Energetics of high temperature degradation of fentanyl into primary and secondary products.

Fentanyl is a synthetic opioid used for managing chronic pain. Due to its higher potency (50-100×) than morphine, fentanyl is also an abused drug. A sensor that could detect illicit fentanyl by identifying its thermally degraded fragments would be helpful to law enforcement. While experimental studies have probed the thermal degradation of fentanyl, little theoretical work has been done to understand the mechanism. Here, we studied the thermal degradation pathways of fentanyl using extensive ab initio molecular dynamics simulations combined with enhanced sampling via multiple-walker metadynamics. We calculated the free energy profile for each bond suggested earlier as a potential degradation point to map the thermodynamic driving forces. We also estimated the forward attempt rate of each bond degradation reaction to gain information about degradation kinetics.

Trends in Recurrent Coronary Heart Disease After Myocardial Infarction Among US Women and Men Between 2008 and 2017.

BACKGROUND: Rates for recurrent coronary heart disease (CHD) events have declined in the United States. However, few studies have assessed whether this decline has been similar among women and men. METHODS: Data were used from 770 408 US women and 700 477 US men <65 years of age with commercial health insurance through MarketScan and ≥66 years of age with government health insurance through Medicare who had a myocardial infarction (MI) hospitalization between 2008 and 2017. Women and men were followed up for recurrent MI, recurrent CHD events (ie, recurrent MI or coronary revascularization), heart failure hospitalization, and all-cause mortality (Medicare only) in the 365 days after MI. RESULTS: From 2008 to 2017, age-standardized recurrent MI rates per 1000 person-years decreased from 89.2 to 72.3 in women and from 94.2 to 81.3 in men (multivariable-adjusted P interaction by sex <0.001). Recurrent CHD event rates decreased from 166.3 to 133.3 in women and from 198.1 to 176.8 in men (P interaction <0.001). Heart failure hospitalization rates decreased from 177.4 to 158.1 in women and from 162.9 to 156.1 in men (P interaction=0.001). All-cause mortality rates decreased from 403.2 to 389.5 in women and from 436.1 to 417.9 in men (P interaction=0.82). In 2017, the multivariable-adjusted rate ratios comparing women with men were 0.90 (95% CI, 0.86-0.93) for recurrent MI, 0.80 (95% CI, 0.78-0.82) for recurrent CHD events, 0.99 (95% CI, 0.96-1.01) for heart failure hospitalization, and 0.82 (95% CI, 0.80-0.83) for all-cause mortality. CONCLUSIONS: Rates of recurrent MI, recurrent CHD events, heart failure hospitalization, and mortality in the first year after an MI declined considerably between 2008 and 2017 in both men and women, with proportionally greater reductions for women than men. However, rates remain very high, and rates of recurrent MI, recurrent CHD events, and death continue to be higher among men than women.

Trends in the Prevalence of Multiple Chronic Conditions Among US Adults With Hypertension From 1999-2000 Through 2017-2020.

BACKGROUND: The prevalence of many chronic conditions has increased among US adults. Many adults with hypertension have other chronic conditions. METHODS: We estimated changes in the age-adjusted prevalence of multiple (≥3) chronic conditions, not including hypertension, using data from the National Health and Nutrition Examination Survey, from 1999-2000 to 2017-2020, among US adults with (n = 24,851) and without (n = 24,337 hypertension. Hypertension included systolic blood pressure (BP) ≥130 mm Hg, diastolic BP ≥80 mm Hg, or antihypertensive medication use. We studied 14 chronic conditions: arthritis, asthma, cancer, coronary heart disease, chronic kidney disease, depression, diabetes, dyslipidemia, hepatitis B, hepatitis C, heart failure, lung disease, obesity, and stroke. RESULTS: From 1999-2000 to 2017-2020, the age-adjusted mean number of chronic conditions increased more among US adults with vs. without hypertension (2.2 to 2.8 vs. 1.7 to 2.0; P-interaction <0.001). Also, the age-adjusted prevalence of multiple chronic conditions increased from 39.0% to 52.0% among US adults with hypertension and from 26.0% to 30.0% among US adults without hypertension (P-interaction = 0.022). In 2017-2020, after age, gender, and race/ethnicity adjustment, US adults with hypertension were 1.94 (95% confidence interval: 1.72-2.18) times as likely to have multiple chronic conditions compared to those without hypertension. In 2017-2020, dyslipidemia, obesity, and arthritis were the most common 3 co-occurring chronic conditions among US adults with and without hypertension (age-adjusted prevalence 16.5% and 3.1%, respectively). CONCLUSIONS: In 2017-2020, more than half of US adults with hypertension had ≥3 additional chronic conditions, a substantial increase from 20 years ago.

Persistence and Adherence to PCSK9 Inhibitor Monoclonal Antibodies Versus Ezetimibe in Real-World Settings.

INTRODUCTION: The cardiovascular disease risk reduction benefits of proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibodies (PCSK9i mAb) and ezetimibe are dependent on remaining on treatment and being persistent and adherent. We estimated the percentage of patients on therapy, persistent and adherent at 182 and 365 days among US adults with health insurance who initiated a PCSK9i mAb (n = 16,588) or ezetimibe (n = 83,086) between July 2015 and December 2019. METHODS: Using pharmacy fill claims, being on therapy was defined as having a day of medication supply in the last 60 of 182 and 365 days following treatment initiation, being persistent was defined as not having a gap of 60 days or more between the last day of supply from one prescription fill and the next fill, and being adherent was defined by having medication available to take on ≥ 80% of the 182 and 365 days following treatment initiation. We estimated multivariable-adjusted risk ratios for being persistent and adherent comparing patients initiating PCSK9i mAb versus ezetimibe using Poisson regression. RESULTS: At 182 days following initiation, 80% and 68% were on therapy and 76% and 64% were persistent among patients who initiated a PCSK9i mAb and ezetimibe, respectively. Among patients who were on therapy and persistent at 182 days following initiation, 88% and 81% of those who initiated a PCSK9i mAb and ezetimibe, respectively, were on therapy at 365 days. Among those on therapy and persistent at 182 days following initiation, being persistent and being adherent at 365 days were each more common among PCSK9i mAb versus ezetimibe initiators (persistent: 82% versus 76%, multivariable-adjusted risk ratio 1.07; 95% confidence interval [CI] 1.06-1.08; adherent: 74% versus 71%, multivariable-adjusted risk ratio 1.02; 95% CI 1.01-1.03). CONCLUSIONS: These data suggest approaches to increase persistence and adherence to PCSK9i mAb and ezetimibe should be implemented prior to or within 182 days following treatment initiation.

Membrane mediated mechanical stimuli produces distinct active-like states in the AT1 receptor.

The Angiotensin II Type 1 (AT1) receptor is one of the most widely studied GPCRs within the context of biased signaling. While the AT1 receptor is activated by agonists such as the peptide AngII, it can also be activated by mechanical stimuli such as membrane stretch or shear in the absence of a ligand. Despite the importance of mechanical activation of the AT1 receptor in biological processes such as vasoconstriction, little is known about the structural changes induced by external physical stimuli mediated by the surrounding lipid membrane. Here, we present a systematic simulation study that characterizes the activation of the AT1 receptor under various membrane environments and mechanical stimuli. We show that stability of the active state is highly sensitive to membrane thickness and tension. Structural comparison of membrane-mediated vs. agonist-induced activation shows that the AT1 receptor has distinct active conformations. This is supported by multi-microsecond free energy calculations that show unique landscapes for the inactive and various active states. Our modeling results provide structural insights into the mechanical activation of the AT1 receptor and how it may produce different functional outcomes within the framework of biased agonism.

Hypertension Statistics for US Adults: An Open-Source Web Application for Analysis and Visualization of National Health and Nutrition Examination Survey Data.

BACKGROUND: Data from the US National Health and Nutrition Examination Survey are freely available and can be analyzed to produce hypertension statistics for the noninstitutionalized US population. The analysis of these data requires statistical programming expertise and knowledge of National Health and Nutrition Examination Survey methodology. METHODS: We developed a web-based application that provides hypertension statistics for US adults using 10 cycles of National Health and Nutrition Examination Survey data, 1999 to 2000 through 2017 to 2020. We validated the application by reproducing results from prior publications. The application's interface allows users to estimate crude and age-adjusted means, quantiles, and proportions. Population counts can also be estimated. To demonstrate the application's capabilities, we estimated hypertension statistics for noninstitutionalized US adults. RESULTS: The estimated mean systolic blood pressure (BP) declined from 123 mm Hg in 1999 to 2000 to 120 mm Hg in 2009 to 2010 and increased to 123 mm Hg in 2017 to 2020. The age-adjusted prevalence of hypertension (ie, systolic BP≥130 mm Hg, diastolic BP≥80 mm Hg or self-reported antihypertensive medication use) was 47.9% in 1999 to 2000, 43.0% in 2009 to 2010, and 44.7% in 2017 to 2020. In 2017 to 2020, an estimated 115.3 million US adults had hypertension. The age-adjusted prevalence of controlled BP, defined by the 2017 American College of Cardiology/American Heart Association BP guideline, among nonpregnant US adults with hypertension was 9.7% in 1999 to 2000, 25.0% in 2013 to 2014, and 21.9% in 2017 to 2020. After age adjustment and among nonpregnant US adults who self-reported taking antihypertensive medication, 27.5%, 48.5%, and 43.0% had controlled BP in 1999 to 2000, 2013 to 2014, and 2017 to 2020, respectively. CONCLUSIONS: The application developed in the current study is publicly available at https://bcjaeger.shinyapps.io/nhanesShinyBP/ and produced valid, transparent and reproducible results.

Lipoprotein(a) and the Risk for Recurrent Atherosclerotic Cardiovascular Events Among Adults With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

Rationale & Objective: Many adults with chronic kidney disease (CKD) and atherosclerotic cardiovascular disease (ASCVD) have high lipoprotein(a) levels. It is unclear whether high lipoprotein(a) levels confer an increased risk for recurrent ASCVD events in this population. We estimated the risk for recurrent ASCVD events associated with lipoprotein(a) in adults with CKD and prevalent ASCVD. Study Design: Observational cohort study. Setting & Participants: We included 1,439 adults with CKD and prevalent ASCVD not on dialysis enrolled in the Chronic Renal Insufficiency Cohort study between 2003 and 2008. Exposure: Baseline lipoprotein(a) mass concentration, measured using a latex-enhanced immunoturbidimetric assay. Outcomes: Recurrent ASCVD events (primary outcome), kidney failure, and death (exploratory outcomes) through 2019. Analytical Approach: We used Cox proportional-hazards regression models to estimate adjusted HR (aHRs) and 95% CIs. Results: Among participants included in the current analysis (mean age 61.6 years, median lipoprotein(a) 29.4 mg/dL [25th-75th percentiles 9.9-70.9 mg/dL]), 641 had a recurrent ASCVD event, 510 developed kidney failure, and 845 died over a median follow-up of 6.6 years. The aHR for ASCVD events associated with 1 standard deviation (SD) higher log-transformed lipoprotein(a) was 1.04 (95% CI, 0.95-1.15). In subgroup analyses, 1 SD higher log-lipoprotein(a) was associated with an increased risk for ASCVD events in participants without diabetes (aHR, 1.23; 95% CI, 1.02-1.48), but there was no evidence of an association among those with diabetes (aHR, 0.99; 95% CI, 0.88-1.10, P comparing aHRs = 0.031). The aHR associated with 1 SD higher log-lipoprotein(a) in the overall study population was 1.16 (95% CI, 1.04-1.28) for kidney failure and 1.02 (95% CI, 0.94-1.11) for death. Limitations: Lipoprotein(a) was not available in molar concentration. Conclusions: Lipoprotein(a) was not associated with the risk for recurrent ASCVD events in adults with CKD, although it was associated with a risk for kidney failure.

Comparison of the association of masked hypertension defined by the 2017 ACC/AHA BP guideline versus the JNC7 guideline with left ventricular hypertrophy.

BACKGROUND: Compared with the Seventh Report of the Joint National Committee (JNC7), the 2017 American College of Cardiology/American Heart Association (ACC/AHA) blood pressure (BP) guideline uses lower BP thresholds to define hypertension and BP control. METHODS: We pooled data from five US-based studies to compare the association of masked hypertension (MHT) and masked uncontrolled hypertension, defined using the 2017 ACC/AHA guideline ( n  = 1653 without high office BP; <130/80 mmHg) versus the JNC7 guideline ( n  = 2451 without high office BP; <140/90 mmHg), with left ventricular hypertrophy (LVH). MHT and masked uncontrolled hypertension were defined using office BP and awake BP alone and awake, asleep, or 24-h BP. LVH was assessed by echocardiography. RESULTS: Among participants without high office BP not taking antihypertensive medication, the prevalence of MHT defined by the JNC7 guideline and the 2017 ACC/AHA BP guideline was 25.0 and 33.5% using awake BP only and 37.1 and 52.0% when using awake, asleep, or 24-h BP. The adjusted prevalence ratios for LVH associated with MHT versus sustained normotension defined by the JNC7 and 2017 ACC/AHA BP guidelines were 1.72 [95% confidence interval (CI): 1.12-2.64] and 1.56 (95% CI: 0.97-2.51), respectively, when using awake BP only and 2.16 (95% CI: 1.36-3.44) and 1.03 (95% CI: 0.58-1.82), respectively, when using awake, asleep or 24-h BP. There was no evidence that masked uncontrolled hypertension was associated with LVH when defined using the BP thresholds in either the JNC7 or the 2017 ACC/AHA BP guideline. CONCLUSION: The association of MHT with LVH may depend on the BP thresholds used.

Estimated number and percentage of US adults with atherosclerotic cardiovascular disease recommended add-on lipid-lowering therapy by the 2018 AHA/ACC multi-society cholesterol guideline.

Study objective: The 2018 American Heart Association/American College of Cardiology (AHA/ACC) cholesterol guideline recommends a maximally-tolerated statin with add-on lipid-lowering therapy, ezetimibe and/or proprotein convertase subtilisin/kexin type 9 (PCSK9) for adults with very-high atherosclerotic cardiovascular disease (ASCVD) risk to achieve a low-density lipoprotein cholesterol (LDL-C) <70 mg/dL. We estimated the percentage of US adults with ASCVD recommended, by the 2018 AHA/ACC cholesterol guideline, and receiving add-on lipid-lowering therapy. Design setting and participants: Cross-sectional study including 805 participants from the US National Health and Nutrition Examination Survey (NHANES) 2013-2020 data. NHANES sampling weights were used to obtain estimates for the US adult population. Main measures: Very-high ASCVD risk was defined as either: ≥2 ASCVD events, or one ASCVD event with ≥2 high-risk conditions. Being recommended add-on lipid-lowering therapy was defined as having very-high ASCVD risk and LDL-C ≥ 70 mg/dL, or LDL-C < 70 mg/dL while taking ezetimibe or a PCSK9 inhibitor. Results: An estimated 18.7 (95%CI, 16.0-21.4) million US adults had ASCVD, of whom 81.6 % (95%CI, 76.7 %-86.4 %) had very-high ASCVD risk, and 60.1 % (95%CI, 54.5 %-65.7 %) had very-high ASCVD risk and LDL-C ≥ 70 mg/dL. Overall, 61.4 % (95%CI, 55.8 %-66.9 %) were recommended add-on lipid-lowering therapy and 3.2 % (95 % CI, 1.2 %-5.3 %) were taking it. Smokers, adults with diabetes, hypertension and chronic kidney disease were more likely, while those taking atorvastatin or rosuvastatin were less likely, to be recommended add-on lipid-lowering therapy. Conclusion: The majority of US adults with ASCVD are recommended add-on lipid-lowering therapy by the 2018 AHA/ACC cholesterol guideline but few are receiving it.

Characteristics of patients with diabetes and a history of myocardial infarction initiating PCSK9 and SGLT2 inhibitors.

Study objective: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk for atherosclerotic cardiovascular disease (ASCVD) events in patients with diabetes and ASCVD. We assessed factors associated with initiating either medication among patients with diabetes and a prior myocardial infarction (MI). Setting/participants: US adults ≥19 years old with private health insurance (MarketScan) or government health insurance (Medicare) who had diabetes and a prior MI and initiated a PCSK9i or an SGLT2i in 2017 or 2018. Main outcome measures: PCSK9i or SGLT2i initiation was identified using pharmacy claims. Results: Overall, 8102 patients initiated a PCSK9i (n = 1501; 18.5%) or an SGLT2i (n = 6601; 81.5%). Patients with 2 and ≥3 versus 1 prior MI (risk ratio [RR]: 1.32 [95%CI: 1.17-1.48] and 1.68 [1.41-2.01], respectively), prior coronary revascularization (1.47 [1.31-1.64]), prior stroke (1.28 [1.06-1.56]), history of peripheral artery disease (1.27 [1.14-1.41]), receiving cardiologist care (1.51 [1.36-1.67]) or taking ezetimibe (2.57 [2.35-2.82]) were more likely to initiate a PCSK9i versus an SGLT2i. Patients with a history of short-term (RR 1.07 [95%CI 1.05-1.09]) or long-term (1.07 [1.04-1.09]) diabetes complications, and taking a low/moderate- and high-intensity statin dosage (1.61 [1.51-1.70] and 1.68 [1.58-1.77], respectively) were more likely to initiate an SGLT2i versus a PCSK9i. Among patients who initiated a PCSK9i, 2.9% subsequently initiated an SGLT2i; 0.8% who initiated an SGLT2i subsequently initiated a PCSK9i. Conclusion: The decision to initiate PCSK9i or SGLT2i is explained by having very high cardiovascular disease risk for those initiating PCSK9i and diabetes complications for those initiating SGLT2i.

Impact of Asleep and 24-Hour Blood Pressure Data on the Prevalence of Masked Hypertension by Race/Ethnicity.

BACKGROUND: We pooled ambulatory blood pressure monitoring data from 5 US studies, including the Jackson Heart Study (JHS), the Coronary Artery Risk Development in Young Adults (CARDIA) study, the Masked Hypertension Study, the Improving the Detection of Hypertension Study, and the North Carolina Masked Hypertension Study. Using a cross-sectional study design, we estimated differences in the prevalence of masked hypertension by race/ethnicity when out-of-office blood pressure (BP) included awake, asleep, and 24-hour BP vs. awake BP alone. METHODS: We restricted the analyses to participants with office systolic BP (SBP) <130 mm Hg and diastolic BP (DBP) <80 mm Hg. High awake BP was defined as mean SBP/DBP ≥130/80 mm Hg, high asleep BP as mean SBP/DBP ≥110/65 mm Hg, and high 24-hour BP as mean SBP/DBP ≥125/75 mm Hg. RESULTS: Among participants not taking antihypertensive medication (n = 1,292), the prevalence of masked hypertension with out-of-office BP defined by awake BP alone or by awake, asleep, or 24-hour BP was 34.5% and 48.7%, respectively, among non-Hispanic White, 39.7% and 67.6% among non-Hispanic Black, and 19.4% and 35.1% among Hispanic participants. After multivariable adjustment, non-Hispanic Black were more likely than non-Hispanic White participants to have masked hypertension by asleep or 24-hour BP but not awake BP (adjusted odds ratio [OR] 2.14 95% confidence interval [CI] 1.45-3.15) and by asleep or 24-hour BP and awake BP (OR 1.61; 95% CI 1.12-2.32) vs. not having masked hypertension. CONCLUSIONS: Assessing asleep and 24-hour BP measures increases the prevalence of masked hypertension more among non-Hispanic Black vs. non-Hispanic White individuals.

Lipid-Lowering Therapy Use and Intensification Among United States Veterans Following Myocardial Infarction or Coronary Revascularization Between 2015 and 2019.

BACKGROUND: Understanding how statins, ezetimibe, and PCSK9i (proprotein convertase subtilisin/kexin type 9 serine protease inhibitors) are prescribed after a myocardial infarction (MI) or elective coronary revascularization may improve lipid-lowering therapy (LLT) intensification and reduce recurrent atherosclerotic cardiovascular disease events. We described the use and intensification of LLT among US veterans who had a MI or elective coronary revascularization between July 24, 2015, and December 9, 2019, within 12 months of hospital discharge. METHODS: LLT intensification was defined as increasing statin dose, or initiating a statin, ezetimibe, or a PCSK9i, overall and among those with an LDL-C (low-density lipoprotein cholesterol) ≥70 or 100 mg/dL. Poisson regression was used to determine patient characteristics associated with a greater likelihood of LLT intensification following hospitalization for MI or elective coronary revascularization. RESULTS: Among 81 372 index events (mean age, 69.0 years, 2.3% female, mean LDL-C 89.6 mg/dL, 33.8% with LDL-C <70 mg/dL), 39.7% were not taking any LLT, and 22.0%, 37.2%, and 0.6% were taking a low-moderate intensity statin, a high-intensity statin, and ezetimibe, respectively, before MI/coronary revascularization during the study period. Within 14 days, 3 months, and 12 months posthospitalization, 33.3%, 41.9%, and 47.3%, respectively, of veterans received LLT intensification. LLT intensification was most common among veterans taking no LLT (82.5%, n=26 637) before MI/coronary revascularization. Higher baseline LDL-C, having a lipid test, and attending a cardiology visit were each associated with a greater likelihood of LLT intensification, while age ≥75 versus <65 years was associated with a lower likelihood of LLT intensification within 12 months posthospitalization. CONCLUSIONS: Less than half of veterans received LLT intensification in the year after MI or coronary revascularization suggesting a missed opportunity to reduce atherosclerotic cardiovascular disease risk.

Death, long-term nursing home placement, and impoverishment after recurrent myocardial infarction.

Study objective: To determine whether recurrent myocardial infarction (MI) is associated with increased risk of mortality, long-term nursing home placement, and impoverishment. Design: Retrospective cohort study. Setting: United States Medicare program. Participants: Individuals age > 65 years with recurrent MI hospitalizations (n = 228,826) between January 1, 2007 and June 30, 2017 and controls with initial but not recurrent MI (n = 915,304). Main outcome measures: Death, nursing home placement, and impoverishment (Medicaid enrollment or subsidies for low-income and -resource individuals) through December 31, 2017. Results: In the recurrent MI and control cohorts, 47% and 41% of individuals were age > 80 years, respectively, and 56% of both cohorts were women. After 1 year, 48% of the recurrent MI cohort and 16% of the control cohort died, 9% and 7% experienced nursing home placement, and 4% and 2% experienced impoverishment. Multivariable-adjusted hazard ratios (95% confidence intervals) comparing the recurrent MI and control cohorts were 2.04 (2.03-2.06) for death, 0.89 (0.88-0.91) for nursing home placement, and 1.32 (1.28-1.36) for impoverishment. Conclusions: Older US adults with recurrent MI had higher risk of death and impoverishment than controls who had experienced an initial MI. Unadjusted, recurrent MI was associated with higher risk of nursing home placement; however, after adjusting for sociodemographic characteristics and comorbidities, individuals with recurrent MI had slightly lower risk of nursing home placement. Preventing recurrent MI may also reduce the risk of death and impoverishment among older US adults.

Lifestyle Behaviors Among Adults Recommended for Ambulatory Blood Pressure Monitoring According to the 2017 ACC/AHA Blood Pressure Guideline.

BACKGROUND: The 2017 American College of Cardiology/American Heart Association blood pressure (BP) guideline recommends ambulatory BP monitoring to exclude white coat hypertension (WCH) among adults with office systolic BP (SBP)/diastolic BP (DBP) of 130-159/80-99 mm Hg, and masked hypertension (MHT) among adults with office SBP/DBP of 120-129/75-79 mm Hg after a 3-month trial of lifestyle modification. We estimated the proportion of individuals with ideal lifestyle factors among those who meet these office BP criteria. METHODS: We analyzed data from participants not taking antihypertensive medication in the Coronary Artery Risk Development in Young Adults (CARDIA) and Jackson Heart Study (JHS) who met the office BP criteria for screening for WCH (CARDIA n = 490, JHS n = 873) and MHT (CARDIA n = 486, JHS n = 614). We estimated the prevalence of lifestyle factors including ideal body mass index (BMI), physical activity, diet, and alcohol use among participants who met office BP criteria for WCH or MHT screening. RESULTS: Among participants who met office BP criteria for WCH screening, 15.5% in CARDIA and 3.6% in JHS had 3 or more ideal lifestyle factors. Among participants who met office BP criteria for MHT screening, 22.6% in CARDIA and 4.7% in JHS had 3 or more ideal lifestyle factors. Ideal BMI, diet, and physical activity were present in less than half of participants in each sample. CONCLUSIONS: Few participants who met office BP criteria for the screening of WCH or MHT had ideal lifestyle factors.

Atherosclerotic Cardiovascular Disease Events in Adults With CKD Taking a Moderate- or High-Intensity Statin: The Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The 2018 American Heart Association/American College of Cardiology (AHA/ACC) cholesterol guideline uses risk stratification to guide the decision to initiate nonstatin lipid-lowering medication among adults with atherosclerotic cardiovascular disease (CVD). We determined atherosclerotic CVD (ASCVD) event rates among adults with chronic kidney disease (CKD) taking statin therapy within 2018 AHA/ACC cholesterol guideline risk categories. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Adults with CKD not on dialysis in the Chronic Renal Insufficiency Cohort (CRIC) study who were taking a moderate/high-intensity statin 1 year after enrollment (baseline for the current analysis, n = 1,753). EXPOSURE: 2018 AHA/ACC cholesterol guideline risk categories: without a history of ASCVD, a history of 1 major ASCVD event and multiple high-risk conditions, and a history of ≥2 major ASCVD events. OUTCOME: Adjudicated ASCVD events after the year 1 study visit. ANALYTICAL APPROACH: We calculated age-sex standardized rates for ASCVD events and age-sex adjusted hazard ratios for ASCVD events accounting for the competing risk of death. RESULTS: There were 394 ASCVD events over a median follow-up period of 8 years. The ASCVD event rates (with 95% CI) per 1,000 person-years among participants without a history of ASCVD, with a history of 1 major ASCVD event and multiple high-risk conditions, and with a history of ≥2 major ASCVD events were 21.7 (18.4-25.1), 45.0 (37.8-52.3), and 73.3 (53.3-93.4), respectively. Compared with participants without a history of ASCVD, the HR (95% CI) rates for ASCVD events among those with a history of 1 major ASCVD event and multiple high-risk conditions, and with a history of ≥2 major ASCVD events were 1.89 (1.52-2.36) and 2.50 (1.85-3.39), respectively. LIMITATIONS: Data on whether participants were taking a maximally tolerated statin dosage were unavailable. CONCLUSIONS: The 2018 AHA/ACC cholesterol guideline identifies adults with CKD who have very high ASCVD risk despite taking a moderate/high-intensity statin.

Factors Associated With PCSK9 Inhibitor Initiation Among US Veterans.

Background Few adults at high risk for atherosclerotic cardiovascular disease events use a PCSK9i (proprotein convertase subtilisin/kexin type 9 inhibitor). Methods and Results Using data from the US Veterans Health Administration, we identified veterans who initiated a PCSK9i between January 2018 and December 2019, matched 1:4 to veterans who did not initiate this medication over this time period (case-cohort study). Two cohorts of veterans were analyzed: (1) atherosclerotic cardiovascular disease, with a most recent low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL; and (2) severe hypercholesterolemia (ie, familial hypercholesterolemia or any prior LDL-C ≥190 mg/dL, with most recent LDL-C ≥100 mg/dL). Conditional logistic regression was used to analyze factors associated with PCSK9i initiation, adjusting for all factors, simultaneously. There were 2394 initiators and 9576 noninitiators in the atherosclerotic cardiovascular disease cohort (median LDL-C, 141 and 96 mg/dL, respectively; P<0.001). Factors associated with a higher likelihood of PCSK9i initiation included age 65 to <75 versus <65 years, highest versus lowest quartile of median area-level income, familial hypercholesterolemia, former statin use, and current ezetimibe use. PCSK9i initiation was lower among veterans of a race/ethnicity other than non-Hispanic White. There were 245 initiators and 980 noninitiators in the severe hypercholesterolemia cohort (median LDL-C, 183 and 151 mg/dL, respectively; P<0.001). Age ≥75 versus <65 years, history of chronic kidney disease, former statin use, and current ezetimibe use were associated with a higher likelihood of PCSK9i initiation. Conclusions Several patient-level factors, including age, sex, and race/ethnicity, were significantly associated with PCSK9i initiation, suggesting an unmet treatment need in several patient groups.

Race/ethnic and sex differences in the initiation of non-statin lipid-lowering medication following myocardial infarction.

BACKGROUND: Adults with atherosclerotic cardiovascular disease (ASCVD) at very high-risk for recurrent events who have low-density lipoprotein cholesterol ≥ 70 mg/dL despite maximally-tolerated statin therapy are recommended to initiate ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. OBJECTIVE: Compare the initiation of ezetimibe and a PCSK9 inhibitor after a myocardial infarction (MI) among very high-risk ASCVD patients by race/ethnicity and sex. METHODS: We analyzed data from 374,786 adults ≥ 66 years of age with Medicare fee-for-service coverage who had an MI between July 1, 2015 and December 31, 2018, were not taking ezetimibe or a PCSK9 inhibitor, and had very high-risk ASCVD defined by the 2018 American Heart Association/American College of Cardiology multi-society cholesterol guideline. Pharmacy claims through December 31, 2018 were used to determine ezetimibe and PCSK9 inhibitor initiation. RESULTS: Overall, 6980 (1.9%) beneficiaries initiated ezetimibe, and 1433 (0.4%) initiated a PCSK9 inhibitor. Adjusted hazard ratios (aHR) for ezetimibe initiation among non-Hispanic Black, Hispanic, and Asian versus non-Hispanic White beneficiaries were 0.77 (95% confidence interval [95%CI]: 0.70-0.86), 0.92 (95%CI: 0.76-1.11) and 0.73 (95%CI: 0.59-0.89), respectively. Compared to non-Hispanic White beneficiaries, the aHRs for PCSK9 inhibitor initiation were 0.63 (95%CI: 0.48-0.81) among non-Hispanic Black, 0.70 (95%CI: 0.43-1.13) among Hispanic, and 0.93 (95%CI: 0.62-1.39) among Asian beneficiaries. The aHRs for ezetimibe and PCSK9 inhibitor initiation comparing women to men were 1.11 (95%CI: 1.06-1.17) and 1.13 (95%CI: 1.01-1.25), respectively. CONCLUSION: There are race/ethnic and sex disparities in the initiation of ezetimibe and a PCSK9 inhibitor following MI among very high-risk ASCVD patients.

Sex Differences in Incident and Recurrent Coronary Events and All-Cause Mortality.

BACKGROUND: Women have lower age-specific rates of incident coronary heart disease (CHD) than men. It is unclear whether women remain at lower risk for CHD events versus men following a myocardial infarction (MI). OBJECTIVES: This study assessed sex differences in recurrent MI, recurrent CHD events, and mortality among patients with MI and compared these associations with sex differences in a control group without a history of CHD. METHODS: This study analyzed data for 171,897 women and 167,993 men age 21 years or older with health insurance in the United States who had a MI hospitalization in 2015 or 2016. Patients with a MI were frequency matched by age and calendar year to 687,588 women and 671,972 men without CHD. Beneficiaries were followed until December 2017 for MI, CHD (i.e., MI or coronary revascularization), and in Medicare for all-cause mortality. RESULTS: Age-standardized rates of MI per 1,000 person-years were 4.5 in women and 5.7 in men without CHD (hazard ratio [HR]: 0.64; 95% confidence interval [CI]: 0.62 to 0.67) and 60.2 in women and 59.8 in men with MI (HR: 0.94; 95% CI: 0.92 to 0.96). CHD rates in women versus men were 6.3 versus 10.7 among those without CHD (HR: 0.53; 95% CI: 0.51 to 0.54) and 84.5 versus 99.3 among those with MI (HR: 0.87; 95% CI: 0.85 to 0.89). All-cause mortality rates in women versus men were 63.7 versus 59.0 among those without CHD (HR: 0.72; 95% CI: 0.71 to 0.73) and 311.6 versus 284.5 among those with MI (HR: 0.90; 95% CI: 0.89 to 0.92). CONCLUSIONS: The lower risk for MI, CHD, and all-cause mortality in women versus men is considerably attenuated following a MI.

Ambulatory Blood Pressure Phenotypes in Adults Taking Antihypertensive Medication with and without CKD.

BACKGROUND AND OBJECTIVES: Recent guidelines recommend out-of-clinic BP measurements. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We compared the prevalence of BP phenotypes between 561 black patients, with and without CKD, taking antihypertensive medication who underwent ambulatory BP monitoring at baseline (between 2000 and 2004) in the Jackson Heart Study. CKD was defined as an albumin-to-creatinine ratio ≥30 mg/g or eGFR <60 ml/min per 1.73 m2. Sustained controlled BP was defined by BP at goal both inside and outside of the clinic and sustained uncontrolled BP as BP above goal both inside and outside of the clinic. Masked uncontrolled hypertension was defined by controlled clinic-measured BP with uncontrolled out-of-clinic BP. RESULTS: CKD was associated with a higher multivariable-adjusted prevalence ratio for uncontrolled versus controlled clinic BP (prevalence ratio, 1.44; 95% CI, 1.02 to 2.02) and sustained uncontrolled BP versus sustained controlled BP (prevalence ratio, 1.66; 95% CI, 1.16 to 2.36). There were no statistically significant differences in the prevalence of uncontrolled daytime or nighttime BP, nondipping BP, white-coat effect, and masked uncontrolled hypertension between participants with and without CKD after multivariable adjustment. After multivariable adjustment, reduced eGFR was associated with masked uncontrolled hypertension versus sustained controlled BP (prevalence ratio, 1.42; 95% CI, 1.00 to 2.00), whereas albuminuria was associated with uncontrolled clinic BP (prevalence ratio, 1.76; 95% CI, 1.20 to 2.60) and sustained uncontrolled BP versus sustained controlled BP (prevalence ratio, 2.02; 95% CI, 1.36 to 2.99). CONCLUSIONS: The prevalence of BP phenotypes defined using ambulatory BP monitoring is high among adults with CKD taking antihypertensive medication.

Prevalence of ambulatory blood pressure phenotypes using the 2017 American College of Cardiology/American Heart Association blood pressure guideline thresholds: data from the Coronary Artery Risk Development in Young Adults study.

BACKGROUND: The 2017 American College of Cardiology/American Heart Association (ACC/AHA) blood pressure (BP) guideline lowered the BP thresholds for defining hypertension compared with the Seventh Report of the Joint National Committee (JNC7) guideline. METHODS: We analyzed clinic and ambulatory BP monitoring data from 717 Coronary Artery Risk Development in Young Adults study participants and compared the prevalence of clinic and out-of-clinic BP phenotypes using thresholds from the 2017 ACC/AHA and JNC7 guidelines. RESULTS: Among participants not taking antihypertensive medication and according to the JNC7 and 2017 ACC/AHA guidelines, 11.1 and 30.1% of participants had clinic hypertension, 37.5 and 57.9% had awake hypertension, 35.7 and 58.1% had asleep hypertension, and 35.7 and 58.6% had 24-h hypertension, respectively. According to the JNC7 and 2017 ACC/AHA guideline definitions, 1.9 and 3.2% had white-coat hypertension, 28.2 and 31.0% had masked hypertension and 9.3 and 26.9% had sustained hypertension, respectively. Among participants taking antihypertensive medication and when defined using the JNC7 and 2017 ACC/AHA guideline BP thresholds, 18.6 and 45.3% had uncontrolled clinic BP, 48.1 and 62.5% had uncontrolled awake BP, 48.1 and 70.2% had uncontrolled asleep BP and, 47.7 and 65.3% had uncontrolled 24-h BP, respectively. Using JNC7 and 2017 ACC/AHA guideline BP thresholds, the prevalence was 1.4 and 5.2% for white-coat effect, 30.9 and 22.5% for masked uncontrolled hypertension, and 17.2 and 40.0% for sustained uncontrolled BP, respectively. CONCLUSION: The 2017 ACC/AHA guideline results in a substantially higher prevalence of awake, asleep, 24-h, and sustained hypertension.