Secondary Prevention Population Research Articles

Lowering Targeted Atherogenic Lipoprotein Cholesterol Goals for Patients at "Extreme" ASCVD Risk.

To review randomized interventional clinical and imaging trials that support lower targeted atherogenic lipoprotein cholesterol goals in "extreme" and "very high" atherosclerotic cardiovascular disease (ASCVD) risk settings. Major atherosclerotic cardiovascular event (MACE) prevention among the highest risk patients with ASCVD requires aggressive management of global risks, including lowering of the fundamental atherogenic apolipoprotein B-associated lipoprotein cholesterol particles [i.e., triglyceride-rich lipoprotein remnant cholesterol, low-density lipoprotein cholesterol (LDL-C), and lipoprotein(a)]. LDL-C has been the long-time focus of imaging studies and randomized clinical trials (RCTs). The 2004 adult treatment panel (ATP-III) update recognized that the long-standing targeted LDL-C goal of < 100mg/dL potentially fostered substantial undertreatment of the very highest coronary heart disease (CHD) risk individuals and was lowered to < 70mg/dL as an "optional" goal for "very high" 10-year CHD [CHD death + myocardial infarction (MI)] risk exceeding 20%. This evidence-based guideline change was supported by the observed benefits demonstrated in the high-risk primary and secondary prevention populations in the Heart Protection Study (HPS), the acute coronary syndrome (ACS) population in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 trial (PROVE-IT), and the secondary prevention population in the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) intravascular ultrasound (IVUS) study. Subsequent national and international guidelines maintained a targeted LDL-C goal < 70mg/dL, or a threshold for management of > 70mg/dL for patients with CHD, CHD risk equivalency, or ASCVD. Subgroup or meta-analyses of several RCTs, IVUS imaging studies, and the ACS population in IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) supported the evidence-based 2017 American Association Clinical Endocrinologist (AACE) guideline change establishing a targeted LDL-C goal < 55mg/dL, non-HDL-C < 80mg/dl, and apolipoprotein B (apo B) < 70mg/dL for patients at "Extreme" ASCVD risk, i.e., 10-year 3-point-MACE-composite (CV death, non-fatal MI, or ischemic stroke) risk exceeding 30%. Moreover, with no recognized lower-limit-associated intolerance or safety issues, even more intensive lowering of atherogenic cholesterol levels is supported by the following evidence base: (1) analysis of eight high-intensity statin-based prospective secondary prevention IVUS atheroma volume regression trials; (2) a distribution analysis of on-treatment, ezetimibe and background-statin, of the very low LDL-C levels reached and CVD event risk in the IMPROVE-IT ACS population; (3) the secondary prevention Global Assessment of Pl\aque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) on background-statin; and (4) the secondary prevention population of Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER). By example, in FOURIER, the population on background-statin at a baseline median 92mg/dL achieved median LDL-C level of 30mg/dL and non-HDL-C to < 65mg/dl, and apo B to < 50mg/dL, and subgroup and post hoc analyses all demonstrated additional ASCVD event reduction benefits as LDL-C was further reduced. The level of ASCVD risk determines the degree, urgency, and persistence in global risk management, including fundamental atherogenic lipoprotein cholesterol particle lowering. "Extreme" risk patients may require extremely low targeted LDL-C, non-HDL-C and apo B goals; such efforts, implied by more recent interventional trials and analyses, are aimed at maximal atheroma plaque regression, stabilization, and MACE event reduction with the aspiration of improved quality lifespan.

Primary versus secondary cardiorenal prevention in type 2 diabetes: Which newer anti-hyperglycaemic drug matters?

We are observing a resurgence of major diabetic vascular complications after a period of dramatic decrease during the period 1990 to 2010. The classical division of cardiovascular prevention into primary (with an event) and secondary (without an event) is largely used to describe cardiovascular risk in type 2 diabetes (T2D); however, there is evidence that the cardiovascular risk in diabetes may range from highest in patients who experienced a previous cardiovascular event to mild in patients with the main risk factors at target. Herein, we present details of the 14 cardiovascular outcome trials (CVOTs) published to date, including the total population investigated, and their separation into primary (T2D + multiple risk factors) and secondary prevention (T2D + established cardiovascular disease [CVD]) populations as detailed within the trials. We also summarize evidence for the effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium glucose co-transporter-2 inhibitors (SGLT-2i) versus placebo on the risk of major cardiovascular events (MACE), heart failure (HF) and diabetic kidney disease (DKD). In primary prevention, SGLT-2i reduce both the risk of hospitalization for HF and progression of DKD; in secondary prevention, SGLT-2i are effective on the three endpoints, DPP-4i are neutral, while GLP1-RA show mixed results.

Comparison of Frequency of Atherosclerotic Cardiovascular Disease Events Among Primary and Secondary Prevention Subgroups of the Systolic Blood Pressure Intervention Trial

The Pooled Cohort Equation (PCE) predicts 10-year risk of first-time atherosclerotic cardiovascular disease (ASCVD) events and was incorporated in analyses of a primary and secondary prevention population in the Systolic Blood Pressure Intervention Trial (SPRINT). Whether PCE enhances risk prediction among secondary prevention populations is unknown. We sought to compare ASCVD events by level of PCE-predicted risk among primary and secondary prevention SPRINT populations. SPRINT randomized adults with hypertension and ≥1 CVD risk factor or previous CVD events to systolic blood pressure control targeting <120 mm Hg or 135 to 139 mm Hg. We calculated the hazard ratio (HR) of ASCVD events among secondary versus primary (reference) prevention subgroups overall and by predicted 10-year ASCVD risk categories (<10%, 10% to <20%, 20% to <30%, and ≥30%) and within risk subgroups, comparing to the lowest risk category. Among 8,151 participants, 16% with previous CVD, mean age was 66 years and 35% were women. The HR for ASCVD events overall was 2.51 (1.96, 3.20). HR was 2.97 (1.47, 5.99) among <10% 10-year risk and 2.23 (1.38, 3.59) among ≥30% risk. Within subgroups comparing ≥30% to <10% risk (reference) categories, the HR was 2.85 (1.76, 4.63) for primary and 2.14 (1.07, 4.30) for the secondary prevention. In conclusion, history of previous events was a potent risk factor for subsequent ASCVD events. The PCE does not enhance risk prediction among secondary prevention populations and may differentially underestimate risk in secondary prevention populations with lowest predicted risk.

The cost-effectiveness of omega-3 polyunsaturated fatty acids – The Australian healthcare perspective

ObjectivesTo examine the cost-effectiveness of a triglyceride lowering medication–icosapent ethyl added on to statin from Australian healthcare system perspective. MethodsA Markov-model was developed using data from the pivotal trial of icosapent ethyl in a secondary prevention population. Probabilities of CVD events were derived and extrapolated from the published Kaplan-Meier curve using a valid algorithm. Management cost of CVD, health-related quality of life, and background non-CVD mortality were extracted from publicly available sources. Acquisition cost of icosapent ethyl from the United States was used in the current analysis. Australian patients with histories of CVD were modelled for a 25 year time horizon and costs and benefits were discounted. Sensitivity analyses (SA) were undertaken. Value of perfect information (VPI) was quantified. ResultsTreatment with icosapent ethyl was associated with both higher costs and benefits (i.e. quality-adjusted life year [QALY] and life year [LY]), resulting in an incremental cost-effectiveness ratio (ICER) of AUD59,036/QALY or AUD54,358/LY. Using the often quoted willingness-to-pay (WTP)/QALY of AUD50,000/QALY, icosapent ethyl was not considered cost-effective. SA showed that time horizon, drug cost, and discount rate were the key drivers of the ICER. Total monetary VPI for icosapent ethyl was over AUD15 million over 5 years. ConclusionsPatients with established CVD in whom level of triglycerides is high would benefit from the treatment using icosapent ethyl, however, it is not a cost-effective from an Australian healthcare system perspective. The government may consider subsidising this medication given the clinical need but at a discounted acquisition cost.

Evidence of heterogeneity in statin-associated type 2 diabetes mellitus risk: A meta-analysis of randomized controlled trials and observational studies

AimsTo conduct a meta-analysis of statin-associated type 2 diabetes mellitus (T2D) risk among randomized controlled trials (RCTs) and observational studies (OBSs), excluding studies conducted among secondary prevention populations. MethodsStudies were identified by searching PubMed (1994-present) and EMBASE (1994-present). Articles had to meet the following criteria: (1) follow-up >one year; (2) >50% of participants free of clinically diagnosed ASCVD; (3) adult participants ≥30 years old; (4) reported statin-associated T2D effect estimates; and (5) quantified precision using 95% confidence interval. Data were pooled using random-effects model. ResultsWe identified 23 studies (35% RCTs) of n = 4,012,555 participants. OBS participants were on average younger (mean difference = 6.2 years) and had lower mean low-density lipoprotein cholesterol (LDL-C, mean difference = 20.6 mg/dL) and mean fasting plasma glucose (mean difference = 5.2 mg/dL) compared to RCT participants. There was little evidence for publication bias (P > 0.1). However, evidence of heterogeneity was observed overall and among OBSs and RCTs (PCochran = <0.05). OBS designs, younger baseline mean ages, lower LDL-C concentrations, and high proportions of never or former smokers were significantly associated with increased statin-associated T2D risk. ConclusionsPotentially elevated statin-associated T2D risk in younger populations with lower LDL-C merits further investigation in light of evolving statin guidelines targeting primary prevention populations.

Recent Updates on the Use of PCSK9 Inhibitors in Patients with Atherosclerotic Cardiovascular Disease

Atherosclerotic cardiovascular disease (ASCVD) is caused by elevated levels of low-density lipoprotein cholesterol (LDL-C). Although statins significantly reduce ASCVD risk, there remains a high degree of residual risk in statin-treated patients. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition has emerged as a significant therapeutic target for further lowering of LDL-C when used in combination with statins. The purpose of this review is to provide an update on recent evidence supporting the use of PCSK9 inhibitors in patients with ASCVD. Alirocumab and evolocumab were approved by the US Food and Drug Administration in 2015. Multiple phase II and III studies have demonstrated that these agents reduce LDL-C levels by up to 60% and are relatively safe, with the exception of injection site reactions. Additionally, two randomized controlled clinical trials have demonstrated that both alirocumab and evolocumab reduce ASCVD events when used in combination with statin therapy compared to statin alone. In light of this evidence, the 2018 Cholesterol Guideline incorporated PCSK9 inhibitors into the treatment algorithm for select secondary prevention patients unable to achieve an LDL-C below 70mg/dL despite maximally tolerated statin plus ezetimibe. Although PCSK9 inhibitors provide substantial reductions in LDL-C levels and reduce ASCVD events in secondary prevention populations, the cost-effectiveness of alirocumab and evolocumab limit widespread use. Additional research is needed to explore the role of PCSK9 inhibitors in other populations, including primary prevention, patients unable to tolerate statins, and acute myocardial infarction.

Abstract P366: Pooled Cohort Equation Performance in Primary and Secondary Prevention Subgroups of the SystolicBlood Pressure Intervention Trial (SPRINT)

Background: The Pooled Cohort Equation (PCE) estimates 10-y atherosclerotic cardiovascular disease (ASCVD) risk among adults aged 40-79 years without CVD. Recent studies applied the PCE to mixed primary (1°) and secondary (2°) prevention populations to predict risk of future CVD events. However, the PCE is not validated in 2° prevention populations. We studied the impact of prior CVD on PCE performance in a 2° prevention population of the SPRINT trial. Methods: SPRINT randomized 9,361 adults with hypertension and ≥1 CVD risk factor or prior ASCVD to standard or intensive BP control. Excluding those age &gt;79 years (n=1,158) or missing PCE covariates (n=52), we calculated 10-year ASCVD risk at baseline using the PCE. We assessed PCE discrimination with the C-statistic among all SPRINT participants and among 1° and 2° prevention subgroups. We estimated the hazard ratio (HR) for incident ASCVD events comparing the 2° to the 1° prevention group, controlling for baseline PCE-predicted 10-y risk. Results: Of the 8,151 included participants, 6,874 (84%) and 1,277 (16%) were in the 1° and 2° prevention groups, respectively. Mean (SD) age was 66 (8) years, 35% were female, 34% were black. Median (IQR) baseline predicted 10-year ASCVD risk in the 1° prevention group was lower than the 2° prevention group (P&lt;0.001; Table ). In the 3.3 years of follow-up, ASCVD events occurred more frequently in the 2° prevention group than the 1° prevention group (P&lt;0.001). The C-statistic was 0.618 (95% CI 0.589, 0.646) in the entire analytic population, and was non-significantly higher among the 1° prevention subgroup. Comparing the 2° to 1° prevention population, HR for incident ASCVD events was 2.6 (95% CI 2.1, 3.3) when controlling for baseline PCE-estimated 10-y risk. Conclusions: Adults with prior ASCVD events have a nearly 3-fold higher risk of subsequent events. This study demonstrates that the PCE underestimates risk of recurrent events in 2° prevention populations and use in mixed populations should be avoided.

Systematic review of the predictors of statin adherence for the primary prevention of cardiovascular disease.

IntroductionPrevious research has shown that statin adherence for the primary prevention of CVD is lower compared to secondary prevention populations. Therefore the aim of this systematic review was to review predictors of statin adherence for the primary prevention of CVD.MethodsA systematic search of papers published between Jan 1984 and May 2017 was conducted in PubMed, PsycINFO, EMbase and CINAHL databases. A study was eligible for inclusion if; 1) it was a study of the general population or of patients with familial hypercholesterolemia, hypertension, diabetes or arthritis; 2) statins were prescribed; 3) adherence was defined and measured as the extent to which patients followed their statin regimen during the period of prescription, and 4) it was an original trial or observational study (excluding case reports). A study was subsequently excluded if 1) results were not presented separately for primary prevention; 2) it was a trial of an intervention (for example patient education). Papers were reviewed by two researchers and consensus agreed with a third. A quality assessment (QA) tool was used to formally assess each included article. To evaluate the effect of predictors, data were quantitatively and qualitatively synthesised.ResultsIn total 19 studies met the inclusion criteria and nine were evaluated as high quality using the QA tool. The proportion of patients classed as “adherent” ranged from 17.8% to 79.2%. Potential predictors of statin adherence included traditional risk factors for CVD such as age, being male, diabetes and hypertension. Income associated with adherence more strongly in men than women, and highly educated men were more likely and highly educated women less likely to be adherent. Alcohol misuse and high BMI associated with non-adherence. There was no association between polypharmacy and statin adherence. The evidence base for the effect of other lifestyle factors and health beliefs on statin adherence was limited.ConclusionCurrent evidence suggests that patients with more traditional risk factors for CVD are more likely to be adherent to statins. The implications for future research are discussed.

Cost-Effectiveness of Left Atrial Appendage Closure With the WATCHMAN Device Compared With Warfarin or Non-Vitamin K Antagonist Oral Anticoagulants for Secondary Prevention in Nonvalvular Atrial Fibrillation.

Once a patient with atrial fibrillation experiences an embolic event, the risk of a recurrent event increases 2.6-fold. New treatments have emerged as viable treatment alternatives to warfarin for stroke risk reduction in secondary prevention populations. This analysis sought to assess the cost-effectiveness of left atrial appendage closure (LAAC) compared with warfarin and the non-vitamin K antagonist oral anticoagulants dabigatran 150 mg, apixaban and rivaroxaban in the prevention of stroke in nonvalvular atrial fibrillation patients with a prior stroke or transient ischemic attack. A Markov model was constructed using data from the secondary prevention subgroup analyses of the non-vitamin K antagonist oral anticoagulant and LAAC pivotal trials. Costs were from 2016 US Medicare reimbursement rates and the literature. The cost-effectiveness analysis was conducted from a US Medicare perspective over a lifetime (20 years) horizon. The model was populated with a cohort of 10 000 patients aged 70 years with a CHA2DS2-VASc score of 7 (annual stroke risk=9.60%) and HAS-BLED score of 3 (annual bleeding risk=3.74%). LAAC achieved cost-effectiveness relative to dabigatran at year 5 and warfarin and apixaban at year 6. At 10 years, LAAC had more quality-adjusted life years (4.986 versus 4.769, 4.869, 4.888, and 4.810) and lower costs ($42 616 versus $53 770, $58 774, $55 656, and $58 655) than warfarin, dabigatran, apixaban, and rivaroxaban, respectively, making LAAC the dominant (more effective and less costly) stroke risk reduction strategy. LAAC remained the dominant strategy over the lifetime analysis. Upfront procedure costs initially make LAAC higher cost than warfarin and the non-vitamin K antagonist oral anticoagulants, but within 10 years, LAAC delivers more quality-adjusted life years and has lower total costs, making LAAC the most cost-effective treatment strategy for secondary prevention of stroke in atrial fibrillation.

Genetic Risk Prediction for Primary and Secondary Prevention of Atherosclerotic Cardiovascular Disease: an Update.

This review aims to summarize the research on genetic risk scores and their ability to improve risk prediction in both a primary and a secondary prevention population. Several groups have examined the role of genetic scores in different patient populations. Recent studies have capitalized on the growing number of identified genetic variants to construct polygenic risk scores that include hundreds and sometimes thousands of SNPs. Also, recent studies have demonstrated that individuals with high genetic risk scores can attenuate their risk with lifestyle modifications and with statins, for which the benefit of treatment may be greater in those at highest genetic risk. Genetic risk scores when added to existing clinical models appear to improve risk prediction, particularly in the setting of incident cardiovascular disease and may provide actionable information to optimize prevention early in life. Future research will need to establish how to best use this genetic risk information either as a means to further individualize treatment decisions or to better identify high-risk populations.

The challenges of proprotein convertase subtilisin-kexin-9 inhibitors for lipid guidelines and models of care.

The article reviews the challenges facing cardiovascular disease (CVD) guidelines committees. Clinical trials in high-risk populations have shown additional CVD event reduction with ezetimibe and proprotein convertase subtilisin-kexin-9 inhibitors. These trials recruit middle-aged secondary prevention populations, whereas increasingly the population at risk of CVD comprises the elderly in primary prevention. Some major guidelines have moved from a lipid-target to a risk-based approach. Some guidelines wish to preserve treatment targets to optimize the risk profile of individual patients as opposed to using population-based approaches. A numbers needed to treat approach has been suggested as a way of prioritizing patients for treatment, while retaining an individual's LDL cholesterol risk. However, the main barrier to implementation of some novel therapies in medicine is not their efficacy or safety but their cost. Health economic approaches that consider both benefits and costs can help guideline committees to define populations mostly likely to benefit. The efficacy and expense of novel treatments is challenging traditional guideline development. Previously guideline committees used only to review clinical efficacy and safety endpoints but now they also have to consider costs to derive recommendations that are practical to implement.

Low glycaemic index diets for the prevention of cardiovascular disease.

The glycaemic index (GI) is a physiological measure of the ability of a carbohydrate to affect blood glucose. Interest is growing in this area for the clinical management of people at risk of, or with, established cardiovascular disease. There is a need to review the current evidence from randomised controlled trials (RCTs) in this area. This is an update of the original review published in 2008. To assess the effect of the dietary GI on total mortality, cardiovascular events, and cardiovascular risk factors (blood lipids, blood pressure) in healthy people or people who have established cardiovascular disease or related risk factors, using all eligible randomised controlled trials. We searched CENTRAL, MEDLINE, Embase and CINAHL in July 2016. We also checked reference lists of relevant articles. No language restrictions were applied. We selected RCTs that assessed the effects of low GI diets compared to diets with a similar composition but a higher GI on cardiovascular disease and related risk factors. Minimum trial duration was 12 weeks. Participants included were healthy adults or those at increased risk of cardiovascular disease, or previously diagnosed with cardiovascular disease. Studies in people with diabetes mellitus were excluded. Two reviewers independently screened and selected studies. Two review authors independently assessed risk of bias, evaluated the overall quality of the evidence using GRADE, and extracted data following the Cochrane Handbook for Systematic Reviews of Interventions. We contacted trial authors for additional information. Analyses were checked by a second reviewer. Continuous outcomes were synthesized using mean differences and adverse events were synthesized narratively. Twenty-one RCTs were included, with a total of 2538 participants randomised to low GI intervention (1288) or high GI (1250). All 21 included studies reported the effect of low GI diets on risk factors for cardiovascular disease, including blood lipids and blood pressure.Twenty RCTs (18 of which were newly included in this version of the review) included primary prevention populations (healthy individuals or those at high risk of CVD, with mean age range from 19 to 69 years) and one RCT was in those diagnosed with pre-existing CVD (a secondary prevention population, with mean age 26.9 years). Most of the studies did not have an intervention duration of longer than six months. Difference in GI intake between comparison groups varied widely from 0.6 to 42.None of the included studies reported the effect of low GI dietary intake on cardiovascular mortality and cardiovascular events such as fatal and nonfatal myocardial infarction, unstable angina, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, and stroke. The unclear risk of bias of most of the included studies makes overall interpretation of the data difficult. Only two of the included studies (38 participants) reported on adverse effects and did not observe any harms (low-quality evidence). There is currently no evidence available regarding the effect of low GI diets on cardiovascular disease events. Moreover, there is currently no convincing evidence that low GI diets have a clear beneficial effect on blood lipids or blood pressure parameters.

Antiplatelet Therapy and Clinical Outcomes Following Myocardial Infarction Among Patients in a U.S. Employer-Based Insurance Database.

Estimates of residual cardiovascular risks among patients who have experienced a recent acute myocardial infarction (MI) are predominantly derived from secondary prevention trial populations, patient registries, and population-based cohorts. To generate real-world evidence of antiplatelet treatment and recurrent events following MI in patients on antiplatelet treatment among commercial, employer-based insured patients in a large administrative database. This was a retrospective cohort claims database study using the Truven Health MarketScan Commercial Claims and Encounters and Medicare Supplemental databases between 2007-2011. Patients with an acute MI hospitalization with a discharge date between 2008 and 2010 were included. Excluded were those patients with documentation of stroke, transient ischemic attack (TIA), or severe bleeding at or before index hospitalization and with concomitant use of anticoagulant therapy following index hospitalization. Patients treated with clopidogrel following the index MI hospitalization were followed up to 1 year for repeat MI, stroke, and coronary revascularization. Among 33,943 post-MI continuous clopidogrel users without history of stroke, TIA, or bleeding, 22% had diabetes, whereas angina and renal impairment were less prevalent (5% and 7%, respectively). Over the 1-year follow-up, 2.4% experienced a repeat MI or stroke, and 8.2% underwent coronary revascularization. Angina, diabetes, and renal impairment were associated with elevated 1-year risk of repeat MI or stroke. This study suggests that there is residual cardiovascular risk, although relatively low, in an insured, secondary prevention population on antiplatelet treatment following an MI. In patients with MI, identifying angina, diabetes, and renal impairment may aid risk stratification and guide the effective management of these higher-risk patients. Funding for this research was provided by Merck & Co. Although Merck & Co. formally reviewed a penultimate draft, the opinions expressed are those of the authorship and may not necessarily reflect those of the company. Reed Chase, Wu, Mavros, Heithoff, and Hanson are employees of Merck Sharp & Dohme, a subsidiary of Merck & Co., and may own stock and/or hold stock options in the company. Patel was an employee of Merck & Co. during the conduct of this study and preparation of the manuscript. Simpson is a paid consultant for Merck, Pfizer, and Amgen and has received speaker's fees from Merck and Pfizer. Study concept and design were contributed by all authors except Hanson. Heifhoff and Patel collected the data, and data interpretation was performed by Simpson, Mavros, Patel, Wu, and Hanson. The manuscript was written by Hanson, Mavros, and Patel and revised by Heithoff, Wu, Simpson, and Reed Chase.

Evolocumab for Treating Primary Hypercholesterolaemia and Mixed Dyslipidaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its single technology appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer of evolocumab (Amgen) to submit evidence on the clinical and cost effectiveness of evolocumab. The appraisal assessed evolocumab as monotherapy or in combination with a statin with or without ezetimibe, or in combination with ezetimibe (without statin therapy), in adult patients with primary hypercholesterolaemia (which includes mixed dyslipidaemia), for whom statins do not provide optimal control of their low-density lipoprotein cholesterol (LDL-C) levels and/or for whom statins are contraindicated or not tolerated. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based on the company's submission to NICE. The evidence was derived mainly from four randomised controlled trials comparing evolocumab with either ezetimibe or placebo in adults with primary familial or non-familial hypercholesterolaemia, who were either able to take statins or who were statin intolerant. The clinical-effectiveness review found that evolocumab is efficacious at lowering LDL-C but that there was uncertainty regarding its impact on cardiovascular disease (CVD) outcomes. In response to the ERG's critique of the submitted health economic model, the company submitted an amended model, which also included a patient access scheme (PAS). Based on this, the deterministic incremental cost-effectiveness ratios (ICERs) for evolocumab against ezetimibe were above £74,000 and £45,000 per quality-adjusted life-year (QALY) gained within the non-familial primary and secondary prevention populations, respectively, whilst the ICER within the heterozygous familial hypercholesterolaemia (HeFH) population was approximately £23,000 per QALY gained. The final determination was that evolocumab would be a clinically and cost-effective use of UK NHS resource in certain patient subgroups.

Estimated burden of cardiovascular disease and value-based price range for evolocumab in a high-risk, secondary-prevention population in the US payer context

Aim: To estimate real-world cardiovascular disease (CVD) burden and value-based price range of evolocumab for a US-context, high-risk, secondary-prevention population.Materials and methods: Burden of CVD was assessed using the UK-based Clinical Practice Research Datalink (CPRD) in order to capture complete CV burden including CV mortality. Patients on standard of care (SOC; high-intensity statins) in CPRD were selected based on eligibility criteria of FOURIER, a phase 3 CV outcomes trial of evolocumab, and categorized into four cohorts: high-risk prevalent atherosclerotic CVD (ASCVD) cohort (n = 1448), acute coronary syndrome (ACS) (n = 602), ischemic stroke (IS) (n = 151), and heart failure (HF) (n = 291) incident cohorts. The value-based price range for evolocumab was assessed using a previously published economic model. The model incorporated CPRD CV event rates and considered CV event reduction rate ratios per 1 mmol/L reduction in low-density lipoprotein-cholesterol (LDL-C) from a meta-analysis of statin trials by the Cholesterol Treatment Trialists Collaboration (CTTC), i.e. CTTC relationship.Results: Multiple-event rates of composite CV events (ACS, IS, or coronary revascularization) per 100 patient-years were 12.3 for the high-risk prevalent ASCVD cohort, and 25.7, 13.3, and 23.3, respectively, for incident ACS, IS, and HF cohorts. Approximately one-half (42%) of the high-risk ASCVD patients with a new CV event during follow-up had a subsequent CV event. Combining these real-world event rates and the CTTC relationship in the economic model, the value-based price range (credible interval) under a willingness-to-pay threshold of $150,000/quality-adjusted life-year gained for evolocumab was $11,990 ($9,341–$14,833) to $16,856 ($12,903–$20,678) in ASCVD patients with baseline LDL-C levels ≥70 mg/dL and ≥100 mg/dL, respectively.Conclusion: Real-world CVD burden is substantial. Using the observed CVD burden in CPRD and the CTTC relationship, the cost-effectiveness analysis showed that, accounting for uncertainties, the expected value-based price for evolocumab is higher than its current annual cost, as long as the payer discount off list price is greater than 20%.

A Novel Protein Glycan-Derived Inflammation Biomarker Independently Predicts Cardiovascular Disease and Modifies the Association of HDL Subclasses with Mortality.

Evidence suggests that systemic inflammation may adversely impact HDL function. In this study we sought to evaluate the independent and incremental predictive performance of GlycA-a novel serum inflammatory biomarker that is an aggregate measure of enzymatically glycosylated acute phase proteins-and HDL subclasses on adverse events in a retrospective observational study of a secondary prevention population and to understand a priori defined potential interactions between GlycA and HDL subclasses. GlycA and HDL subclasses were measured using proton nuclear magnetic resonance spectroscopy in 7617 individuals in the CATHGEN (CATHeterization GENetics) cardiac catheterization biorepository. GlycA was associated with presence [odds ratio (OR) 1.07 (1.02-1.13), P = 0.01] and extent [OR 1.08 (1.03, 1.12) P < 0.0005] of coronary artery disease and with all-cause mortality [hazard ratio (HR) 1.34 (1.29-1.39), P < 0.0001], cardiovascular mortality [1.37 (1.30-1.45), P < 0.0001] and noncardiovascular mortality [1.46 (1.39-1.54) P < 0.0001] in models adjusted for 10 cardiovascular risk factors. GlycA and smaller HDL subclasses had independent but opposite effects on mortality risk prediction, with smaller HDL subclasses being protective [HR 0.69 (0.66-0.72), P < 0.0001]. There was an interaction between GlycA and smaller HDL subclasses-increasing GlycA concentrations attenuated the inverse association of smaller HDL subclasses with mortality. Adding GlycA and smaller HDL subclasses into the GRACE (Global Registry of Acute Coronary Events) and Framingham Heart Study Risk Scores improved mortality risk prediction, discrimination and reclassification. These findings highlight the interaction of systemic inflammation and HDL with clinical outcomes and may increase precision for clinical risk assessment in secondary prevention populations.

Apolipoprotein L1 Genetic Variants Are Associated with Chronic Kidney Disease but Not with Cardiovascular Disease in a Population Referred for Cardiac Catheterization

Background: While the association between APOL1 genetic variants and chronic kidney disease (CKD) has been established, their association with cardiovascular disease (CVD) is unclear. This study sought to understand CKD and cardiovascular risk conferred by APOL1 variants in a secondary cardiovascular prevention population. Methods: Two risk variants in APOL1 were genotyped in African-Americans (n = 1,641) enrolled in the CATHGEN biorepository, comprised of patients referred for cardiac catheterization at Duke University Hospital, Durham, NC, USA (2001-2010). Individuals were categorized as noncarriers (n = 722), heterozygote (n = 771), or homozygote carriers (n = 231) of APOL1 risk alleles. Multivariable logistic regression and Cox proportional hazards models adjusted for CVD risk factors were used to assess the association between APOL1 risk variants and prevalent and incident CKD, prevalent coronary artery disease (CAD), incident CVD events, and mortality. Results: The previously identified association between APOL1 variants and prevalent CKD was confirmed (OR: 1.85, 95% CI: 1.33-2.57, p = 0.0002). No statistically significant associations were detected between APOL1 variants and incident CKD or prevalent CAD, incident CVD events or mortality. Age, type 2 diabetes, and ejection fraction at baseline were significant clinical factors that predicted the risk of incident CKD in a subgroup analysis of APOL1 homozygous individuals. Conclusion:APOL1 genetic variants are not associated with CAD or incident CVD events in a cohort of individuals with a high burden of cardiometabolic risk factors. In individuals with homozygous APOL1 status, factors that predicted subsequent CKD included age, presence of type 2 diabetes, and ejection fraction at baseline.

Abstract 12926: New Use of Low-dose Aspirin is Not Associated With a Significantly Increased Risk of Intracranial Bleeds: Results From a Population-based Nested Case-control Study in the United Kingdom

Introduction: Low-dose aspirin protects against ischemic cardio- and cerebrovascular disease (CVD/CeVD) and colorectal cancer yet may be associated with a small increased risk of intracranial bleeds (ICB). Aim: To quantify the risk of ICB associated with new use of low-dose aspirin for CVD/CeVD prevention using The Health Improvement Network in the UK. Methods: From a source population aged 40-84 years from 2000-2012 and free of previous low-dose aspirin use, a cohort of new users of low-dose aspirin (75-300 mg; N=199,049) was identified. Each member was matched to a person free of low-dose aspirin on that day by age, sex and primary care practitioner visits in the previous year. Cohorts (mean age at entry, 59.6 years) were followed for up to 14 years (median 5.4 years) to identify incident cases of ICB, with validation by manual review of patient records and/or linkage to hospitalization data. Nested case-control analysis was conducted using cases from both cohorts. To account for changes in aspirin exposure over time, an ‘as-treated’ analysis was used. Controls (n=10,000) were frequency-matched to cases by age, sex and calendar year. Two definitions of current use were used for low-dose aspirin: use on i) 0-7 days or ii) 0-365 days before the index date (ICB date for cases, random date for controls). Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by logistic regression overall and stratified by CVD/CeVD status at study entry (primary or secondary prevention populations). Results: A total of 1635 incident cases of ICB were identified. As shown in the Table, compared with never use, current use of low-dose aspirin was not associated with a significant increase risk of ICB among the primary or secondary CVD/CeVD prevention populations, or any ICB subtype. For current use, no significant changes in ICB risk were seen between doses of 75mg, 150mg and 300mg. Conclusions: New use of low-dose aspirin does not significantly increase the risk of any type of ICB.

A Systematic Review of Cardiovascular Outcomes-Based Cost-Effectiveness Analyses of Lipid-Lowering Therapies.

Previous reviews have evaluated economic analyses of lipid-lowering therapies using lipid levels as surrogate markers for cardiovascular disease. However, drug approval and health technology assessment agencies have stressed that surrogates should only be used in the absence of clinical endpoints. The aim of this systematic review was to identify and summarise the methodologies, weaknesses and strengths of economic models based on atherosclerotic cardiovascular disease event rates. Cost-effectiveness evaluations of lipid-lowering therapies using cardiovascular event rates in adults with hyperlipidaemia were sought in Medline, Embase, Medline In-Process, PubMed and NHS EED and conference proceedings. Search results were independently screened, extracted and quality checked by two reviewers. Searches until February 2016 retrieved 3443 records, from which 26 studies (29 publications) were selected. Twenty-two studies evaluated secondary prevention (four also assessed primary prevention), two considered only primary prevention and two included mixed primary and secondary prevention populations. Most studies (18) based treatment-effect estimates on single trials, although more recent evaluations deployed meta-analyses (5/10 over the last 10years). Markov models (14 studies) were most commonly used and only one study employed discrete event simulation. Models varied particularly in terms of health states and treatment-effect duration. No studies used a systematic review to obtain utilities. Most studies took a healthcare perspective (21/26) and sourced resource use from key trials instead of local data. Overall, reporting quality was suboptimal. This review reveals methodological changes over time, but reporting weaknesses remain, particularly with respect to transparency of model reporting.

Distribution of Estimated 10-Year Risk of Recurrent Vascular Events and Residual Risk in a Secondary Prevention Population.

Among patients with clinically manifest vascular disease, the risk of recurrent vascular events is likely to vary. We assessed the distribution of estimated 10-year risk of recurrent vascular events in a secondary prevention population. We also estimated the potential risk reduction and residual risk that can be achieved if patients reach guideline-recommended risk factor targets. The SMART score (Second Manifestations of Arterial Disease) for 10-year risk of myocardial infarction, stroke, or vascular death was applied to 6904 patients with vascular disease. The risk score was externally validated in 18 436 patients with various manifestations of vascular disease from the TNT (Treating to New Targets), IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering), SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), and CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trials. The residual risk at guideline-recommended targets was estimated by applying relative risk reductions from meta-analyses to the estimated risk for targets for systolic blood pressure, low-density lipoprotein cholesterol, smoking, physical activity, and use of antithrombotic agents. The external performance of the SMART risk score was reasonable, apart from overestimation of risk in patients with 10-year risk >40%. In patients with various manifestations of vascular disease, median 10-year risk of a recurrent major vascular event was 17% (interquartile range, 11%-28%), varying from <10% in 18% to >30% in 22% of the patients. If risk factors were at guideline-recommended targets, the residual 10-year risk would be <10% in 47% and >30% in 9% of the patients (median, 11%; interquartile range, 7%-17%). Among patients with vascular disease, there is very substantial variation in estimated 10-year risk of recurrent vascular events. If all modifiable risk factors were at guideline-recommended targets, half of the patients would have a 10-year risk <10%. These data suggest that even with optimal treatment, many patients with vascular disease will remain at >20% and even >30% 10-year risk, clearly delineating an area of substantial unmet medical need.