for 38±14 months for the development of a first major adverse cardiovascular event [MACE: CV death, nonfatal myocardial infarction (MI) or hospitalization for heart failure]. Original and BIAS-augmented perfusion status were compared in their ability to detect coronary artery disease (CAD) and for prediction of MACE. RESULTS: Adverse events occurred in 14 (11%) women and CAD was present in 13 (10%). There was a positive correlation of maximum coronary artery stenosis and BIAS score for MRI and SPECT (P<0.001). Receiver operator characteristic (ROC) analysis was conducted and showed an increase in the area under the curve of the BIAS-augmented MPI interpretation of MACE vs. the original for MRISQ (0.78 vs. 0.54), MRIQL (0.78 vs. 0.64), SPECT (0.82 vs. 0.63) and the average of the three readings (0.80±0.02 vs. 0.60±0.05, P<0.05). CONCLUSIONS: Increasing values of the BIAS score generated by both MRI and SPECT corresponded to the increasing prevalence of CAD and MACE. The BIAS-augmented detection of ischemia better predicted MACE compared with the Original reading for the MPI data for both MRI and SPECT.

Noninvasive Imaging to Evaluate Women With Stable Ischemic Heart Disease.

Declines in cardiovascular deaths have been dramatic for men but occur significantly less in women. Among patients with symptomatic ischemic heart disease (IHD), women experience relatively worse outcomes compared with their male counterparts. Evidence to date has failed to adequately explore unique female imaging targets and their correlative signs and symptoms of IHD as major determinants of IHD risk. We highlight sex-specific anatomic and functional differences in contemporary imaging and introduce imaging approaches that leverage refined targets that may improve IHD risk prediction and identify potential therapeutic strategies for symptomatic women.

A training program in cardiovascular cell-based therapy: from the NHLBI Cardiovascular Cell Therapy Research Network.

Stem/progenitor cell-based therapies offer novel treatment for many prevalent diseases. However, most physicians are not trained or introduced to cell therapy. We describe a model of a training program aimed at empowering physician-scientists with the knowledge and skills necessary for advancing the field of cardiovascular cell therapy. To date, five full-time scholars have completed this training program, obtained a full-time academic appointment in Cardiovascular Disease, and continue to actively contribute to the advancement of cell therapy applications. Another has returned to his parent institution to complete his PhD and several part-time scholars have continued in scholarly activities in other academic programs.

Clinical implications of the Women's Ischemia Syndrome Evaluation: inter-relationships between symptoms, psychosocial factors and cardiovascular outcomes.

Cardiovascular disease remains the leading cause of death in the USA and is associated with several modifiable (hypertension, diabetes, high cholesterol, tobacco use, physical inactivity, obesity and unhealthy diet) and nonmodifiable (age, gender and family history) risk factors. The role of psychosocial risk factors in the development of cardiovascular disease has a growing body of literature, and differences in men and women have been identified. The Women's Ischemia Syndrome Evaluation provides insight into psychosocial risk factors in a cohort of women presenting with chest pain who had a comprehensive battery of psychosocial assessments and long-term follow-up. This review focuses on symptom presentation for chest pain and its relationship to cardiovascular disease morbidity and mortality, quality of life, healthcare costs and psychosocial predictor variables, including anxiety, depression, hostility and social networks. In the Women's Ischemia Syndrome Evaluation, persistent chest pain was associated with an increased rate of adverse events and relatively high rates of depression and anxiety, with reduced functional capacity and impaired quality of life, over a median of 6 years of follow-up. More research is needed to better understand the relationships between symptoms and negative emotions and to determine whether psychological (pharmacologic and/or cognitive) interventions might impact both psychological and cardiovascular outcomes.

Anxiety associations with cardiac symptoms, angiographic disease severity, and healthcare utilization: the NHLBI-sponsored Women's Ischemia Syndrome Evaluation.

BACKGROUND: Anxiety is common among patients presenting with suspected coronary artery disease (CAD). In a sample of women with signs and symptoms of ischemia, we examined three anxiety markers as predictors of CAD endpoints including: 1) cardiac symptom indicators; 2) angiographic CAD severity; and 3) healthcare utilization (cardiac hospitalizations and 5-year cardiovascular [CVD] healthcare costs). METHODS: Participants completed a baseline protocol including coronary angiogram, cardiac symptoms, psychosocial measures and a median 5.9-year follow-up to track hospitalizations. We calculated CVD costs based on cardiac hospitalizations, treatment visits, and CVD medications. Anxiety measures included anxiolytic medication use, Spielberger Trait Anxiety Inventory (STAI) scores, and anxiety disorder treatment history. RESULTS: The sample numbered 514 women with anxiety measure data and covariates (mean age=57.5 [11.1]). One in five (20.4%) women reported using anxiolytic agents. Anxiety correlated with cardiac symptom indicators (anxiolytic use with nighttime angina and nitroglycerine use; STAI scores and anxiety disorder treatment history with nighttime angina, shortness of breath, and angina frequency). Anxiety disorder treatment history (but not STAI scores or anxiolytics) predicted less severe CAD. Anxiolytic use (but not STAI scores or anxiety disorder treatment history) predicted hospitalizations for chest pain and coronary catheterization (HRs=2.0, 95% CIs=1.1-4.7). Anxiety measures predicted higher 5-year CVD costs (+9.0-42.7%) irrespective of CAD severity. CONCLUSIONS: Among women with signs and symptoms of myocardial ischemia, anxiety measures predict cardiac endpoints ranging from cardiac symptom severity to healthcare utilization. Based on these findings, anxiety may warrant greater consideration among women with suspected CAD.