Characterizing a Clinical Trial - Representative, Real-World Population with Heart Failure with Reduced Ejection Fraction.

PURPOSE: Given known differences between real-world and clinical trial populations, we characterized demographics, clinical characteristics, and outcomes using real-world (RW) data for patients with heart failure with reduced ejection fraction (HFrEF), including those similar to subjects enrolled in an HFrEF clinical trial to better understand patient populations that could benefit from novel therapies. PATIENTS AND METHODS: Using Vanderbilt University Medical Center electronic health records (2006-2019), two RW cohorts of HFrEF patients were identified. The "Clinical Cohort" was based on a validated HFrEF algorithm and left ventricular ejection fraction (LVEF) ≤40%. The "GALACTIC-HF-like Cohort" mirrored enrollment requirements of the GALACTIC-HF clinical trial including hospitalizations, medications, laboratory values, and LVEF ≤35%. RESULTS: Median age at index for the Clinical Cohort (N = 3954) and GALACTIC-HF-like Cohort (N = 1541) were 65 and 61 years, respectively; both were 67% male and 80% white. Over half had coronary artery disease (55% Clinical vs 64% GALACTIC-HF-like); hypercholesterolemia was common (69% Clinical vs 74% GALACTIC-HF-like). Chronic kidney disease (31 vs 21%), atrial fibrillation (32 vs 29%), and cardiac resynchronization or implantable cardioverter defibrillator (26 vs 23%) were higher in the GALACTIC-HF-like Cohort. ACE inhibitor use was high in both groups but more common in the GALACTIC-HF-like Cohort (71% and 82%, respectively). Beta-blockers or loop diuretics were used by >90% of both cohorts. HF hospitalization rates were 261 (95% CI 224, 297) per 1000 person-years in Clinical versus 523 (484, 562) in GALACTIC-HF-like Cohort (median follow-up of 2.9 and 4.2 years, respectively). CONCLUSION: Approximately 40% of RW HFrEF patients met criteria for the GALACTIC-HF trial. While findings of ongoing clinical trials may be directly generalizable to this sizable proportion of patients, future trials should examine whether the majority of patients with lower prevalence of comorbidities and rate of HF hospitalization could benefit from emerging HF treatments.

Designing, Conducting, Monitoring, and Analyzing Data from Pragmatic Randomized Clinical Trials: Proceedings from a Multi-stakeholder Think Tank Meeting.

In late 2018, the Food and Drug Administration (FDA) outlined a framework for evaluating the possible use of real-world evidence (RWE) to support regulatory decision-making. This framework was created to facilitate studies that would generate high-quality RWE, including pragmatic clinical trials (PCTs), which are randomized trials designed to inform clinical or policy decisions by assessing the real-world effectiveness of an intervention. There is general agreement among experts that the use of existing healthcare and patient-generated data holds promise for making randomized trials more efficient, less costly, and more generalizable. Yet the benefits of relying on real-world data sources must be weighed against difficulties with ensuring data integrity and completeness. Additionally, appropriately monitoring patient safety in randomized trials of new drugs using healthcare system data that might not be available in real time can be quite difficult. Recognizing that these and other concerns are critical to the development and acceptability of PCTs, a group of stakeholders from academia, industry, professional organizations, regulatory bodies, government agencies, and patient advocates discussed a path forward for PCT growth and sustainability at a think tank meeting entitled "Monitoring and Analyzing Data from Pragmatic Streamlined Randomized Clinical Trials," which took place in January 2019 (Washington, DC). The goals of this meeting were to: (1) evaluate study design and methodological options specific to PCTs that have the potential to yield high-quality evidence; (2) discuss best practices to ensure data quality in PCTs; and (3) identify appropriate methods for study monitoring. Proceedings from the think tank meeting are summarized in this manuscript.

Persistent Safety and Efficacy of Evolocumab in Patients with Statin Intolerance: a Subset Analysis of the OSLER Open-Label Extension Studies.

PURPOSE: Evolocumab reduced low-density lipoprotein cholesterol (LDL-C) in 12-week trials in statin-intolerant patients (GAUSS-1 and GAUSS-2); however, the persistence of efficacy during longer-term treatment is unknown. This subset analysis of the open-label extension studies (OSLER-1 and OSLER-2) aimed to evaluate the safety and efficacy of evolocumab up to 2 years in statin-intolerant patients. METHODS: Patients who completed GAUSS-1 and GAUSS-2 were enrolled in the OSLER studies and rerandomized 2:1 to evolocumab (140 mg biweekly or 420 mg monthly) plus standard of care (SOC) or SOC during year 1, and thereafter, evolocumab plus SOC. RESULTS: A total of 382 statin-intolerant patients who completed the GAUSS-1 and GAUSS-2 parent studies were enrolled and rerandomized into the OSLER studies. After year 1, 246 (98%) patients randomized to evolocumab plus SOC and 124 (95%) on SOC during year 1 remained in the OSLER studies; after year 2, 364 (95%) remained on study. Mean parent study baseline LDL-C concentration was 4.97-5.02 mmol/L (192-194 mg/dL). The median percentage reduction from baseline in LDL-C was 13% for SOC and 57% for evolocumab plus SOC at year 1, and 59% for evolocumab plus SOC at year 2. The patient incidence of muscle-related adverse events during year 1 in the SOC and evolocumab plus SOC groups was 16% and 14%, respectively, and 11% for evolocumab plus SOC at year 2. No patient discontinued the study due to adverse events. CONCLUSION: Evolocumab plus SOC was persistently safe, tolerable, and efficacious for up to 2 years in statin-intolerant patients.

Willingness to be Reinitiated on a Statin (from the REasons for Geographic and Racial Differences in Stroke Study).

Guidelines recommend attempting to reinitiate statins in patients who discontinue treatment. Previous experiences while taking a statin, including side effects, may reduce a patient's willingness to reinitiate treatment. We determined the percentage of adults who are willing to reinitiate statin therapy after treatment discontinuation. Factors associated with willingness to reinitiate a statin were also examined. A statin questionnaire was administered and study examination conducted in black and white US adults enrolled in the nationwide REasons for Geographic And Racial Differences in Stroke study from 2013 to 2017. In participants who self-reported ever having taken a statin (n = 7,216, mean age 72 years, 53% women, 34% black), 1,081 (15%) reported having discontinued treatment. Among those who discontinued treatment, statin side effects, perceived lack of need for a statin, and cost were reported by 66%, 31%, and 3% of participants, respectively. Overall, 37% of participants who had discontinued treatment were willing to reinitiate statin therapy. Participants who discontinued treatment due to cost (prevalence ratio [PR] 1.61; 95% confidence interval (CI) 1.01, 2.57) were more likely to report a willingness to reinitiate therapy. Participants with a low-density lipoprotein-cholesterol ≥130 mg/dl versus <100 mg/dl (PR 0.69; 95% CI 0.53, 0. 88) and who discontinued treatment due to side effects (PR 0.51; 95% CI 0.41, 0.64) were less likely to report willingness to reinitiate statin therapy. In conclusion, a substantial proportion of participants who discontinued statin therapy were willing to reinitiate treatment. Healthcare providers should discuss reinitiation of statin therapy with their patients who have discontinued treatment.

Healthcare Utilization and Statin Re-Initiation Among Medicare Beneficiaries With a History of Myocardial Infarction.

BACKGROUND: Contact with the healthcare system represents an opportunity for individuals who discontinue statins to re-initiate treatment. To help identify opportunities for healthcare providers to emphasize the risk-lowering benefits accrued through restarting statins, we determined the types of healthcare utilization associated with statin re-initiation among patients with history of a myocardial infarction. METHODS AND RESULTS: Medicare beneficiaries with a statin pharmacy fill claim within 30 days of hospital discharge for a myocardial infarction in 2007 to 2012 (n=158 795) were followed for 182 days postdischarge to identify treatment discontinuation, defined as 60 continuous days without statins (n=24 461). Re-initiation was defined as a statin fill within 365 days of the discontinuation date (n=13 136). Using a case-crossover study design and each beneficiary as their own control, healthcare utilization during 0 to 14 days before statin re-initiation (case period) was compared with healthcare utilization 30 to 44 days before statin re-initiation (control period). The mean age of beneficiaries was 75.4 years; 52.8% were women and 81.9% were white. For routine healthcare utilization, the odds ratio (95% confidence interval) for statin re-initiation associated with lipid panel testing was 2.65 (1.93-3.65), outpatient primary care was 1.31 (1.23-1.40), and outpatient cardiologist care was 1.38 (1.28-1.50). For acute healthcare utilization, the odds ratio (95% confidence interval) for statin re-initiation associated with emergency department visits was 1.77 (1.31-2.40), coronary heart disease (CHD) hospitalizations was 3.16 (2.41-4.14) and non-coronary heart disease hospitalizations was 1.73 (1.49-2.01). CONCLUSIONS: The weaker association of routine versus acute healthcare utilization with statin re-initiation suggests missed opportunities to reinforce the importance of statin therapy for secondary prevention.

Long-term safety, tolerability, and efficacy of evolocumab in patients with heterozygous familial hypercholesterolemia.

BACKGROUND: Evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9, is safe and effective when dosed biweekly (Q2W) or monthly (QM) in patients with heterozygous familial hypercholesterolemia (HeFH) as demonstrated in two 12-week trials: Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD; phase 2) and RUTHERFORD-2 (phase 3). OBJECTIVE: The objective of the study was to evaluate long-term efficacy, safety, and tolerability of evolocumab during open-label extension trials. METHODS: Patients completing parent trials were re-randomized 2:1 to evolocumab plus standard of care (SOC) or SOC alone for 52 weeks (Open-Label Study of Long-term Evaluation Against LDL-C [OSLER-1]) or 48 weeks (OSLER-2). Evolocumab dosing was 420 mg QM (OSLER-1) and 140 mg Q2W or 420 mg QM (OSLER-2). A pooled analysis of OSLER data was performed from this subset of HeFH patients. RESULTS: Four hundred forty HeFH patients from RUTHERFORD (n = 147) and RUTHERFORD-2 (n = 293) (mean [standard deviation] age 51 [12] years, 58% male, 90% White) were randomized to evolocumab plus SOC (n = 289) or SOC (n = 151). The 48-week period was completed by 425 patients (96.6%). Eight patients discontinued evolocumab plus SOC (2.8%) and 7 discontinued SOC (4.6%). Compared to parent study baseline, patients receiving evolocumab plus SOC experienced a mean 53.6% reduction in low-density lipoprotein cholesterol after 48 weeks. No patient experienced an adverse event leading to permanent evolocumab discontinuation during the 1-year SOC-controlled period. Serious adverse event rates were similar between groups (evolocumab plus SOC, 7.3%; SOC, 8.6%). CONCLUSION: Continued use of evolocumab added to SOC in patients with HeFH yields persistent and marked low-density lipoprotein cholesterol reductions during 48 weeks of follow-up. Long-term dosing of evolocumab with SOC was safe and well tolerated.

Systematic Review and Network Meta-Analysis on the Efficacy of Evolocumab and Other Therapies for the Management of Lipid Levels in Hyperlipidemia.

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors evolocumab and alirocumab substantially reduce low-density lipoprotein cholesterol (LDL-C) when added to statin therapy in patients who need additional LDL-C reduction. METHODS AND RESULTS: We conducted a systematic review and network meta-analysis of randomized trials of lipid-lowering therapies from database inception through August 2016 (45 058 records retrieved). We found 69 trials of lipid-lowering therapies that enrolled patients requiring further LDL-C reduction while on maximally tolerated medium- or high-intensity statin, of which 15 could be relevant for inclusion in LDL-C reduction networks with evolocumab, alirocumab, ezetimibe, and placebo as treatment arms. PCSK9 inhibitors significantly reduced LDL-C by 54% to 74% versus placebo and 26% to 46% versus ezetimibe. There were significant treatment differences for evolocumab 140 mg every 2 weeks at the mean of weeks 10 and 12 versus placebo (-74.1%; 95% credible interval -79.81% to -68.58%), alirocumab 75 mg (-20.03%; 95% credible interval -27.32% to -12.96%), and alirocumab 150 mg (-13.63%; 95% credible interval -22.43% to -5.33%) at ≥12 weeks. Treatment differences were similar in direction and magnitude for PCSK9 inhibitor monthly dosing. Adverse events were similar between PCSK9 inhibitors and control. Rates of adverse events were similar between PCSK9 inhibitors versus placebo or ezetimibe. CONCLUSIONS: PCSK9 inhibitors added to medium- to high-intensity statin therapy significantly reduce LDL-C in patients requiring further LDL-C reduction. The network meta-analysis showed a significant treatment difference in LDL-C reduction for evolocumab versus alirocumab.

Statin Discontinuation, Reinitiation, and Persistence Patterns Among Medicare Beneficiaries After Myocardial Infarction: A Cohort Study.

BACKGROUND: Although the benefits of statins accrue over time, treatment discontinuation is common. Examining the patterns of statin discontinuation, reinitiation, and persistence after reinitiation among Medicare beneficiaries after hospital discharge for a myocardial infarction may help increase statin use in high-risk patients. METHODS AND RESULTS: Medicare beneficiaries with a statin fill claim within 30 days after hospital discharge for myocardial infarction in 2007 to 2012 (n=158 795) were followed for 182 days post-discharge to identify discontinuation, defined as 60 continuous days without statins available. Reinitiation, defined by a statin fill, was identified in the 365 days post-discontinuation. High persistence was defined as proportion of days covered ≥80% with ≥1 day of statin supply 182 days after reinitiation. Follow-up ended on December 31, 2014. In the 182 days after myocardial infarction hospital discharge, 15.4% of beneficiaries discontinued statins. Of this group, 53.7% reinitiated statins. On reinitiation, 27.1% changed statin type, 6.9% up-titrated intensity, 14.4% down-titrated intensity, and 66.0% had the same statin and intensity. In the 182 days after reinitiation, 45.8% had high persistence. Moderate- and high- versus low-intensity statins were associated with a lower risk for statin discontinuation (moderate intensity: relative risk [RR], 0.93; 95% confidence interval [CI], 0.89-0.96; high-intensity: RR, 0.95; 95% CI, 0.91-0.99). High persistence was less common after reinitiating high- versus low-intensity statins (RR, 0.80; 95% CI, 0.75-0.86), but no association was present for those reinitiating a moderate- versus low-intensity statin (RR, 0.95; 95% CI, 0.90-1.01). Down-titrating versus reinitiating the same statin intensity (RR, 1.10; 95% CI, 1.05-1.16) and reinitiating a different versus the same statin (RR, 1.10; 95% CI, 1.06-1.14) were associated with high persistence after treatment reinitiation. CONCLUSIONS: Although many people who discontinue a statin reinitiate treatment, statin persistence after reinitiation was low. Reinitiating therapy with moderate-intensity statins, down-titration, and using a different statin may promote persistence.

Anti-PCSK9 antibodies for hypercholesterolaemia: Overview of clinical data and implications for primary care.

OBJECTIVES: To put data from our recent systematic review of phase 3 studies of anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies into the context of clinical practice. METHODS: Data from studies previously identified by a systematic review of phase 3 studies of alirocumab and evolocumab and additional references from non-systematic literature searches were used. We evaluated the hypothetical cardiovascular (CV) benefit in cases of typical patients in whom anti-PCSK9 antibodies may be recommended, using preliminary major CV event (CVE) rates from long-term clinical trials of anti-PCSK9 antibodies and from extrapolations derived from correlation between low-density lipoprotein cholesterol (LDL-C) reduction and CV benefit with other lipid-lowering therapies (LLTs). RESULTS: Rapid (within 1-2 weeks) and persistent (8-74 weeks) reductions in LDL-C levels were achieved with anti-PCSK9 antibodies. When combined with statins (± ezetimibe), high rates of LDL-C goal achievement were observed (41%-87% with alirocumab and 63%-100% with evolocumab). In long-term alirocumab and evolocumab studies, reductions in major CVEs of 48% and 53%, respectively, were observed. For every 38.7 mg/dL (1 mmol/L) reduction in LDL-C, a 22% reduction in relative CVE risk is predicted. Applying these assumptions to typical patients who have high-very high risk (15%-60% absolute 10-year CVE risk) and elevated LDL-C despite maximally tolerated statins, the 10-year number needed to treat with an anti-PCSK9 antibody to prevent one additional CVE varies from 4 to 26, depending on baseline LDL-C levels and residual absolute CVE risk. CONCLUSIONS: Anti-PCSK9 antibodies effectively lower LDL-C levels in a broad patient population. While awaiting comprehensive data from CV outcome trials, these agents should be considered in very high risk patients, such as those in secondary prevention and those with familial hypercholesterolaemia who are already receiving maximally tolerated LLTs, have not achieved their LDL-C goal and require substantial reductions in LDL-C.

Primary Care Physician Perspectives on Barriers to Statin Treatment.

PURPOSE: Discontinuation of statin therapy represents a major challenge for effective cardiovascular disease prevention. It is unclear how often primary care physicians (PCPs) re-initiate statins and what barriers they encounter. We aimed to identify PCP perspectives on factors influencing statin re-initiation. METHODS: We conducted six nominal group discussions with 23 PCPs from the Deep South Continuing Medical Education network. PCPs answered questions about statin side effects, reasons their patients reported for discontinuing statins, how they respond when discontinuation is reported, and barriers they encounter in getting their patients to re-initiate statin therapy. Each group generated a list of responses in round-robin fashion. Then, each PCP independently ranked their top three responses to each question. For each PCP, the most important reason was given a weight of 3 votes, and the second and third most important reasons were given weights of 2 and 1, respectively. We categorized the individual responses into themes and determined the relative importance of each theme using a "percent of available votes" metric. RESULTS: PCPs reported that side effects, especially muscle/joint-related symptoms, were the most common reason patients reported for statin discontinuation (47% of available votes). PCPs reported statin re-challenge as their most common response when a patient discontinues statin use (31% of available votes). Patients' fear of side effects was ranked as the biggest challenge PCPs encounter in getting their patients to re-initiate statin therapy (70% of available votes). CONCLUSION: PCPs face challenges getting their patients to re-initiate statins, particularly after a patient reports side effects.

Practical Considerations for the Use of Subcutaneous Treatment in the Management of Dyslipidaemia.

Suboptimal drug adherence represents a major challenge to effective primary and secondary prevention of cardiovascular disease. While adherence is influenced by multiple considerations, polypharmacy and dosing frequency appear to be rate-limiting factors in patient satisfaction and subsequent adherence. The cardiovascular and metabolic therapeutic areas have recently benefited from a number of advances in drug therapy, in particular protease proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and incretin-based therapies, respectively. These drugs are administered subcutaneously and offer efficacious treatment options with reduced dosing frequency. Whilst patients with diabetes and diabetologists are well initiated to injectable therapies, the cardiovascular therapeutic arena has traditionally been dominated by oral agents. It is therefore important to examine the practical aspects of treating patients with these new lipid-lowering agents, to ensure they are optimally deployed in everyday clinical practice.

Prevention of cardiovascular disease in patients with familial hypercholesterolaemia: The role of PCSK9 inhibitors.

Familial hypercholesterolaemia is an autosomal dominant inherited disorder characterised by elevated low-density lipoprotein cholesterol levels and consequently an increased risk of atherosclerotic cardiovascular disease (ASCVD). Familial hypercholesterolaemia is relatively common, but is often underdiagnosed and undertreated. Cardiologists are likely to encounter many individuals with familial hypercholesterolaemia; however, patients presenting with premature ASCVD are rarely screened for familial hypercholesterolaemia and fasting lipid levels are infrequently documented. Given that individuals with familial hypercholesterolaemia and ASCVD are at a particularly high risk of subsequent cardiac events, this is a missed opportunity for preventive therapy. Furthermore, because there is a 50% chance that first-degree relatives of individuals with familial hypercholesterolaemia will also be affected by the disorder, the underdiagnosis of familial hypercholesterolaemia among patients with ASCVD is a barrier to cascade screening and the prevention of ASCVD in affected relatives. Targeted screening of patients with ASCVD is an effective strategy to identify new familial hypercholesterolaemia index cases. Statins are the standard treatment for individuals with familial hypercholesterolaemia; however, low-density lipoprotein cholesterol targets are not achieved in a large proportion of patients despite treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to reduce low-density lipoprotein cholesterol levels considerably in individuals with familial hypercholesterolaemia who are concurrently receiving the maximal tolerated statin dose. The clinical benefit of PCSK9 inhibitors must, however, also be considered in terms of their cost-effectiveness. Increased awareness of familial hypercholesterolaemia is required among healthcare professionals, particularly cardiologists and primary care physicians, in order to start early preventive measures and to reduce the mortality and morbidity associated with familial hypercholesterolaemia and ASCVD.

Identification and Management of Statin-Associated Symptoms in Clinical Practice: Extension of a Clinician Survey to 12 Further Countries.

PURPOSE: Statins are the first-choice pharmacological treatment for patients with hypercholesterolemia and at risk for cardiovascular disease; however, a minority of patients experience statin-associated symptoms (SAS) and are considered to have reduced statin tolerance. The objective of this study was to establish how patients with SAS are identified and managed in clinical practice in Austria, Belgium, Colombia, Croatia, the Czech Republic, Denmark, Portugal, Switzerland, Russia, Saudi Arabia, Turkey, and the United Arab Emirates. METHODS: A cross-sectional survey was conducted (2015-2016) among clinicians (n = 60 per country; Croatia: n = 30) who are specialized/experienced in the treatment of hypercholesterolemia. Participants were asked about their experience of patients presenting with potential SAS and how such patients were identified and treated. RESULTS: Muscle-related symptoms were the most common presentation of potential SAS (average: 51%; range across countries [RAC] 17-74%); other signs/symptoms included persistent elevation in transaminases. To establish whether symptoms are due to statins, clinicians required rechallenge after discontinuation of statin treatment (average: 77%; RAC 40-90%); other requirements included trying at least one alternative statin. Clinicians reported that half of high-risk patients with confirmed SAS receive a lower-dose statin (average: 53%; RAC 43-72%), and that most receive another non-statin lipid-lowering therapy with or without a concomitant statin (average: 65%; RAC 52-83%). CONCLUSIONS: The specialists and GPs surveyed use stringent criteria to establish causality between statin use and signs or symptoms, and persevere with statin treatment where possible.

Pooled Safety Analysis of Evolocumab in Over 6000 Patients From Double-Blind and Open-Label Extension Studies.

BACKGROUND: Evolocumab, a fully human monoclonal antibody to PCSK9 (proprotein convertase subtilisin/kexin type 9), markedly reduces low-density lipoprotein cholesterol across diverse patient populations. The objective of this study was to assess the safety and tolerability of evolocumab in a pooled safety analysis from phase 2 or 3 randomized and placebo or comparator-controlled trials (integrated parent trials) and the first year of open-label extension (OLE) trials that included a standard-of-care control group. METHODS: This analysis included adverse event (AE) data from 6026 patients in 12 phase 2 and 3 parent trials, with a median exposure of 2.8 months, and, of those patients, from 4465 patients who continued with a median follow-up of 11.1 months in 2 OLE trials. AEs were analyzed separately for the parent and OLE trials. Overall AE rates, serious AEs, laboratory assessments, and AEs of interest were evaluated. RESULTS: Overall AE rates were similar between evolocumab and control in the parent trials (51.1% versus 49.6%) and in year 1 of OLE trials (70.0% versus 66.0%), as were those for serious AEs. Elevations of serum transaminases, bilirubin, and creatine kinase were infrequent and similar between groups. Muscle-related AEs were similar between evolocumab and control. Neurocognitive AEs were infrequent and balanced during the double-blind parent studies (5 events [0.1%], evolocumab groups versus 6 events [0.3%], control groups). In the OLE trials, 27 patients (0.9%) in the evolocumab groups and 5 patients (0.3%) in the control groups reported neurocognitive AEs. No neutralizing antievolocumab antibodies were detected. CONCLUSIONS: Overall, this integrated safety analysis of 6026 patients pooled across phase 2/3 trials and 4465 patients who continued in OLE trials for 1 year supports a favorable benefit-risk profile for evolocumab.

Statin Intolerance and Risk of Coronary Heart Events and All-Cause Mortality Following Myocardial Infarction.

BACKGROUND: Many patients report adverse reactions to, and may not tolerate, statin therapy. These patients may be at increased risk for coronary heart disease (CHD) events and mortality. OBJECTIVES: This study evaluated the risk for recurrent myocardial infarction (MI), CHD events, and all-cause mortality in Medicare beneficiaries with statin intolerance and in those with high adherence to statin therapy. METHODS: We studied 105,329 Medicare beneficiaries who began a moderate- or high-intensity statin dosage after hospitalization for MI between 2007 and 2013. Statin intolerance was defined as down-titrating statins and initiating ezetimibe therapy, switching from statins to ezetimibe monotherapy, having International Classification of Diseases, 9th revision, diagnostic codes for rhabdomyolysis or an antihyperlipidemic adverse event, followed by statin down-titration or discontinuation, or switching between ≥3 types of statins within 1 year after initiation. High statin adherence over the year following hospital discharge was defined as proportion of days covered ≥80%. Recurrent MI, CHD events (recurrent MI or a coronary revascularization procedure), and mortality were identified from 1 year after hospital discharge through December 2014. RESULTS: Overall, 1,741 patients (1.65%) had statin intolerance, and 55,567 patients (52.8%) had high statin adherence. Over a median of 1.9 to 2.3 years of follow-up, there were 4,450 recurrent MIs, 6,250 CHD events, and 14,311 deaths. Compared to beneficiaries with high statin adherence, statin intolerance was associated with a 36% higher rate of recurrent MI (41.1 vs. 30.1 per 1,000 person-years, respectively), a 43% higher rate of CHD events (62.5 vs. 43.8 per 1,000 person-years, respectively), and a 15% lower rate of all-cause mortality (79.9 vs. 94.2 per 1,000 person-years, respectively). The multivariate-adjusted hazard ratios (HR) comparing beneficiaries with statin intolerance versus those with high statin adherence were 1.50 (95% confidence interval [CI]: 1.30 to 1.73) for recurrent MI, 1.51 (95% CI: 1.34 to 1.70) for CHD events, and 0.96 (95% CI: 0.87 to 1.06) for all-cause mortality. CONCLUSIONS: Statin intolerance was associated with an increased risk for recurrent MI and CHD events but not all-cause mortality.

Evidence-based goals in LDL-C reduction.

The evidence from trials of statin therapy suggests that benefits in cardiovascular disease (CVD) event reduction are proportional to the magnitude of low-density lipoprotein cholesterol (LDL-C) lowering. The lack of a threshold at which LDL-C lowering is not beneficial, in terms of CVD prevention observed in these trials, is supported by epidemiological and genetic studies reporting the cardio-protective effects of lifelong low exposure to atherogenic cholesterol in a graded fashion. Providing that intensive LDL-C lowering is safe, these observations suggest that many individuals even at current LDL-C treatment targets could benefit. Here, we review recent safety and efficacy data from trials of adjunctive therapy, with LDL-C lowering beyond that achieved by statin therapy, and their potential implications for current guideline targets. Finally, the application of current guidance in the context of pre-treatment LDL-C concentration and deployment of statin therapy is also discussed. The number of patients requiring treatment to prevent a CVD event with statin treatment has been shown to differ markedly according to the pre-treatment LDL-C concentration even when absolute CVD risk is similar. It produces more likelihood of benefit when absolute LDL-C reduction is greater which is largely dependent on pre-treatment LDL-C concentration. This also has to be taken in consideration when deploying new agents like proprotein convertase subtilisin/kexin type 9 monoclonal antibodies. Patients with highest LDL-C concentration despite maximum statin and ezetimibe therapy will attain most absolute LDL-C reduction when treated with proprotein convertase subtilisin/kexin type 9 monoclonal antibodies, hence benefit most in term of CVD risk reduction.

Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism.

BACKGROUND: Monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9), such as evolocumab, lower plasma low-density lipoprotein (LDL)-cholesterol concentrations. Evolocumab is under investigation for its effects on cardiovascular outcomes in statin-treated, high-risk patients. The mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism remains to be fully evaluated. Stable isotope tracer kinetics can effectively elucidate the mode of action of new lipid-regulating pharmacotherapies. METHODS: We conducted a 2-by-2 factorial trial of the effects of atorvastatin (80 mg daily) and subcutaneous evolocumab (420 mg every 2 weeks) for 8 weeks on the plasma kinetics of very-low-density lipoprotein (VLDL)-apolipoprotein B-100 (apoB), intermediate-density lipoprotein-apoB, and LDL-apoB in 81 healthy, normolipidemic, nonobese men. The kinetics of apoB in these lipoproteins was studied using a stable isotope infusion of D3-leucine, gas chromatography/mass spectrometry, and multicompartmental modeling. RESULTS: Atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL-apoB (P<0.001 and P.032, respectively), intermediate-density lipoprotein-apoB (P=0.021 and P=.002, respectively), and LDL-apoB (P<0.001, both interventions). Evolocumab but not atorvastatin decreased the production rate of intermediate-density lipoprotein-apoB (P=0.043) and LDL-apoB (P<0.001), which contributed to the reduction in the plasma pool sizes of these lipoprotein particles. The reduction in LDL-apoB and LDL-cholesterol concentrations was significantly greater with combination versus either monotherapy (P<0.001). Whereas evolocumab but not atorvastatin lowered the concentration of free PCSK9, atorvastatin lowered the lathosterol/campesterol ratio (a measure of cholesterol synthesis/absorption) and apoC-III concentration. Both interventions decreased plasma apoE, but neither significantly altered lipoprotein lipase and cholesteryl ester protein mass or measures of insulin resistance. CONCLUSIONS: In healthy, normolipidemic subjects, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism. Reductions in intermediate-density lipoprotein and LDL production also contributed to the decrease in LDL particle concentration with evolocumab by a mechanism distinct from that of atorvastatin. These kinetic findings provide a metabolic basis for understanding the potential benefits of PCSK9 monoclonal antibodies incremental to statins in on-going clinical end point trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02189837.

Statin non-adherence and residual cardiovascular risk: There is need for substantial improvement.

Although statin therapy has proven to be the cornerstone for prevention and treatment of cardiovascular disease (CVD), there are many patients for whom long-term therapy remains suboptimal. The aims of this article are to review the current complex issues associated with statin use and to explore when novel treatment approaches should be considered. Statin discontinuation as well as adherence to statin therapy remain two of the greatest challenges for lipidologists. Evidence suggests that between 40 and 75% of patients discontinue their statin therapy within one year after initiation. Furthermore, whilst the reasons for persistence with statin therapy are complex, evidence shows that low-adherence to statins negatively impacts clinical outcomes and residual CV risk remains a major concern. Non-adherence or lack of persistence with long-term statin therapy in real-life may be the main cause of inadequate low density lipoprotein cholesterol lowering with statins. There is a large need for the improvement of the use of statins, which have good safety profiles and are inexpensive. On the other hand, in a non-cost-constrained environment, proprotein convertase subtilisin/kexin type 9 inhibitors should arguably be used more often in those patients in whom treatment with statins remains unsatisfactory.

Very low LDL-C levels may safely provide additional clinical cardiovascular benefit: the evidence to date.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in Europe and increased low-density lipoprotein cholesterol (LDL-C) is a major contributor to CVD risk. Extensive evidence from clinical studies of statins has demonstrated a linear relationship between LDL-C levels and CVD risk. It has been proposed that lower LDL-C levels than those currently recommended may provide additional clinical benefit to patients. AIM: This review summarises the genetic and clinical evidence on the efficacy and safety of achieving very low LDL-C levels. METHODS: Relevant epidemiological and clinical studies were identified using PubMed and by searching abstracts published at major congresses. RESULTS: Genetic evidence demonstrates that individuals with naturally very low LDL-C levels are healthy and have a low risk of CVD. Clinical evidence has shown that those patients who achieve very low LDL-C levels through using lipid-lowering therapies (LLTs), such as statins, have reduced CVD risk compared with patients who only just achieve recommended target LDL-C levels. These data show that the incidence of adverse events in patients achieving very low LDL-C levels using LLT is comparable to those reaching the recommended LDL-C targets. CONCLUSIONS: Genetic and clinical evidence supports the concept that reduction in LDL-C levels below current recommended targets may provide additional clinical benefit to patients without adversely impacting patient safety. Statin add-on therapies, such as ezetimibe and the recently approved proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab, allow patients to achieve very low LDL-C levels and are likely to impact on future treatment paradigms.