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Patients with atherosclerotic cardiovascular disease (ASCVD) and prior revascularization are at high risk of further cardiovascular events and may require additional lipid-lowering therapies beyond maximally tolerated statin therapy. We assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in patients with ASCVD, with or without prior coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]).Data from eight controlled (placebo/ezetimibe) phase 3 ODYSSEY trials were pooled and stratified by trial design: alirocumab 150 mg or 75 mg with possible dose increase to 150 mg (75/150 mg) every 2 weeks (Q2W) versus placebo, and alirocumab 75/150 mg Q2W versus ezetimibe. Most patients received background maximally tolerated statin therapy.Among 4629 randomized patients with hypercholesterolemia, 3382 had ASCVD including 2191 with prior revascularization. Although baseline characteristics were comparable between alirocumab and control groups, revascularized patients were more likely to be male, have had prior myocardial infarction/stroke, have higher lipoprotein (a) and PCSK9 levels, and were more often treated with high-intensity statin therapy. Alirocumab significantly reduced low-density lipoprotein cholesterol (LDL-C; primary endpoint; p 0.0001), lipoprotein (a), non-high-density lipoprotein cholesterol, and apolipoprotein B levels from baseline to week 24 (vs. control), regardless of stratified treatment group or revascularization status. On-treatment LDL-C levels with alirocumab ranged from 45.6 to 64.8 mg/dL. Alirocumab had a similar safety profile regardless of revascularization status, and higher rates of injection-site reactions versus controls.Alirocumab is generally well-tolerated and effective with a similar safety profile in high-risk patients with or without prior revascularization (PCI/CABG).

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.Statin use and intensity were evaluated in 5,905 statin-eligible primary or secondary prevention patients from 138 PALM Registry practices.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).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.

Background and aims Guidelines recommend high-intensity statins for patients with atherosclerotic cardiovascular disease (ASCVD). Subgroups with comorbidities that increase cardiovascular risk, such as diabetes mellitus (DM), chronic kidney disease (CKD) or polyvascular disease (PoVD), may derive greater absolute benefit from addition of non-statin therapies. We assessed the relationship between lower low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) risk reduction during alirocumab phase III ODYSSEY trials among these subgroups. Methods Patient data were pooled from nine trials comparing alirocumab with control (placebo/ezetimibe), predominantly on background maximally tolerated statin. Patients with baseline ASCVD were stratified into subgroups with DM, CKD or PoVD, or without comorbidities, and between-group relative and absolute benefits were compared. Results Among 3505 patients with ASCVD, 1573 had no comorbidities, 981 had DM, 660 had CKD and 943 had PoVD, with overlap between comorbidities; mean baseline LDL-C levels were 119 (ASCVD overall), 123, 117, 114 and 113 mg/dL, respectively. Overall, each 39 mg/dL lower on-study LDL-C was associated with a 25% lower MACE risk, hazard ratio 0.75 (95% confidence interval, 0.62–0.90, p = 0.0023), with a similar lower risk observed in each very high-risk subgroup (DM, CKD or PoVD; 30–35%) but not in the subgroup without these comorbidities (9%). Absolute benefits were greater for very high-risk subgroups; lowering LDL-C from 120 to 40 mg/dL would result in 2.76–4.35 fewer MACE/100 patient-years versus 0.3 for no comorbidities. Conclusions Among patients with ASCVD and mean baseline LDL-C >100 mg/dL, patients with DM, CKD or PoVD appeared to derive greater absolute cardiovascular benefits from further LDL-C reduction than those without.

Background The 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults recommended testing low‐density lipoprotein cholesterol ( LDL ‐C) to identify untreated patients with LDL ‐C ≥190 mg/dL, assess lipid‐lowering therapy adherence, and consider nonstatin therapy. We sought to determine whether clinician lipid testing practices were consistent with these guidelines. Methods and Results The PALM (Patient and Provider Assessment of Lipid Management) registry enrolled primary and secondary prevention patients from 140 US cardiology, endocrinology, and primary care offices in 2015 and captured demographic data, lipid treatment history, and the highest LDL ‐C level in the past 2 years. Core laboratory lipid levels were drawn at enrollment. Among 7627 patients, 2787 (36.5%) had no LDL ‐C levels measured in the 2 years before enrollment. Patients without chart‐documented LDL ‐C levels were more often women, nonwhite, uninsured, and non–college graduates (all P P =0.0034), a high‐intensity statin (21.5% versus 24.3%; P =0.016), nonstatin lipid‐lowering therapy (24.8% versus 27.3%; P =0.037), and had higher core laboratory LDL ‐C levels at enrollment (median 97 versus 92 mg/dL; P LDL ‐C testing. Of 166 individuals with core laboratory LDL ‐C levels ≥190 mg/dL, 36.1% had no LDL ‐C measurement in the prior 2 years, and 57.2% were not on a statin at the time of enrollment. Conclusions In routine clinical practice, LDL ‐C testing is associated with higher‐intensity lipid‐lowering treatment and lower achieved LDL ‐C levels.

Background In statin trials, men and women derived similar relative risk reductions in cardiovascular events per 39 mg/ dL low‐density lipoprotein cholesterol ( LDL ‐C) reduction. We explored whether lower LDL ‐C levels and greater LDL ‐C percentage reductions than those achieved with statins are associated with reduced major adverse cardiovascular event ( MACE ) rates in women as well as men. Methods and Results Data pooled from 10 phase 3 ODYSSEY randomized trials (n=4983) comparing alirocumab with control (placebo/ezetimibe) were assessed for association between 39 mg/dL lower on‐treatment LDL ‐C and percentage LDL ‐C change from baseline, and MACE risk by sex, using multivariable Cox regression. Mean baseline LDL ‐C was 135 mg/dL (women) and 121 mg/dL (men). Average on‐treatment LDL ‐C levels with alirocumab, ezetimibe, and placebo were 71, 114, and 134 mg/dL, respectively, in women (n=1882) and 52, 93, and 122 mg/dL, respectively, in men (n=3090). Overall, 36.5% and 58.7% of women and men, respectively, achieved on‐treatment LDL ‐C LDL ‐C was associated with a 33% and 22% lower risk of MACE in women ( P =0.0209) and men ( P =0.0307), respectively, with no significant between‐sex difference ( P for heterogeneity=0.4597). Results were similar when analyzed per 50% LDL ‐C reduction, 24% ( P =0.1094) and 29% ( P =0.0125) lower MACE risk in women and men, respectively ( P for heterogeneity=0.7499). Alirocumab was generally well tolerated in both sexes. Conclusions The present analysis reinforces the notion that both sexes derive a similar cardiovascular benefit from LDL ‐C lowering. Although women had slightly higher on‐treatment LDL ‐C than men, both sexes showed a similar lower MACE risk with lower LDL ‐C.

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.To evaluate differences in statin use between white and African American patients and identify the potential causes for any observed differences.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.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.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).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.

Background Current statin use and symptoms among older adults in routine community practice have not been well characterized since the release of the 2013 American College of Cardiology/American Heart Association guideline. Methods and Results We compared statin use and dosing between adults >75 and ≤75 years old who were eligible for primary or secondary prevention statin use without considering guideline‐recommended age criteria. The patients were treated at 138 US practices in the Patient and Provider Assessment of Lipid Management (PALM) registry in 2015. Patient surveys also evaluated reported symptoms while taking statins. Multivariable logistic regression models examined the association between older age and statin use and dosing. Among 6717 people enrolled, 1704 (25%) were >75 years old. For primary prevention, use of any statin or high‐dose statin did not vary by age group: any statin, 62.6% in those >75 years old versus 63.1% in those ≤75 years old ( P =0.83); high‐dose statin, 10.2% versus 12.3% in the same groups ( P =0.14). For secondary prevention, older patients were slightly less likely to receive any statin (80.1% versus 84.2% [ P =0.003]; adjusted odds ratio, 0.81; 95% confidence interval, 0.66–1.01 [ P =0.06]), but were much less likely to receive a high‐intensity statin (23.5% versus 36.2% [ P P =0.0001]). Among current statin users, older patients were slightly less likely to report any symptoms (41.3% versus 46.6%; P =0.003) or myalgias (27.3% versus 33.3%; P Conclusions Overall use of statins was similar for primary prevention in those aged >75 years versus younger patients, yet older patients were less likely to receive high‐intensity statins for secondary prevention. Statins appear to be similarly tolerated in older and younger adults.

When compared against placebo in randomized trials, statins are extremely well tolerated, causing muscle-related side effects in 1% or fewer of treated patients.1 Yet in routine practice, patients often report having symptoms which are misattributed to their statin.2–4 Using data from the PALM Registry, we examined patient-reported rates of statin intolerance, characteristics of patients with perceived side effects, and response to perceived statin intolerance in contemporary practice. The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results. The PALM Registry enrolled 7938 patients from 140 primary care, cardiology, and endocrinology practices in the United States (May 27, 2015 to November 12, 2015) and has been described in detail.5 Trained study coordinators identified eligible patients (patients on a statin, at risk for cardiovascular disease [CVD], or with prevalent CVD, in the Data Supplement) at the time of their visit, who were then sequentially enrolled. Of 9788 eligible patients, n=7937 (81%) consented and enrolled in the study. Patients were then surveyed on statin use, perceived statin-related symptoms and response to symptoms, beliefs about statins and CVD, and sociodemographic characteristics (response rate 95.3%, in the Data Supplement). Clinical characteristics and medications were abstracted from the medical record by study coordinators. All patients had core laboratory lipid levels (LabCorp, Burlington, NC). Categorical variables were compared with Mantel–Haenszel χ2 tests and continuous variables using Wilcoxon rank-sum tests. Multivariable logistic regression modeling was used to evaluate factors associated with symptoms using generalized estimating equations to account for clustering within site, with backward model selection at P

Low-density lipoprotein cholesterol (LDL-C) reductions with the PCSK9 monoclonal antibody alirocumab may be affected by background statin dose due to increased PCSK9 levels with higher statin doses. Data from 8 Phase 3 trials conducted with background statin (n = 4629) were pooled by alirocumab dose (75 or 150 mg every 2 weeks) and control (placebo/ezetimibe), and analyzed by background statin type/dose. Overall, 58.4% received high-dose statins (atorvastatin 40–80 mg, rosuvastatin 20–40 mg, simvastatin 80 mg), 28.6% moderate-dose statins (atorvastatin 20–P-values non-significant). Incidence of adverse events was similar for alirocumab versus control, except for a higher rate of injection-site reactions with alirocumab. In summary, alirocumab provided consistent LDL-C reductions and was generally well tolerated independent of background statin type/dose.

A novel 18F-labeled ligand for the norepinephrine transporter (N-[3-bromo-4-(3-18F-fluoro-propoxy)-benzyl]-guanidine [LMI1195]) is in clinical development for mapping cardiac nerve terminals in vivo using PET. Human safety, whole-organ biodistribution, and radiation dosimetry of LMI1195 were evaluated in a phase 1 clinical trial. Methods: Twelve healthy subjects at 3 clinical sites were injected intravenously with 150–250 MBq of LMI1195. Dynamic PET images were obtained over the heart for 10 min, followed by sequential whole-body images for approximately 5 h. Blood samples were obtained, and heart rate, electrocardiogram, and blood pressure were monitored before and during imaging. Residence times were determined from multiexponential regression of organ region-of-interest data normalized by administered activity (AA). Radiation dose estimates were calculated using OLINDA/EXM. Myocardial, lung, liver, and blood-pool standardized uptake values were determined at different time intervals. Results: No adverse events due to LMI1195 were seen. Blood radioactivity cleared quickly, whereas myocardial uptake remained stable and uniform throughout the heart over 4 h. Liver and lung activity cleared relatively rapidly, providing favorable target-to-background ratios for cardiac imaging. The urinary bladder demonstrated the largest peak uptake (18.3% AA), followed by the liver (15.5% AA). The mean effective dose was 0.026 ± 0.0012 mSv/MBq. Approximately 1.6% AA was seen in the myocardium initially, remaining above 1.5% AA (decay-corrected) through 4 h after injection. The myocardium-to-liver ratio was approximately unity initially, increasing to more than 2 at 4 h. Conclusion: These preliminary data suggest that LMI1195 is well tolerated and yields a radiation dose comparable to that of other commonly used PET radiopharmaceuticals. The kinetics of myocardial and adjacent organ activity suggest that cardiac imaging should be possible with acceptable patient radiation dose.

In the United States heart disease causes more than one-third of all deaths and most of these occur in women, not men, although women and health care professionals alike continue to view death from heart disease as a threat primarily to middle-aged men. The disparity between genders in the incidence of cardiovascular disease (CVD) may be the result of significant differences in both cardiovascular risk factors and presentation between men and women. This article reviews recent data regarding unique sex-specific characteristics of both risk for, and presentation of, CVD in women.

Background Despite improvements in diagnosis and treatment, the prevalence of hyperlipidemia among adults in the United States remains high. Data are limited on treatment patterns and patient perceptions of cardiovascular disease risk since the release of new lipid guidelines. Objectives The objectives of the PALM registry are to assess contemporary patterns of lipid-lowering therapy use among adults receiving care in a nationally representative cohort of community clinics, determine consistency of treatment with varying lipid guidelines, identify factors affecting use of lipid-lowering therapy including patient-reported statin intolerance, and assess patient and provider knowledge of cardiovascular risk reduction goals. Study Design The PALM registry will enroll 7,500 patients likely to be considered for lipid-lowering therapy from 175 cardiology, primary care, and endocrinology practices across the United States. In this cross-sectional, observational registry, a novel tablet-based platform will be used to collect patient-reported knowledge, attitudes, and beliefs regarding cardiovascular risk reduction and lipid management. Chart abstraction and core laboratory lipid levels will describe current lipid management. Provider surveys will assess perception of current lipid-lowering goals and barriers to optimal cardiovascular risk reduction. Conclusion The PALM registry will allow for better understanding of current practice patterns, patient experiences, and patient and provider attitudes toward cholesterol management for cardiovascular disease risk reduction. These data can be used to better understand gaps in care and design targeted interventions to improve uptake of lipid-lowering therapies for cardiovascular risk reduction.

Abstract Recently, increases in the plasma concentration of soluble fibrin (SF) have been suggested to be sensitive and specific for myocardial infarction (MI). However, the relationship between elevations in the SF concentration and the onset of symptoms and clinical course of MI is unknown. In addition, there are no data regarding the relationship between SF concentrations and concentrations of other markers of procoagulant (fibrinopeptide A [FPA]) and fibrinolytic (cross-linked fibrin degradation products [XL-FDPs]) activity in patients with MI. In this study, concentrations of SF were measured with a novel antigen-based assay for 93 MI patients and 29 control subjects, and the relationship between SF concentrations and those of XL-FDPs and FPA was determined. Increases in SF, FPA, and XL-FDP concentrations were documented in 55.9%, 45.2%, and 73.9%, respectively, of patients with MI, but there was no relationship between the concentrations of these markers. Increases in the concentration of SF or XL-FDPs did not show a relationship to increases in the concentration of FPA. Concentrations of XL-FDPs but not of SF were elevated to a greater extent in patients with MI complications (defined as death, ventricular arrhythmia, severe congestive heart failure, or mural thrombus). Increases in SF and XL-FDPs were not sensitive enough for the diagnosis of MI, but increased concentrations of XL-FDPs appear to predict those patients who are at higher risk for MI-related complications.

Hirudin is a potent, direct, and highly specific inhibitor of both free and clot-bound thrombin. Previous reports have shown hirudin to be superior to heparin when given with tissue plasminogen activator and aspirin for improving the incidence and rate of reperfusion as well as reducing reocclusion of infarct-related arteries. Patients with acute myocardial infarction were randomized to hirudin versus heparin in conjunction with streptokinase (1.5 × 10 6 U) and aspirin (325 mg/day). Study drug treatment was a 5-day infusion of either heparin, as a 5,000 U bolus, followed by a 1,000 U/hour infusion adjusted to a target activated partial thromboplastin time of 65 to 90 seconds (n = 71), or a constant infusion of hirudin at 1 of 3 doses (dose 1, n = 55: 0.15 mg/kg bolus + 0.05 mg/kg/hour infusion; dose 2, n = 31: 0.3 mg/kg bolus + 0.1 mg/kg/hour infusion; or dose 3, n = 36: 0.6 mg/kg bolus + 0.2 mg/kg/hour infusion). The incidence of major hemorrhage was similar between the heparin group (5.6%) and any of the hirudin dose groups (dose 1 = 5.5%, dose 2 = 6.5%, dose 3 = 5.6%). At hospital discharge the occurrence of death, nonfatal reinfarction, congestive heart failure, or cardiogenic shock was greater in patients receiving the lowest dose of hirudin (21.6%) than in those receiving the higher doses of hirudin (dose 2 = 9.7%, dose 3 = 11.4%). A trend toward a reduction in mortality and nonfatal reinfarction was seen at hospital discharge with the 2 higher doses of hirudin (dose 2 = 9.7%, dose 3 = 5.7%) when compared with the lowest dose of hirudin (13.7%) and at 6 weeks (dose 2 = 9.7%, dose 3 = 5.7% vs dose 1 = 17.6%). In this pilot trial, hirudin appeared to be as safe as heparin when given with streptokinase and aspirin to patients with acute myocardial infarction. Although this study was not prospectively designed to detect a difference in efficacy, a trend toward a lower rate of death, reinfarction, cardiogenic shock, and congestive heart failure was observed with the higher doses of hirudin when compared with the lowest dose.

Background The purpose of this study was to evaluate the pulmonary and systemic hemodynamic effects of Definity in patients with normal as well as those with elevated pulmonary artery pressure at baseline. Secondary objectives of the study were to evaluate safety and determine whether any potential immunologic reactions develop after Definity administration. Methods Patients with normal and elevated pulmonary artery systolic pressure undergoing right-heart catheterization received Definity (10 μL/kg) as a slow bolus over 30 to 60 sec. Multiple sequential measurements of right atrial pressure, pulmonary artery systolic pressure, pulmonary artery diastolic pressure, mean pulmonary artery pressure, cardiac output, and pulmonary capillary wedge pressure were made before and after Definity administration. Vital signs, electrocardiograms, and blood samples were taken at multiple time points. Patients were followed for the development of adverse events. Results A total of 32 patients (16 with elevated pulmonary artery systolic pressure > 35 mm Hg) were enrolled. No significant changes in any pulmonary or systemic hemodynamic parameters, vital sign values, electrocardiographic data, or laboratory variables were found for data obtained before versus after receipt of Definity. Conclusions The administration of Definity at the approved dosage does not change pulmonary or systemic hemodynamics in control patients or those with mild to moderate pulmonary hypertension. No significant changes were noted in a wide array of clinical and laboratory safety assessments after patients were exposed to Definity.

The rates of cardiovascular disease (CVD) have decreased significantly for men over the past few decades, but similar reductions have not occurred in women. Consequently, CVD remains the leading killer of women in the United States. Men usually develop heart disease earlier than women, but women develop heart disease more rapidly once menopause has occurred. A review of risk factors that are common between men and women demonstrates some notable sex-dependent differences. Many of these changes appear related to the hormonal changes that occur in menopause, such as the development of hypertension, changes in lipid concentrations, and central adiposity. In addition, diabetes is a more significant risk factor for CVD in women than men. Sociologic and physiologic factors need to be considered in treatment of risk factors, such as smoking, lack of exercise, obesity, and depression. Prevention is known to significantly reduce CVD risk, but new goals are being established for women as the sex-dependent differences have become apparent.