Cost-Effectiveness of Icosapent Ethyl in REDUCE-IT USA: Results From Patients Randomized in the United States.

BACKGROUND: In 3146 REDUCE-IT USA (Reduction of Cardiovascular Events With Icosapent Ethyl Intervention Trial USA) participants, icosapent ethyl (IPE) reduced first and total cardiovascular events by 31% and 36%, respectively, over 4.9 years of follow-up. METHODS AND RESULTS: We used participant-level data from REDUCE-IT USA, 2021 US costs, and IPE costs ranging from $4.59 to $11.48 per day, allowing us to examine a range of possible medication costs. The in-trial analysis was participant-level, whereas the lifetime analysis used a Markov model. Both analyses considered value from a US health sector perspective. The incremental cost-effectiveness ratio (incremental costs divided by incremental quality-adjusted life-years) of IPE compared with standard care (SC) was the primary outcome measure. There was incremental gain in quality-adjusted life-years with IPE compared with SC using in-trial (3.28 versus 3.13) and lifetime (10.36 versus 9.83) horizons. Using an IPE cost of $4.59 per day, health care costs were lower with IPE compared with SC for both in-trial ($29 420 versus $30 947) and lifetime ($216 243 versus $219 212) analyses. IPE versus SC was a dominant strategy in trial and over the lifetime, with 99.7% lifetime probability of an incremental cost-effectiveness ratio <$50 000 per quality-adjusted life-year gained. At a medication cost of $11.48 per day, the cost per quality-adjusted life-year gained was $36 208 in trial and $9582 over the lifetime. CONCLUSIONS: In this analysis, at $4.59 per day, IPE offers better outcomes than SC at lower costs in trial and over a lifetime and is cost-effective at $11.48 per day for conventional willingness-to-pay thresholds. Treatment with IPE should be strongly considered in US patients like those enrolled in REDUCE-IT USA. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.

A Cost-Effectiveness Analysis of Biomarkers for Risk Prediction in Atrial Fibrillation.

RATIONALE: Atrial fibrillation (AF) is associated with an increased risk of thromboembolism. This risk is currently assessed with scoring systems based on clinical characteristics. However, these tools have limited prognostic performance. Circulating biomarkers are proposed for improved prediction of major clinical events and individualization of treatments in patients with AF. OBJECTIVE: The aim was to assess the cost-effectiveness of precision medicine (PM), i.e., the use of combined biomarkers and clinical variables, in comparison to standard of care (SOC) for risk stratification in a hypothetical cohort of AF patients at risk of stroke. METHODS: A Markov cohort model was developed to evaluate the costs and quality-adjusted life-years (QALYs) of PM compared to SOC, over 20 years using a Canadian healthcare system perspective. RESULTS: PM decreased the mean per-patient overall costs by 7% ($94,932 vs $102,057 [Canadian dollars], respectively) and increased the QALYs by 12% (8.77 vs 7.68 QALYs, respectively). The calculated incremental cost-effectiveness ratio was negative, indicating that PM is an economically dominant strategy. These results were robust to one-way and probabilistic sensitivity analyses. CONCLUSION: PM compared to SOC is economically dominant and is projected to generate cost savings.

Cost-effectiveness of Icosapent Ethyl for High-risk Patients With Hypertriglyceridemia Despite Statin Treatment.

Importance: The Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial (REDUCE-IT) demonstrated the efficacy of icosapent ethyl (IPE) for high-risk patients with hypertriglyceridemia and known cardiovascular disease or diabetes and at least 1 other risk factor who were treated with statins. Objective: To estimate the cost-effectiveness of IPE compared with standard care for high-risk patients with hypertriglyceridemia despite statin treatment. Design, Setting, and Participants: An in-trial cost-effectiveness analysis was performed using patient-level study data from REDUCE-IT, and a lifetime analysis was performed using a microsimulation model and data from published literature. The study included 8179 patients with hypertriglyceridemia despite stable statin therapy recruited between November 21, 2011, and May 31, 2018. Analyses were performed from a US health care sector perspective. Statistical analysis was performed from March 1, 2018, to October 31, 2021. Interventions: Patients were randomly assigned to IPE, 4 g/d, or placebo and were followed up for a median of 4.9 years (IQR, 3.5-5.3 years). The cost of IPE was $4.16 per day after rebates using SSR Health net cost (SSR cost) and $9.28 per day with wholesale acquisition cost (WAC). Main Outcomes and Measures: Main outcomes were incremental quality-adjusted life-years (QALYs), total direct health care costs (2019 US dollars), and cost-effectiveness. Results: A total of 4089 patients (2927 men [71.6%]; median age, 64.0 years [IQR, 57.0-69.0 years]) were randomly assigned to receive IPE, and 4090 patients (2895 men [70.8%]; median age, 64.0 years [IQR, 57.0-69.0 years]) were randomly assigned to receive standard care. Treatment with IPE yielded more QALYs than standard care both in trial (3.34 vs 3.27; mean difference, 0.07 [95% CI, 0.01-0.12]) and over a lifetime projection (10.59 vs 10.35; mean difference, 0.24 [95% CI, 0.15-0.33]). In-trial, total health care costs were higher with IPE using either SSR cost ($18 786) or WAC ($24 544) than with standard care ($17 273; mean difference from SSR cost, $1513 [95% CI, $155-$2870]; mean difference from WAC, $7271 [95% CI, $5911-$8630]). Icosapent ethyl cost $22 311 per QALY gained using SSR cost and $107 218 per QALY gained using WAC. Over a lifetime, IPE was projected to be cost saving when using SSR cost ($195 276) compared with standard care ($197 064; mean difference, -$1788 [95% CI, -$9735 to $6159]) but to have higher costs when using WAC ($202 830) compared with standard care (mean difference, $5766 [95% CI, $1094-$10 438]). Compared with standard care, IPE had a 58.4% lifetime probability of costing less and being more effective when using SSR cost and an 89.4% probability of costing less than $50 000 per QALY gained when using SSR cost and a 72.5% probability of costing less than $50 000 per QALY gained when using WAC. Conclusions and Relevance: This study suggests that, both in-trial and over the lifetime, IPE offers better cardiovascular outcomes than standard care in REDUCE-IT participants at common willingness-to-pay thresholds.

Factors Associated With Burnout, Post-traumatic Stress and Anxio-Depressive Symptoms in Healthcare Workers 3 Months Into the COVID-19 Pandemic: An Observational Study.

Objective: This study examined how best to identify modifiable protective and risk factors for burnout in healthcare workers in the face of the COVID-19 pandemic. Individual, occupational, organizational and social factors were investigated. The study also assessed the impact of these factors on post-traumatic stress disorder (PTSD), anxiety, and depression. Methods: Healthcare workers in the Quebec (Canada) healthcare system were recruited between May 21 to June 5, 2020. Participants answered an electronic survey 3 months after the COVID-19 epidemic outbreak began in Canada. Using the Maslach Burnout Inventory, PTSD Checklist for DSM-5, and Hospital Anxiety and Depression Scale, we studied the prevalence of burnout, PTSD, anxiety and depression in this cohort. Multivariable logistic or linear regression models including resilience, social and organizational support, workload and access to mental health help, simulation techniques and protective personal equipment (PPE) as well as perception of PPE security were conducted for each outcome. Results: In mid-June 2020, 467 participants completed the survey. We found that half (51.8%) of the respondents experienced burnout characterized by emotional exhaustion and/or depersonalization at least once a week. In total, 158 healthcare workers (35.6%) displayed severe symptoms of at least one of the mental health disorders (24.3% PTSD, 23.3% anxiety, 10.6% depression). Resilience (OR = 0.69, 95% CI: [0.55-0.87]; p = 0.002) and perceived organizational support (OR = 0.75, 95% CI: [0.61-0.93]; p = 0.009) were significantly associated with burnout and other outcomes. Social support satisfaction, perception of PPE security, work type and environment, mental health antecedents and reassignment were associated with PTSD and/or anxiety and/or depression, but not burnout. Conclusion: Future studies should address primarily resilience and perceived organizational support to promote mental health and prevent burnout, PTSD, anxiety and depression.

Cost-effectiveness of low-dose colchicine after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT).

AIMS: In the randomized, placebo-controlled Colchicine Cardiovascular Outcomes Trial (COLCOT) of 4745 patients enrolled within 30 days after myocardial infarction (MI), low-dose colchicine (0.5 mg once daily) reduced the incidence of the primary composite endpoint of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization. To assess the in-trial period and lifetime cost-effectiveness of low-dose colchicine therapy compared to placebo in post-MI patients on standard-of-care therapy. METHODS AND RESULTS: A multistate Markov model was developed incorporating the primary efficacy and safety results from COLCOT, as well as healthcare costs and utilities from the Canadian healthcare system perspective. All components of the primary outcome, non-cardiovascular deaths, and pneumonia were included as health states in the model as both primary and recurrent events. In the main analysis, a deterministic approach was used to estimate the incremental cost-effectiveness ratio (ICER) for the trial period (24 months) and lifetime (20 years). Over the in-trial period, the addition of colchicine to post-MI standard-of-care treatment decreased the mean overall per-patient costs by 47%, from $502 to $265 Canadian dollar (CAD), and increased the quality-adjusted life years (QALYs) from 1.30 to 1.34. The lifetime per-patient costs were further reduced (69%) and QALYs increased with colchicine therapy (from 8.82 to 11.68). As a result, both in-trial and lifetime ICERs indicated colchicine therapy was a dominant strategy. CONCLUSION: Cost-effectiveness analyses indicate that the addition of colchicine to standard-of-care therapy after MI is economically dominant and therefore generates cost savings.

Racial Disparities in Acute Coronary Syndrome Management Within a Universal Healthcare Context: Insights From the AMI-OPTIMA Trial.

BACKGROUND: Although prior studies have demonstrated racial disparities regarding acute coronary syndrome (ACS) care within private or mixed healthcare systems, few researchers have explored such disparities within universal healthcare systems. We aimed to evaluate the quality and outcomes of in-hospital ACS management for White patients vs patients of colour, within a universal healthcare context. METHODS: We performed a post hoc analysis of the Acute Myocardial Infarction - Knowledge Translation to Optimize Adherence to Evidence-Based Therapy study, a cluster-randomized trial evaluating a knowledge-translation intervention at 24 hospitals in Quebec, Canada (years: 2009 and 2012). The primary endpoint was coronary catheterization. The secondary endpoints included in-hospital mortality, percutaneous and surgical coronary revascularization, major bleeding, total stroke, and discharge prescription of evidence-based medical therapy. RESULTS: Of 3444 included patients, 2738 were White, and 706 were people of colour. The mean age was 68.2 years (33.3% women) among White patients and 69.5 years (36.0% women) among patients of colour. Patients of colour were less likely to undergo in-hospital coronary catheterization than were White patients (74.5% vs 80.3%, P = 0.001). This difference was attenuated after adjusting for patient-level characteristics (odds ratio 0.89; 95% confidence interval 0.73-1.09), and it was eliminated after adjusting for hospital-level characteristics (odds ratio 1.04; 95% confidence interval 0.73-1.49). CONCLUSIONS: Racial disparity in coronary catheterization for ACS persists within a universal healthcare context. Patients' comorbidities and hospital-level factors may be partially responsible for this inequality. Future research on cardiovascular healthcare in patients with diverse racial/ethnic backgrounds in universal healthcare systems is needed to remediate racial inequality in ACS management.

CONTEXTE: Bien que des études antérieures aient démontré l'existence de disparités raciales dans la prise en charge du syndrome coronarien aigu (SCA) au sein de systèmes de santé privés ou mixtes, peu de chercheurs ont étudié ces disparités au sein de systèmes universels de soins de santé. Nous avons cherché à évaluer la qualité et les résultats de la prise en charge du SCA à l'hôpital pour les patients blancs par rapport aux patients de couleur, dans un contexte de soins de santé universels. MÉTHODOLOGIE: Nous avons effectué une analyse a posteriori de l'étude AMI-OPTIMA, un essai sur échantillon en grappes aléatoire évaluant une intervention d'application des connaissances dans 24 hôpitaux du Québec, au Canada (années : 2009 et 2012). Le paramètre d'évaluation principal était le cathétérisme coronaire. Les paramètres d'évaluation secondaires comprenaient la mortalité à l'hôpital, la revascularisation coronaire percutanée et chirurgicale, l'hémorragie majeure, l'accident vasculaire cérébral et la prescription au congé d'un traitement médical fondé sur des données probantes. RÉSULTATS: Sur les 3444 patients étudiés, 2738 étaient blancs et 706 étaient des personnes de couleur. L'âge moyen était de 68,2 ans (33,3 % de femmes) chez les patients blancs, et de 69,5 ans (36,0 % de femmes) chez les patients de couleur. Les patients de couleur étaient moins susceptibles de subir un cathétérisme coronaire à l'hôpital que les patients blancs (74,5 % contre 80,3 %, p = 0,001). Cette différence a été atténuée après ajustement pour tenir compte des caractéristiques des patients (rapport de cotes : 0,89; intervalle de confiance [IC] à 95 % : 0,73-1,09), et éliminée après ajustement pour tenir compte des caractéristiques des hôpitaux (rapport de cotes : 1,04; IC à 95 % : 0,73-1,49). CONCLUSIONS: La disparité raciale en ce qui a trait au cathétérisme coronaire pour un SCA persiste dans un contexte de soins de santé universels. Les comorbidités des patients et des facteurs liés à l'hôpital peuvent être partiellement responsables de cette inégalité. De plus amples recherches sur les soins cardiovasculaires chez les patients de diverses origines raciales ou ethniques dans les systèmes universels de soins de santé sont nécessaires pour remédier aux inégalités raciales dans la prise en charge du SCA.

Reduced Cognitive Assessment Scores Among Individuals With Magnetic Resonance Imaging-Detected Vascular Brain Injury.

Background and Purpose- Little is known about the association between covert vascular brain injury and cognitive impairment in middle-aged populations. We investigated if scores on a cognitive screen were lower in individuals with higher cardiovascular risk, and those with covert vascular brain injury. Methods- Seven thousand five hundred forty-seven adults, aged 35 to 69 years, free of cardiovascular disease underwent a cognitive assessment using the Digital Symbol Substitution test and Montreal Cognitive Assessment, and magnetic resonance imaging (MRI) to detect covert vascular brain injury (high white matter hyperintensities, lacunar, and nonlacunar brain infarctions). Cardiovascular risk factors were quantified using the INTERHEART (A Global Study of Risk Factors for Acute Myocardial Infarction) risk score. Multivariable mixed models tested for independent determinants of reduced cognitive scores. The population attributable risk of risk factors and MRI vascular brain injury on low cognitive scores was calculated. Results- The mean age of participants was 58 (SD, 9) years; 55% were women. Montreal Cognitive Assessment and Digital Symbol Substitution test scores decreased significantly with increasing age (P<0.0001), INTERHEART risk score (P<0.0001), and among individuals with high white matter hyperintensities, nonlacunar brain infarction, and individuals with 3+ silent brain infarctions. Adjusted for age, sex, education, ethnicity covariates, Digital Symbol Substitution test was significantly lowered by 1.0 (95% CI, -1.3 to -0.7) point per 5-point cardiovascular risk score increase, 1.9 (95% CI, -3.2 to -0.6) per high white matter hyperintensities, 3.5 (95% CI, -6.4 to -0.7) per nonlacunar stroke, and 6.8 (95% CI, -11.5 to -2.2) when 3+ silent brain infarctions were present. No postsecondary education accounted for 15% (95% CI, 12-17), moderate and high levels of cardiovascular risk factors accounted for 19% (95% CI, 8-30), and MRI vascular brain injury accounted for 10% (95% CI, -3 to 22) of low test scores. Conclusions- Among a middle-aged community-dwelling population, scores on a cognitive screen were lower in individuals with higher cardiovascular risk factors or MRI vascular brain injury. Much of the population attributable risk of low cognitive scores can be attributed to lower educational attainment, higher cardiovascular risk factors, and MRI vascular brain injury.

Oral Anticoagulant Prescription Trends, Profile Use, and Determinants of Adherence in Patients with Atrial Fibrillation.

BACKGROUND AND PURPOSE: Data on oral anticoagulant (OAC) uptake and pattern of use are limited. Real-life data in patients with atrial fibrillation (AF) are important for understanding patient exposure. A cohort study of new OAC users was built to assess trends of drug use from 2011 to 2017, persistence rate, switching rate, adherence level, and predictors of adherence. METHODS: We built a cohort using the Régie d'Assurance Maladie du Québec (RAMQ) and Med-Echo administrative databases of new adult OAC users within 1 year following hospitalization with a diagnosis of AF. New users of OAC were defined as having no OAC claims in the year before cohort entry. We assessed trends of OAC use; persistence rate, defined as a gap between refills of no longer than two times the duration of the previous prescriptions; and adherence level, defined as the proportion of days covered (PDC) over a 1-year period following initiation. Predictors of nonadherence (PDC less than 80%) were analyzed using logistic regression models. RESULTS: The cohort consisted of 33,311 incident OAC users. Of total OAC claims, the proportions of warfarin claims decreased from 77.9% in 2011 to 12.7% in 2017, with direct oral anticoagulants (DOACs) accounting for 87.3% of claims, of which apixaban and rivaroxaban accounted for 60.1% and 23.4%, respectively, by the end of 2017. One year after OAC initiation, persistence rates ranged from 53% with warfarin to 77% with a high dose of apixaban. Approximately 75% of incident OAC users were considered "adherent" (PDC 80% or more), with a mean PDC of 95.6-98.1%, compared with "nonadherent," with a mean PDC varying between 43.1% and 50.7%. Older age, female sex, higher CHA2 DS2 -VASc score (to predict thromboembolic risk in AF), prior stroke, and treatment with chronic cardiovascular disease drugs were associated with high adherence levels. CONCLUSION: The clinical uptake of DOACs increased over time, accounting for 87.3% of prescriptions in 2017. In our study, 25% of new OAC users presented a low adherence level. Adherence to OACs remains a significant challenge in patients with AF.

A Discrete Event Simulation Model to Assess the Economic Value of a Hypothetical Pharmacogenomics Test for Statin-Induced Myopathy in Patients Initiating a Statin in Secondary Cardiovascular Prevention.

BACKGROUND: Statin (HMG-CoA reductase inhibitor) therapy is the mainstay dyslipidemia treatment and reduces the risk of a cardiovascular (CV) event (CVE) by up to 35%. However, adherence to statin therapy is poor. One reason patients discontinue statin therapy is musculoskeletal pain and the associated risk of rhabdomyolysis. Research is ongoing to develop a pharmacogenomics (PGx) test for statin-induced myopathy as an alternative to the current diagnosis method, which relies on creatine kinase levels. The potential economic value of a PGx test for statin-induced myopathy is unknown. METHODS: We developed a lifetime discrete event simulation (DES) model for patients 65 years of age initiating a statin after a first CVE consisting of either an acute myocardial infarction (AMI) or a stroke. The model evaluates the potential economic value of a hypothetical PGx test for diagnosing statin-induced myopathy. We have assessed the model over the spectrum of test sensitivity and specificity parameters. RESULTS: Our model showed that a strategy with a perfect PGx test had an incremental cost-utility ratio of 4273 Canadian dollars ($Can) per quality-adjusted life year (QALY). The probabilistic sensitivity analysis shows that when the payer willingness-to-pay per QALY reaches $Can12,000, the PGx strategy is favored in 90% of the model simulations. CONCLUSION: We found that a strategy favoring patients staying on statin therapy is cost effective even if patients maintained on statin are at risk of rhabdomyolysis. Our results are explained by the fact that statins are highly effective in reducing the CV risk in patients at high CV risk, and this benefit largely outweighs the risk of rhabdomyolysis.

Homeostasis Model Assessment of Insulin Resistance and Survival in Patients With Diabetes and Acute Coronary Syndrome.

Objective: Insulin resistance has been linked to development and progression of atherosclerosis and is present in most patients with type 2 diabetes. Whether the degree of insulin resistance predicts adverse outcomes in patients with type 2 diabetes and acute coronary syndrome (ACS) is uncertain. Design: The Effect of Aleglitazar on Cardiovascular Outcomes after Acute Coronary Syndrome in Patients with Type 2 Diabetes Mellitus trial compared the peroxisome proliferator-activated receptor-α/γ agonist aleglitazar with placebo in patients with type 2 diabetes and recent ACS. In participants not treated with insulin, we determined whether baseline homeostasis model assessment of insulin resistance (HOMA-IR; n = 4303) or the change in HOMA-IR on assigned study treatment (n = 3568) was related to the risk of death or major adverse cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in unadjusted and adjusted models. Because an inverse association of HOMA-IR with N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been described, we specifically examined effects of adjustment for the latter. Results: In unadjusted analysis, twofold higher baseline HOMA-IR was associated with lower risk of death [hazard ratio (HR): 0.79, 95% CI: 0.68 to 0.91, P = 0.002]. Adjustment for 24 standard demographic and clinical variables had minimal effect on this association. However, after further adjustment for NT-proBNP, the association of HOMA-IR with death was no longer present (adjusted HR: 0.99, 95% CI: 0.83 to 1.19, P = 0.94). Baseline HOMA-IR was not associated with major adverse cardiovascular events, nor was the change in HOMA-IR on study treatment associated with death or major adverse cardiovascular events. Conclusions: After accounting for levels of NT-proBNP, insulin resistance assessed by HOMA-IR is not related to the risk of death or major adverse cardiovascular events in patients with type 2 diabetes and ACS.

Assessment of Inter-Expert Variability and of an Automated Segmentation Method of 40 and 60 MHz IVUS Images of Coronary Arteries.

The objectives were to compare the performance of a segmentation algorithm, based on the minimization of an uncertainty function, to delineate contours of external elastic membrane and lumen of human coronary arteries imaged with 40 and 60 MHz IVUS, and to use values of this function to delineate portions of contours with highest uncertainty. For 8 patients, 40 and 60 MHz IVUS coronary data acquired pre- and post-interventions were used, for a total of 68,516 images. Manual segmentations of contours (on 2312 images) performed by experts at three core laboratories were the gold-standards. Inter-expert variability was highest on contour points with largest values of the uncertainty function (p < 0.001). Inter-expert variability was lower at 60 than 40 MHz for external elastic membrane (p = 0.013) and lumen (p = 0.024). Average differences in plaque (and atheroma) burden between algorithmic contours and experts' contours were within inter-expert variability (p < 0.001).

Clinical outcomes and economic impact of transcatheter mitral leaflet repair in heart failure patients.

BACKGROUND: Mitral regurgitation (MR) is a common valvular heart disorder requiring intervention once it becomes severe. Transcatheter mitral repair with the MitraClip device is a safe and effective therapy for selected patients denied surgery. The authors sought to evaluate the clinical outcomes and economic impact of this therapy compared to medical management in heart-failure patients with symptomatic mitral regurgitation. METHODS AND RESULTS: The study was comprised of two phases; an observational study of patients with heart failure and mitral regurgitation treated with either medical therapy or the MitraClip, and an economic model. Results of the observational study were used to estimate parameters for the decision model, which estimated costs, and benefits in a hypothetical cohort of patients with heart failure and moderate-to-severe mitral regurgitation treated with either standard medical therapy or MitraClip. The cohort of patients treated with the MitraClip was propensity matched to a population of heart failure patients, and their outcomes compared. At a mean follow-up of 22 months, all-cause mortality was 21% in the MitraClip cohort and 42% in the medical management cohort (p = .007). The decision model demonstrated that MitraClip increased life expectancy from 1.87-3.60 years and quality-adjusted life years (QALY) from 1.13-2.76 years. The incremental cost was $52,500 Canadian dollars, corresponding to an incremental cost-effectiveness ratio (ICER) of $32,300.00 per QALY gained. Results were sensitive to the survival benefit. CONCLUSION: In heart failure patients with symptomatic moderate-severe mitral regurgitation, therapy with the MitraClip is associated with superior survival and is cost-effective compared to medical therapy.

A model to assess the cost-effectiveness of pharmacogenomics tests in chronic heart failure: the case of ivabradine.

Pharmacogenomics (PGx) tests have the potential of improving the effectiveness of expensive new drugs by predicting the likelihood, for a particular patient, to respond to a treatment. The objective of this study was to develop a pharmacoeconomic model to determine the characteristics and the cost-effectiveness of a hypothetical PGx test, which would identify patients who are most likely to respond to an expensive treatment for chronic heart failure. For this purpose, we chose the example of ivabradine. Our results suggest that the use of a PGx test that could select a subgroup of patients to be treated with an expensive drug has the potential to provide more efficient drug utilization.

Will personalized drugs for cardiovascular disease become an option? - Defining 'Evidence-based personalized medicine' for its implementation and future use.

It is generally accepted that the implementation of pharmacogenomics and, more broadly, personalized medicine will have to be 'evidence-based'. However, there is a lack of consensus on the level of evidence required to justify the use of pharmacogenomic testing in clinical practice. In the cardiovascular field, this lack of agreement has led to somewhat contradicting recommendations by different organizations regarding the clinical utility and use of pharmacogenomic tests or information. Here, we argue that randomized, controlled trials are paramount in order to enable and accelerate the widespread implementation of pharmacogenomics, not only to demonstrate the clinical efficacy and cost-effectiveness of such tests, but because such level of evidence is required to support the considerable changes associated with the implantation of pharmacogenomics in clinical practice.

Geographical variations in the prevalence and management of cardiovascular risk factors in outpatients with CAD: Data from the contemporary CLARIFY registry.

AIM: To determine the current prevalence and control of major cardiovascular risk factors in stable CAD outpatients worldwide. METHODS: We analysed variations in cardiovascular risk factors in stable CAD outpatients from CLARIFY, a 5-year observational longitudinal cohort study, in seven geographical zones (Western/Central Europe; Canada/South Africa/Australia/UK; Eastern Europe; Central/South America; Middle East; East Asia; and India). RESULTS: Patient presentation (N=32,954, mean age 64.2 years, 78% male) varied between zones, as did prevalence of risk factors (all p < 0.0001). Obesity ranged from 20% (East Asia) to 42% (Middle East), raised blood pressure from 28% (Central/South America and East Asia) to 48% (Eastern Europe), raised LDL cholesterol from 24% (Canada/South Africa/Australia/UK) to 65% (Eastern Europe), elevated heart rate (≥70 bpm) from 38% (Western/Central Europe) to 78% (India), diabetes from 17% (Eastern Europe) to 60% (Middle East), and smoking from 6% (Central/South America) to 19% (Eastern Europe). Aspirin and lipid-lowering drugs were widely used everywhere (≥84% and ≥88%, respectively). Rates of risk factor control varied geographically (all p < 0.0001). Rate of controlled blood pressure in hypertension varied from 47% (Eastern Europe) to 66% (Central/South America), glucose control in diabetes from 23% (India) to 51% (Western/Central Europe and East Asia), controlled LDL cholesterol and dyslipidaemia from 32% (Eastern Europe) to 75% (Canada/South Africa/Australia/UK), heart rate <70 bpm from 22% (India) to 62% (Western/Central Europe), and heart rate ≤60 bpm in angina patients from 2% (India) to 29% (Canada/South Africa/Australia/UK and Central/South America). CONCLUSION: Prevalence and control of major cardiovascular risk factors in stable CAD vary markedly worldwide. Many stable CAD outpatients are being treated suboptimally.

Routine versus selective cardiac magnetic resonance in non-ischemic heart failure - OUTSMART-HF: study protocol for a randomized controlled trial (IMAGE-HF (heart failure) project 1-B).

BACKGROUND: Imaging has become a routine part of heart failure (HF) investigation. Echocardiography is a first-line test in HF given its availability and it provides valuable diagnostic and prognostic information. Cardiac magnetic resonance (CMR) is an emerging clinical tool in the management of patients with non-ischemic heart failure. Current ACC/AHA/CCS/ESC guidelines advocate its role in the detection of a variety of cardiomyopathies but there is a paucity of high quality evidence to support these recommendations.The primary objective of this study is to compare the diagnostic yield of routine cardiac magnetic resonance versus standard care (that is, echocardiography with only selective use of CMR) in patients with non-ischemic heart failure. The primary hypothesisis that the routine use of CMR will lead to a more specific diagnostic characterization of the underlying etiology of non-ischemic heart failure. This will lead to a reduction in the non-specific diagnoses of idiopathic dilated cardiomyopathy and HF with preserved ejection fraction. DESIGN: Tertiary care sites in Canada and Finland, with dedicated HF and CMR programs, will randomize consecutive patients with new or deteriorating HF to routine CMR or selective CMR. All patients will undergo a standard clinical echocardiogram and the interpreter will assign the most likely HF etiology. Those undergoing CMR will also have a standard examination and will be assigned a HF etiology based upon the findings. The treating physician's impression about non-ischemic HF etiology will be collected following all baseline testing (including echo ± CMR). Patients will be followed annually for 4 years to ascertain clinical outcomes, quality of life and cost. The expected outcome is that the routine CMR arm will have a significantly higher rate of infiltrative, inflammatory, hypertrophic, ischemic and 'other' cardiomyopathy than the selective CMR group. DISCUSSION: This study will be the first multicenter randomized, controlled trial evaluating the role of CMR in non-ischemic HF. Non-ischemic HF patients will be randomized to routine CMR in order to determine whether there are any gains over management strategies employing selective CMR utilization. The insight gained from this study should improve appropriate CMR use in HF. TRIAL REGISTRATION: NCT01281384.

Individual patient data meta-analysis for the clinical assessment of coronary computed tomography angiography: protocol of the Collaborative Meta-Analysis of Cardiac CT (CoMe-CCT).

BACKGROUND: Coronary computed tomography angiography has become the foremost noninvasive imaging modality of the coronary arteries and is used as an alternative to the reference standard, conventional coronary angiography, for direct visualization and detection of coronary artery stenoses in patients with suspected coronary artery disease. Nevertheless, there is considerable debate regarding the optimal target population to maximize clinical performance and patient benefit. The most obvious indication for noninvasive coronary computed tomography angiography in patients with suspected coronary artery disease would be to reliably exclude significant stenosis and, thus, avoid unnecessary invasive conventional coronary angiography. To do this, a test should have, at clinically appropriate pretest likelihoods, minimal false-negative outcomes resulting in a high negative predictive value. However, little is known about the influence of patient characteristics on the clinical predictive values of coronary computed tomography angiography. Previous regular systematic reviews and meta-analyses had to rely on limited summary patient cohort data offered by primary studies. Performing an individual patient data meta-analysis will enable a much more detailed and powerful analysis and thus increase representativeness and generalizability of the results. The individual patient data meta-analysis is registered with the PROSPERO database (CoMe-CCT, CRD42012002780). METHODS/DESIGN: The analysis will include individual patient data from published and unpublished prospective diagnostic accuracy studies comparing coronary computed tomography angiography with conventional coronary angiography. These studies will be identified performing a systematic search in several electronic databases. Corresponding authors will be contacted and asked to provide obligatory and additional data. Risk factors, previous test results and symptoms of individual patients will be used to estimate the pretest likelihood of coronary artery disease. A bivariate random-effects model will be used to calculate pooled mean negative and positive predictive values as well as sensitivity and specificity. The primary outcome of interest will be positive and negative predictive values of coronary computed tomography angiography for the presence of coronary artery disease as a function of pretest likelihood of coronary artery disease, analyzed by meta-regression. As a secondary endpoint, factors that may influence the diagnostic performance and clinical value of computed tomography, such as heart rate and body mass index of patients, number of detector rows, and administration of beta blockade and nitroglycerin, will be investigated by integrating them as further covariates into the bivariate random-effects model. DISCUSSION: This collaborative individual patient data meta-analysis should provide answers to the pivotal question of which patients benefit most from noninvasive coronary computed tomography angiography and thus help to adequately select the right patients for this test.

Low-cost three-dimensional imaging system combining fluorescence and ultrasound.

In this paper, we present a dual-modality imaging system combining three-dimensional (3D) continuous-wave transillumination fluorescence tomography with 3D ultrasound (US) imaging. We validated the system with two phantoms, one containing fluorescent inclusions (Cy5.5) at different depths, and another varying-thickness semicylindrical phantom. Using raster scanning, the combined fluorescence/US system was used to collect the boundary fluorescent emission in the X-Y plane, as well as recovered the 3D surface and position of the inclusions from US signals. US images were segmented to provide soft priors for the fluorescence image reconstruction. Phantom results demonstrated that with priors derived from the US images, the fluorescent reconstruction quality was significantly improved. As further evaluation, we show pilot in vivo results using an Apo-E mouse to assess the feasibility and performance of this system in animal studies. Limitations and potential to be used in artherosclerosis studies are then discussed.

Physiological stress responses in defensive individuals: age and sex matter.

The association between defensiveness and physiological responses to stress were evaluated in 81 healthy working men and 118 women, aged 20 to 64 years (M=41; SD=11.45). Participants underwent laboratory testing during which they were exposed to interpersonal stressors. Heart rate (HR), heart rate variability (HRV), blood pressure (BP), and salivary cortisol were measured. Defensiveness was evaluated using the Marlowe-Crowne Social Desirability Scale. In women, higher defensiveness was associated with greater BP and HR reactivity to stress (p<.05). In older men, lower defensiveness was associated with increased systolic BP reactivity to stress (p<.02), delayed HRV recovery (p<.02), and greater salivary cortisol levels (p<.02). In conclusion, greater defensiveness was associated with increased reactivity to stress in women whereas in older men, lower defensiveness was associated with elevated cardiovascular, autonomic, and endocrine responses to stress.