Recruitment strategies in randomised controlled trials of men aged 50 years and older: a systematic review

Objectives: To identify and review evaluations of strategies to recruit men aged 50 years and over to randomised controlled trials (RCTs). Design: Systematic review and narrative synthesis. Data Sources: MEDLINE, EMBASE, CINAHL and ORRCA databases were searched to 1 December 2017. Eligibility Criteria: Studies using quantitative methods to evaluate recruitment strategies to RCTs of men aged 50 years and older. Data Extraction and Synthesis: A single reviewer extracted data (for each strategy, number of participants approached, screened and randomised, and cost). Study quality was assessed using National Heart, Lung and Blood Institute Quality Assessment Tools and considered study design, description of interventions, description and measurement of outcomes, completeness of outcome reporting, performance of statistical testing and consideration of confounders. Recruitment strategies were categorised by the recruitment stage they addressed. Results: Sixteen studies (n >14 000) were included: one good quality, ten fair quality and five poor quality. Studies evaluated strategies to identify prospective participants, and to improve the processes for assessing participant eligibility, providing participant information and seeking consent. In good and fair quality studies, the most effective strategies for identifying participants were referral from an affiliated health service provider (two studies), mass mailing (five studies) and media coverage (two studies). Community outreach activities such as displaying posters and attending local community events were not effective (two studies). Trial-specific training of site recruitment staff, developed using qualitative analysis of recruitment visits (two studies), and provision of study information to prospective participants at a multidisciplinary, group information session (one study) both improved recruitment. Conclusion: Improved engagement of men aged 50 years and older in RCTs is needed. A gender-sensitised approach to RCT recruitment may help to address this need. We have identified several promising recruitment strategies that merit further evaluation.Karen Bracken, Lisa Askie, Anthony C Keech, Wendy Hague, Gary Witter

Cost-effectiveness of Evolocumab therapy for reducing cardiovascular events in patients with atherosclerotic cardiovascular disease

Importance: The proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab has been demonstrated to reduce the composite of myocardial infarction, stroke, or cardiovascular death in patients with established atherosclerotic cardiovascular disease. To our knowledge, long-term cost-effectiveness of this therapy has not been evaluated using clinical trial efficacy data. Objective: To evaluate the cost-effectiveness of evolocumab in patients with atherosclerotic cardiovascular disease when added to standard background therapy. Design, Setting, and Participants: A Markov cohort state-transition model was used, integrating US population-specific demographics, risk factors, background therapy, and event rates along with trial-based event risk reduction. Costs, including price of drug, utilities, and transitional probabilities, were included from published sources. Exposures: Addition of evolocumab to standard background therapy including statins. Main Outcomes and Measures: Cardiovascular events including myocardial infarction, ischemic stroke and cardiovascular death, quality-adjusted life-year (QALY), incremental cost-effectiveness ratio (ICER), and net value-based price. Results: In the base case, using US clinical practice patients with atherosclerotic cardiovascular disease with low-density lipoprotein cholesterol levels of at least 70 mg/dL (to convert to millimoles per liter, multiply by 0.0259) and an annual events rate of 6.4 per 100 patient-years, evolocumab was associated with increased cost and improved QALY: incremental cost, $105 398; incremental QALY, 0.39, with an ICER of$268 637 per QALY gained ($165 689 with discounted price of$10 311 based on mean rebate of 29% for branded pharmaceuticals). Sensitivity and scenario analyses demonstrated ICERs ranging from $100 193 to$488 642 per QALY, with ICER of $413 579 per QALY for trial patient characteristics and event rate of 4.2 per 100 patient-years ($270 192 with discounted price of $10 311) and$483 800 if no cardiovascular mortality reduction emerges. Evolocumab treatment exceeded $150 000 per QALY in most scenarios but would meet this threshold at an annual net price of$9669 ($6780 for the trial participants) or with the discounted net price of$10 311 in patients with low-density lipoprotein cholesterol levels of at least 80 mg/dL. Conclusions and Relevance: At its current list price of $14 523, the addition of evolocumab to standard background therapy in patients with atherosclerotic cardiovascular disease exceeds generally accepted cost-effectiveness thresholds. To achieve an ICER of$150 000 per QALY, the annual net price would need to be substantially lower ($9669 for US clinical practice and$6780 for trial participants), or a higher-risk population would need to be treated

An update on the molecular actions of fenofibrate and its clinical effects on diabetic retinopathy and other microvascular end points in patients with diabetes

10.2337/db13-0800Diabetes62123968-3975DIAE

Fenofibrate rescues diabetes-related impairment of ischemia-mediated angiogenesis by PPARα-independent modulation of thioredoxin-interacting protein

Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, reduces lower limb amputations in patients with type 2 diabetes. The mechanism is, however, unknown. In this study, we demonstrate that fenofibrate markedly attenuates diabetes-related impairment of ischemia-mediated angiogenesis. In a murine model of hindlimb ischemia, daily oral fenofibrate treatment restored diabetes-impaired blood flow recovery, foot movement, hindlimb capillary density, vessel diameter, and vascular endothelial growth factor signaling to nondiabetic levels in both wild-type and PPARα-knockout mice, indicating that these fenofibrate effects are largely PPARα independent. In vitro, fenofibric acid (FFA) rescued high glucose-induced (25 mmol/L) impairment of endothelial cell migration, tubulogenesis, and survival in a PPARα-independent manner. Interestingly, fenofibrate in vivo and FFA in vitro reversed high glucose-induced expression of thioredoxin-interacting protein (TXNIP), an exquisitely glucose-inducible gene previously identified as a critical mediator of diabetes-related impairment in neovascularization. Conversely, adenoviral overexpression of TXNIP abrogated the restorative effects of FFA on high glucose-impaired endothelial cell function in vitro, indicating that the effects of FFA are mediated by TXNIP. We conclude that fenofibrate rescues diabetic impairment in ischemia-mediated angiogenesis, in large part, by PPARα-independent regulation of TXNIP. These findings may therefore explain the reduction in amputations seen in patients with diabetes treated with fenofibrate.Jun Yuan, Joanne T.M. Tan, Kushwin Rajamani, Emma L. Solly, Emily J. King, Laura Lecce, Philippa J.L. Simpson, Yuen Ting Lam, Alicia J. Jenkins, Christina A. Bursill, Anthony C. Keech and Martin K.C. N

Evolocumab and Outcomes in Patients With Peripheral Artery Disease

Cardiolog

Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk Insights From the FOURIER Trial

BACKGROUND: Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition, and cardiovascular risk reduction remains undefined.METHODS: Lp(a) was measured in 25 096 patients in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a randomized trial of evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease (median follow-up, 2.2 years). Cox models were used to assess the independent prognostic value of Lp(a) and the efficacy of evolocumab for coronary risk reduction by baseline Lp(a) concentration.RESULTS: The median (interquartile range) baseline Lp(a) concentration was 37 (13-165) nmol/L. In the placebo arm, patients with baseline Lp(a) in the highest quartile had a higher risk of coronary heart disease death, myocardial infarction, or urgent revascularization (adjusted hazard ratio quartile 4: quartile 1, 1.22; 95% CI, 1.01-1.48) independent of low-density lipoprotein cholesterol. At 48 weeks, evolocumab significantly reduced Lp(a) by a median (interquartile range) of 26.9% (6.2%-46.7%). The percent change in Lp(a) and low-density lipoprotein cholesterol at 48 weeks in patients taking evolocumab was moderately positively correlated (r=0.37; 95% CI, 0.36-0.39; Pmedian, and by 7% (hazard ratio, 0.93; 95% CI, 0.80-1.08; P interaction=0.07) in those <= median. Coupled with the higher baseline risk, the absolute risk reductions, and number needed to treat over 3 years were 2.49% and 40 versus 0.95% and 105, respectively.CONCLUSIONS: Higher levels of Lp(a) are associated with an increased risk of cardiovascular events in patients with established cardiovascular disease irrespective of low-density lipoprotein cholesterol. Evolocumab significantly reduced Lp(a) levels, and patients with higher baseline Lp(a) levels experienced greater absolute reductions in Lp(a) and tended to derive greater coronary benefit from PCSK9 inhibition.Cardiolog

Synopsis of an integrated guidance for enhancing the care of familial hypercholesterolaemia: an Australian perspective

Introduction Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease, with significant potential for positive impact on public health and healthcare savings. New clinical practice recommendations are presented in an abridged guidance to assist practitioners in enhancing the care of all patients with FH. Main recommendations Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. There is a key role for general practitioners (GPs) working in collaboration with specialists with expertise in lipidology. Advice is given on genetic and cholesterol testing and risk notification of biological relatives undergoing cascade testing for FH; all healthcare professionals should develop skills in genomic medicine. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors, and appropriate use of low-density lipoprotein (LDL)-cholesterol lowering therapies, including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Recommendations on service design are provided in the full guidance. Potential impact on care of FH These recommendations need to be utilised using judicious clinical judgement and shared decision making with patients and families. Models of care need to be adapted to both local and regional needs and resources. In Australia new government funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of these recommendations. A broad implementation science strategy is, however, required to ensure that the guidance translates into benefit for all families with FH

Integrated guidance for enhancing the care of familial hypercholesterolaemia in Australia

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all Australian families with or at risk of FH

Essentials of a new clinical practice guidance on familial hypercholesterolaemia for physicians

Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease. New clinical practice recommendations are presented to assist practitioners in enhancing the care of all patients with FH. Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors and appropriate use of low-density lipoprotein (LDL)-cholesterol-lowering therapies including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The recommendations need to be utilised using judicious clinical judgement and shared decision-making with patients and families. New government-funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of the recommendations. However, a comprehensive implementation science and practice strategy is required to ensure that the guidance translates into benefit for all families with FH