Dylan L. Steen

A review of low-density lipoprotein cholesterol, treatment strategies, and its impact on cardiovascular disease morbidity and mortality

Cardiovascular (CV) disease is a leading cause of death worldwide, accounting for approximately 31.4% of deaths globally in 2012. It is estimated that, from 1980 to 2000, reduction in total cholesterol accounted for a 33% decrease in coronary heart disease (CHD) deaths in the United States. In other developed countries, similar decreases in CHD deaths (ranging from 19%-46%) have been attributed to reduction in total cholesterol. Low-density lipoprotein cholesterol (LDL-C) has now largely replaced total cholesterol as a risk marker and the primary treatment target for hyperlipidemia. Reduction in LDL-C levels by statin-based therapies has been demonstrated to result in a reduction in the risk of nonfatal CV events and mortality in a continuous and graded manner over a wide range of baseline risk and LDL-C levels. This article provides a review of (1) the relationship between LDL-C and CV risk from a biologic, epidemiologic, and genetic standpoint; (2) evidence-based strategies for LDL-C lowering; (3) lipid-management guidelines; (4) new strategies to further reduce CV risk through LDL-C lowering; and (5) population-level and health-system initiatives aimed at identifying, treating, and lowering lifetime LDL-C exposure.

Patterns and predictors of lipid-lowering therapy in patients with atherosclerotic cardiovascular disease and/or diabetes mellitus in 2014: Insights from a large US managed-care population

Lowering low‐density lipoprotein cholesterol with statins reduces risk of cardiovascular events. We examined patterns and predictors of filled prescriptions for lipid‐lowering therapy (LLT) in subgroups of patients with atherosclerotic cardiovascular disease (ASCVD) and/or diabetes mellitus (DM).

Impact of an Atrial Fibrillation Decision Support Tool on thromboprophylaxis for atrial fibrillation.

BACKGROUND Appropriate thromboprophylaxis for patients with atrial fibrillation (AF) remains a national challenge. METHODS We hypothesized that provision of decision support in the form of an Atrial Fibrillation Decision Support Tool (AFDST) would improve thromboprophylaxis for AF patients. We conducted a cluster randomized trial involving 15 primary care practices and 1,493 adults with nonvalvular AF in an integrated health care system between April 2014 and February 2015. Physicians in the intervention group received patient-level treatment recommendations made by the AFDST. Our primary outcome was the proportion of patients with antithrombotic therapy that was discordant from AFDST recommendation. RESULTS Treatment was discordant in 42% of 801 patients in the intervention group. Physicians reviewed reports for 240 patients. Among these patients, thromboprophylaxis was discordant in 63%, decreasing to 59% 1 year later (P = .02). In nonstratified analyses, changes in discordant care were not significantly different between the intervention group and control groups. In multivariate regression models, assignment to the intervention group resulted in a nonsignificant trend toward decreased discordance (P = .29), and being a patient of a resident physician (P = .02) and a higher HAS-BLED score predicted decreased discordance (P = .03), whereas female gender (P = .01) and a higher CHADSVASc score (P = .10) predicted increased discordance. CONCLUSIONS Among patients whose physicians reviewed recommendations of the decision support tool discordant therapy decreased significantly over 1 year. However, in nonstratified analyses, the intervention did not result in significant improvements in discordant antithrombotic therapy.

Retrospective examination of lipid-lowering treatment patterns in a real-world high-risk cohort in the UK in 2014: comparison with the National Institute for Health and Care Excellence (NICE) 2014 lipid modification guidelines

Background In 2014, guidelines from the National Institute for Health and Care Excellence (NICE) provided updated recommendations on lipid-modifying therapy (LMT). We assessed clinical practice contemporaneous to release of these guidelines in a UK general practice setting for secondary and high-risk primary-prevention populations, and extrapolated the findings to UK nation level. Methods Patients from The Health Improvement Network database with the following criteria were included: lipid profile in 2014 (index date); ≥20 years of age; ≥2 years representation in database prior to index; ≥1 statin indication either for atherosclerotic cardiovascular disease (ASCVD) or the non-ASCVD conditions high-risk diabetes mellitus and/or chronic kidney disease. Results Overall, 183 565 patients met the inclusion criteria (n=91 479 for ASCVD, 92 086 for non-ASCVD). In those with ASCVD, 79% received statin treatment and 31% received high-intensity statin. In the non-ASCVD group, 62% were on a statin and 57% received medium-intensity or high-intensity statin. In the ASCVD and non-ASCVD cohorts, 6% and 15%, respectively, were already treated according to dosing recommendations as per updated NICE guidelines. Extrapolation to the 2014 UK population indicated that, of the 3.3 million individuals with ASCVD, 2.4 million would require statin uptitration and 680 000 would require statin initiation (31% de novo initiation, 60% reinitiation, 9% addition to non-statin LMT) to achieve full concordance with updated guidelines. Of the 3.5 million high-risk non-ASCVD individuals, 1.6 million would require statin uptitration and 1.4 million would require statin initiation (59% de novo initiation, 36% reinitiation, 5% addition to non-statin LMT). Conclusions A large proportion of UK individuals with ASCVD and high-risk non-ASCVD received statin treatment (79% and 62%, respectively) during the year of NICE 2014 guidelines release. Up to 94% of patients with ASCVD and 85% of high-risk non-ASCVD individuals, representing ∼3 million individuals in each group, would require statin uptitration or initiation to achieve full concordance with updated guidelines.

Using an Atrial Fibrillation Decision Support Tool for Thromboprophylaxis in Atrial Fibrillation: Effect of Sex and Age

To assess the appropriateness of oral anticoagulant therapy (OAT) in women and elderly adults, looking for patterns of undertreatment or unnecessary treatment.

Predictors of Nonuse of a High‐Potency Statin After an Acute Coronary Syndrome: Insights From the Stabilization of Plaques Using Darapladib‐Thrombolysis in Myocardial Infarction 52 (SOLID‐TIMI 52) Trial

Background High‐potency statins reduce cardiovascular events after acute coronary syndromes but remain underused in clinical practice. We examined predictors of nonuse of high‐potency statins after acute coronary syndromes. Methods and Results The Stabilization of pLaques usIng Darapladib‐Thrombolysis in Myocardial Infarction (SOLID‐TIMI 52) trial enrolled patients after an acute coronary syndrome in 36 countries between 2009 and 2011. Statin use was strongly encouraged throughout the trial, and statin potency was at the discretion of the treating physician. A high‐potency statin was defined as ≥40 mg atorvastatin, ≥20 mg rosuvastatin, or 80 mg simvastatin daily. Predictors of nonuse of high‐potency statins were examined using logistic regression. Of the patients included (n=12 446), 11 850 (95.2%) were treated with a statin at baseline after acute coronary syndrome (median 14 days), but only 5212 (41.9%) were on a high‐potency statin. Selected patient factors associated with nonuse of high‐potency statins included age ≥75 years (odds ratio 1.39, 95% CI 1.24–1.56), female sex (odds ratio 1.11, 95% CI 1.02–1.22), renal dysfunction (odds ratio 1.17, 95% CI 1.03–1.32), and heart failure during hospital admission (odds ratio 1.43, 95% CI 1.27–1.62). At 3 months after baseline, only 49% of patients had low‐density lipoprotein cholesterol <70 mg/dL. Among the 5490 patients (59%) who were not on a high‐potency statin at 3 months, lower low‐density lipoprotein cholesterol was a predictor of nonuse of a high‐potency statin after a median of 2.3 years (odds ratio 1.15 for 10 mg/dL decrease, 95% CI 1.11–1.19). Conclusion Despite the widespread use of statins after acute coronary syndromes, most patients are not treated with high‐potency statins early and late after the event, including patients at the highest risk of recurrent cardiovascular events. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01000727.

Atrial fibrillation decision support tool: Population perspective

Background Appropriate thromboprophylaxis for patients with atrial fibrillation or atrial flutter (AF) remains a national challenge. The recent availability of direct oral anticoagulants (DOACs) with comparable efficacy and improved safety compared with warfarin alters the balance between risk factors for stroke and benefit of anticoagulation. Our objective was to examine the impact of DOACs as an alternative to warfarin on the net benefit of oral anticoagulant therapy (OAT) in a real‐world population of AF patients. Methods This is a retrospective cohort study of patients with paroxysmal or persistent nonvalvular AF. We updated an Atrial Fibrillation Decision Support Tool (AFDST) to include DOACs as treatment options. The tool generates patient‐specific recommendations based upon individual patient risk factor profiles for stroke and major bleeding using quality‐adjusted life‐years (QALYs) calculated for each treatment strategy by a decision analytic model. The setting included inpatient and ambulatory sites in an academic health center in the midwestern United States. The study involved 5,121 adults with nonvalvular AF seen for any ambulatory visit or inpatient hospitalization over the 1‐year period (January through December 2016). Outcome measure was net clinical benefit in QALYs. Results When DOACs are a therapeutic option, the AFDST recommends OAT for 4,134 (81%) patients and no antithrombotic therapy or aspirin for 489 (9%). A strong recommendation for OAT could not be made in 498 (10%) patients. When warfarin is the only option, OAT is recommended for 3,228 (63%) patients and no antithrombotic therapy or aspirin for 973 (19%). A strong recommendation for OAT could not be made in 920 (18%) patients. In total, 1,508 QALYs could be gained if treatment were changed to that recommended by the AFDST. Conclusions Availability of DOACs increases the proportion of patients for whom oral anticoagulation therapy is recommended in a real‐world cohort of AF patients and increased projected QALYs by more than 1,500 when all patients are receiving thromboprophylaxis as recommended by the AFDST compared with current treatment.

Widening the path and window of opportunity for FDA approval of non-vitamin K oral anticoagulant specific antidotes and reversal agents.

There remains a need for safe, immediately effective, and easy to administer antidotes for patients taking novel oral anticoagulants (NOACs) in the settings of major bleeding, need for emergency surgery, and accidental overdose. We review considerations for the successful safety and effectiveness evaluation of potential antidotes currently under development. These compounds are in expedited regulatory approval programs aimed at accelerating the preclinical and clinical evaluation and approval processes for treatments of serious conditions. We review the features of these expedited programs as well as the FDA’s efforts to broadly advance the efficiency of drug development and increase the number of new compounds brought to market. The critical path initiative and regulatory science initiative have resulted in numerous successful programs to address current challenges such as a paucity of validated biomarkers and surrogate endpoints as well as unreliable animal models of toxicity. The FDA has also advocated for increased use of pharmacokinetic/pharmacodynamic modeling and adaptive trial design. These efforts foster collaboration between academia, industry and the public sector across interdisciplinary sciences and may continue to widen the pathway for NOAC-specific reversal agents and other novel compounds.

Highlights from the 2018 American College of Cardiology scientific session in Orlando, Florida

The ODYSSEY Outcomes trial tested whether treatment with alirocumab to a LDL-C range of 15–50 mg/dL, compared to placebo, reduces cardiovascular outcomes in patients with recent acute coronary syndromes (ACS) and elevated atherogenic lipoprotein levels despite statin optimization [1]. Alirocumab, a fully human monoclonal antibody, binds and inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), reducing the destruction of hepatic surface LDL receptors, thus increasing LDL removal from the bloodstream. Trial inclusion criteria were: (1) ACS within 1–12 months; (2) atorvastatin 40–80 mg daily, rosuvastatin 20–40 mg daily, or maximally tolerated dose for ≥ 2 weeks; and (3) LDL-C ≥ 70 mg/dL, non-HDL-C ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary endpoint was coronary heart disease (CHD) death, non-fatal myocardial infarction (MI), fatal or non-fatal ischemic stroke, or unstable angina (UA) requiring hospitalization [2]. The study 1:1 randomized 18,924 subjects to alirocumab versus placebo at a median of 2.6 months from the index ACS [1]. Baseline median LDL-C in both arms was 87 mg/ dL. Median follow-up was 2.8 years with during with baseline use of standard-of-care medications and retention were high. As seen in Table 1, alirocumab caused a 15% relative (1.6% absolute) reduction in the primary endpoint, which was statistically significant. Using hierarchical testing, a variety of secondary endpoints also met statistical significance. No evidence for any safety or tolerability issues were found other than a mild increase in injection-site reactions. Importantly, the results were largely consistent with the FOURIER trial results which tested another PCSK9 inhibitor, evolocumab, in a “stable” atherosclerotic population [3].

Highlights from the 2017 American Heart Association Scientific Sessions in Anaheim, California

The Journal of Thrombosis and Thrombolysis is proud to present the first article in a new section entitled “National and International Meeting Highlights”. Each article in this series will review some of the major studies or guideline updates presented at international conferences. The conferences covered in this series will include the American Heart Association Annual Scientific Sessions, American Society of Hematology Annual Meeting, American College of Cardiology Annual Scientific Session, International Society of Thrombosis and Haemostasis Biennial Congress, and European Society of Cardiology Annual Congress. Although all the exciting presentations at each conference cannot be covered in these articles, we hope this series provides readers with a taste of the ones that may shape guidelines and practice.