Quantifying Importance of Major Risk Factors for Coronary Heart Disease.

BACKGROUND: To optimize preventive strategies for coronary heart disease (CHD), it is essential to understand and appropriately quantify the contribution of its key risk factors. Our objective was to compare the associations of key modifiable CHD risk factors-specifically lipids, systolic blood pressure (SBP), diabetes mellitus, and smoking-with incident CHD events based on their prognostic performance, attributable risk fractions, and treatment benefits, overall and by age. METHODS: Pooled participant-level data from 4 observational cohort studies sponsored by the National Heart, Lung, and Blood Institute were used to create a cohort of 22 626 individuals aged 45 to 84 years who were initially free of cardiovascular disease. Individuals were followed for 10 years from baseline evaluation for incident CHD. Proportional hazards regression was used to estimate metrics of prognostic model performance (likelihood ratio, C index, net reclassification, discrimination slope), hazard ratios, and population attributable fractions for SBP, non-high-density lipoprotein cholesterol (non-HDL-C), diabetes mellitus, and smoking. Expected absolute risk reductions for antihypertensive and lipid-lowering treatment were assessed. RESULTS: Age, sex, and race capture 63% to 80% of the prognostic performance of cardiovascular risk models. In contrast, adding either SBP, non-HDL-C, diabetes mellitus, or smoking to a model with other risk factors increases the C index by only 0.004 to 0.013. However, primordial prevention could have a substantial effect as demonstrated by population attributable fractions of 28% for SBP≥130 mm Hg and 17% for non-HDL-C≥130 mg/dL. Similarly, lowering the SBP of all individuals to <130 mm Hg or lowering low-density lipoprotein cholesterol by 30% would be expected to lower a baseline 10-year CHD risk of 10.7% to 7.0 and 8.0, respectively (absolute risk reductions: 3.7% and 2.7%, respectively). Prognostic performance decreases with age (C indices for age groups 45-54, 55-64, 65-74, 75-84 are 0.75, 0.72, 0.66, and 0.62, respectively), whereas absolute risk reductions increase (SBP: 1.1%, 2.3%, 5.4%, 10.3%, respectively; non-HDL-C: 1.1%, 2.0%, 3.7%, 5.9%, respectively). CONCLUSIONS: Although individual modifiable CHD risk factors contribute only modestly to prognostic performance, our models indicate that eliminating or controlling these individual factors would lead to substantial reductions in total population CHD events. Metrics used to judge importance of risk factors should be tailored to the research objectives.

Statin Utilization Patterns and Outcomes for Patients with Acute Coronary Syndrome During and Following Inpatient Admissions.

PURPOSE: High-intensity statins (HIS) are recommended by current treatment guidelines for patients with clinical atherosclerotic cardiovascular disease and should be administered soon after an acute coronary syndrome (ACS) event and maintained thereafter. However, adherence to guidelines remains adequate. Statin utilization patterns during index hospitalization and the first year after ACS event, and the association between statin utilization and post-discharge clinical and economic outcomes, are described. METHODS: Retrospective, observational study of US adults from the MarketScan Research Databases (2002-2014) with ≥ 1 inpatient admission for ACS and no evidence of previous ACS event < 12 months prior to index. RESULTS: In total, 7802 patients met inclusion criteria. The most common index hospitalization primary diagnosis was myocardial infarction (94.6%). In the 3-month period before ACS admission, 3.4 and 14.9% of patients received HIS or low-to-moderate intensity statin, versus 13.2 and 30.7% during index hospitalization, and 16.4 and 45.1% in the year of follow-up. Of 1336 patients with a statin prescription filled on/after discharge, 53.2% filled prescriptions within 15 days of discharge and 14.9% delayed for > 91 days. The most common post-index hospital admissions for cardiovascular events were due to recurrent ACS (incidence rate = 115.2), heart failure (110.0), and revascularization (76.4). During follow-up, 2355 patients (30.2%) had all-cause inpatient admissions and 1136 (14.6%) had cardiovascular-specific admissions; mean all-cause medical and healthcare costs were $2456 and $2870, respectively, per patient per month. CONCLUSIONS: Statin dosing and utilization of HIS remains lower than recommended in current treatment guidelines, leaving patients at considerable risk of subsequent cardiovascular events.

Lipid management in contemporary community practice: Results from the Provider Assessment of Lipid Management (PALM) Registry.

BACKGROUND: The latest cholesterol guidelines have shifted focus from achieving low-density lipoprotein cholesterol (LDL-C) targets toward statin use and intensity guided by atherosclerotic cardiovascular disease (ASCVD) risk. METHODS: Statin use and intensity were evaluated in 5,905 statin-eligible primary or secondary prevention patients from 138 PALM Registry practices. RESULTS: Overall, 74.7% of eligible adults were on statins; only 42.4% were on guideline-recommended intensity. Relative to primary prevention patients, ASCVD patients were more likely to be on a statin (83.6% vs 63.4%, P<.0001) and guideline-recommended intensity (47.3% vs 36.0%, P<.0001). Men were more likely than women to be prescribed recommended intensity for primary (odds ratio [OR] 1.87, 95% CI 1.49-2.34) and secondary (OR 1.47, 95% CI 1.26-1.70) prevention. In primary prevention, increasing age, diabetes, obesity, hypertension, and lower 10-year ASCVD risk were associated with increased odds of receiving recommended intensity. Among ASCVD patients, those with coronary artery disease were more likely to be on recommended intensity than cerebrovascular or peripheral vascular disease patients (OR 1.71, 95% CI 1.41-2.09), as were those seen by cardiologists (OR 1.43, 95% CI 1.12-1.83). Median LDL-C levels were highest among patients not on statins (124.0 mg/dL) and slightly higher among those on lower-than-recommended intensity compared with recommended-therapy recipients (88.0 and 84.0 mg/dL, respectively; P≤.0001). CONCLUSIONS: In routine contemporary practice, 1 in 4 guideline-eligible patients was not on a statin; less than half were on the recommended statin intensity. Untreated and undertreated patients had significantly higher LDL-C levels than those receiving guideline-directed statin treatment.

Alirocumab efficacy and safety by race and ethnicity: Analysis from 3 ODYSSEY phase 3 trials.

BACKGROUND: Differences in lipid and cardiovascular risk profiles have been observed in African-American/black (AA/B), white (W), and Hispanic/Latino (H/L) individuals. Efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, may vary by race and ethnicity and has not been analyzed. OBJECTIVE: This post hoc analysis evaluated alirocumab efficacy and safety vs control in 3 pooled ODYSSEY phase 3 trials (COMBO I, COMBO II, and LONG TERM) by race (AA/B [n = 154] vs W [n = 1982]) and ethnicity (H/L [n = 174] vs non-H/L [n = 3149]). METHODS: Patients with elevated low-density lipoprotein cholesterol (LDL-C) despite maximally tolerated statin received alirocumab (75 mg up to 150 mg every 2 weeks [COMBO I & II] or 150 mg every 2 weeks [LONG TERM]) or control (placebo [COMBO I and LONG TERM] or ezetimibe [COMBO II]). RESULTS: At baseline, LDL-C levels were similar across treatment groups; median lipoprotein(a) levels were higher in AA/B (33.0-120.0 mg/dL) vs W (7.1-66.3 mg/dL) and lower in H/L (5.0-38.3 mg/dL) vs non-H/L (7.7-69.0 mg/dL). At week 24, alirocumab significantly reduced LDL-C vs control. Alirocumab also reduced lipoprotein(a) compared with control across the subgroups. Treatment-emergent adverse events were similar between alirocumab (68.9-85.0%) and control (70.6-82.4%) regardless of race and ethnicity. CONCLUSION: Alirocumab significantly reduced LDL-C and Lp(a) levels compared with control, regardless of race and ethnicity, with overall safety comparable to control across most of the racial and ethnic groups analyzed.

Alirocumab in high-risk patients: Observations from the open-label expanded use program.

BACKGROUND: The alirocumab expanded use program provided open-label access to alirocumab before its commercial availability to patients with severe hypercholesterolemia not controlled with maximally tolerated doses of standard-of-care lipid-lowering therapy. OBJECTIVE: To describe the safety and lipid-lowering efficacy of alirocumab in high-risk patients who were likely to be early users of proprotein convertase subtilisin/kexin type 9 inhibitors after approval. METHODS: Patients with heterozygous familial hypercholesterolemia (HeFH) and/or coronary heart disease (CHD) and baseline low-density lipoprotein cholesterol (LDL-C) of ≥160 mg/dL on maximally tolerated lipid-lowering therapy were enrolled and received alirocumab 150 mg every 2 weeks for 24 weeks. Patients were permitted use of all available statins; those not taking any dose of statin could also be enrolled. RESULTS: Of 100 enrolled patients, 93 were white, 62 were women, and overall mean age was 58 years; 61 had HeFH, 3 had unknown type of familial hypercholesterolemia, 66 had CHD, and 30 had both familial hypercholesterolemia and CHD. Sixty-four patients were identified by their providers to have some level of statin intolerance; of these, 47 were not on statin. Alirocumab reduced LDL-C on average from 221 mg/dL at baseline to 102 mg/dL by week 24 (-55%). Treatment-emergent adverse events were experienced in 61% of patients and treatment-emergent adverse events leading to permanent treatment discontinuation in 3% of patients; no deaths occurred. CONCLUSIONS: Safety and efficacy observations from the open-label alirocumab expanded use program of very high-risk patients with HeFH and/or CHD and baseline LDL-C of ≥160 mg/dL uncontrolled by maximally tolerated lipid-lowering therapy were consistent with those in the placebo/ezetimibe-controlled ODYSSEY trials.

Prescribing Patterns of Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors in Eligible Patients With Clinical Atherosclerotic Cardiovascular Disease or Heterozygous Familial Hypercholesterolemia.

Two proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are approved for patients with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia who require additional low-density lipoprotein cholesterol (LDL-C) lowering. This retrospective study sought to determine differences between eligible patients who were prescribed and those who were not prescribed a PCSK9 inhibitor. Patients from an electronic medical record database were included in the analysis, and their demographic, clinical, and treatment characteristics were evaluated. Of 368,624 PCSK9 inhibitor-eligible patients, 1,752 (<0.5%) received a PCSK9 inhibitor prescription. Patients who received a PCSK9 inhibitor were more frequently associated with a higher cardiovascular disease risk category and a higher baseline LDL-C level (139.4 vs 103.5 mg/dl; p <0.0001) compared with those who did not. Patients with a PCSK9 inhibitor prescription were significantly more likely to be on ezetimibe, alone or in combination with a statin, at baseline compared with those without (29% vs 5%; p <0.0001). The use of a PCSK9 inhibitor was very low in the 2 groups of patients identified as PCSK9 inhibitor-eligible based on the American College of Cardiology Expert Consensus Decision Pathway. In conclusion, this study demonstrates that most PCSK9 inhibitor-eligible patients do not receive a PCSK9 inhibitor prescription, highlighting that many high-risk patients could benefit from additional LDL-C lowering with a PCSK9 inhibitor.

Association of Patient Perceptions of Cardiovascular Risk and Beliefs on Statin Drugs With Racial Differences in Statin Use: Insights From the Patient and Provider Assessment of Lipid Management Registry.

Importance: African American individuals face higher atherosclerotic cardiovascular disease risk than white individuals; reasons for these differences, including potential differences in patient beliefs regarding preventive care, remain unknown. Objective: To evaluate differences in statin use between white and African American patients and identify the potential causes for any observed differences. Design, Setting, and Participants: Using the 2015 Patient and Provider Assessment of Lipid Management (PALM) Registry data, we compared statin use and dosing between African American and white outpatient adults who were potentially eligible for primary or secondary prevention statins. A total of 138 US community health care practices contributed to the data. Data analysis was conducted from March 2017 to May 2018. Main Outcomes and Measures: Primary outcomes were use and dosing of statin therapy according to the 2013 American College of Cardiology/American Heart Association guideline by African American or white race. Secondary outcomes included lipid levels and patient-reported beliefs. Poisson regression was used to evaluate the association between race and statin undertreatment, a category combining people who were not taking a statin or those taking a dose intensity lower than recommended. Results: A total of 5689 patients (806 [14.2%] African American) in the PALM registry were eligible for statin therapy. African American individuals were less likely than white individuals to be treated with a statin (570/807 [70.6%] vs 3654/4883 [74.8%]; P = .02). Among those treated, African American patients were less likely than white patients to receive a statin at guideline-recommended intensity (269 [33.3%] vs 2145 [43.9%], respectively; P < .001; relative risk, 1.07 [95% CI, 1.00-1.15]; P = .05, after adjustment for demographic and clinical factors). The median (interquartile range) low-density lipoprotein cholesterol levels of patients receiving treatment were higher among African American than white individuals (97.0 [76.0-121.0] mg/dL vs 85.0 [68.0-105.0] mg/dL; P < .001). African American individuals were less likely than white individuals to believe statins were safe (292 [36.2%] vs 2800 [57.3%]; P < .001) or effective (564 [70.0%] vs 3635 [74.4%]; P = .008) and were less likely to trust their clinician (663 [82.3%] vs 4579 [93.8%]; P < .001). Group differences in statin undertreatment were not significant after adjusting for demographic, clinical, and clinician factors, socioeconomic status, and patient beliefs (final adjusted relative risk, 1.03 [95% CI 0.96-1.11]; P = .35). Conclusions and Relevance: African American individuals were less likely to receive guideline-recommended statin therapy. Demographic, clinical, socioeconomic, belief-related, and clinician differences contributed to observed differences and represent potential targets for intervention.

A Quantitative Systems Pharmacology Platform to Investigate the Impact of Alirocumab and Cholesterol-Lowering Therapies on Lipid Profiles and Plaque Characteristics.

Reduction in low-density lipoprotein cholesterol (LDL-C) is associated with decreased risk for cardiovascular disease. Alirocumab, an antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduces LDL-C. Here, we report development of a quantitative systems pharmacology (QSP) model integrating peripheral and liver cholesterol metabolism, as well as PCSK9 function, to examine the mechanisms of action of alirocumab and other lipid-lowering therapies, including statins. The model predicts changes in LDL-C and other lipids that are consistent with effects observed in clinical trials of single or combined treatments of alirocumab and other treatments. An exploratory model to examine the effects of lipid levels on plaque dynamics was also developed. The QSP platform, on further development and qualification, may support dose optimization and clinical trial design for PCSK9 inhibitors and lipid-modulating drugs. It may also improve our understanding of factors affecting therapeutic responses in different phenotypes of dyslipidemia and cardiovascular disease.