Medication Discontinuation in the IMPROVE-IT Trial.

BACKGROUND: Although cholesterol-lowering medications can reduce the risk of recurrent cardiovascular events, premature discontinuation limits effectiveness. Discontinuation rates have not been systematically reported for lipid-lowering trials. METHODS AND RESULTS: We evaluated medication discontinuation in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), which evaluated placebo+simvastatin versus ezetimibe+simvastatin in patients hospitalized with the acute coronary syndrome and followed longitudinally postdischarge. Reasons for discontinuation were evaluated from randomization through study end (median 71.9 [interquartile range 51.8-85.8] months). Kaplan-Meier (KM) discontinuation rates were evaluated at 30 days, 1 year, and through year 7, and compared by treatment arm and region, with Cox proportional hazards modeling used to evaluate predictors of discontinuation. Overall, 46.7% of subjects discontinued study medication (KM rate by study end 50.9% [95% CI, 50.1%-51.7%]). The risk of discontinuation was highest early in the trial but decreased with increasing time, with a terminal KM rate per 100 person-years of 8.4 (8.2-8.6) from years 1 to 7. Discontinuation was higher in the placebo+simvastatin versus ezetimibe+simvastatin arm (KM rate 52.0% versus 49.8%, P=0.049) and was highest in the United States (7-year KM rate 57.4%). In multivariable modeling, smoking, prior revascularization, hypertension, unstable angina, female sex, nonwhite race, and US location were associated with higher discontinuation rates. CONCLUSIONS: Although discontinuation was highest early and stabilized to 8% per year, because of prolonged follow-up, most discontinuation occurred after year 1. Adding ezetimibe to statin therapy did not increase discontinuation risk. Geographic differences and patient-level factors should be considered in trial design and analysis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00202878.

Fortalecimiento de los sistemas regulatorios de los medicamentos en la Región de las Américas / Strengthening of regulatory systems for medicines in the Americas

Una de las funciones básicas de la salud pública es la regulación en el ámbito de la salud. Cuando esta función se ejerce de manera eficaz, sirve para promover y proteger la salud de la población al asegurar la calidad, seguridad y eficacia de los medicamentos; fomentar la fabricación, conservación y distribución adecuadas de dichos medicamentos; facilitar la lucha contra los productos médicos de calidad subestándar, espurios, de etiquetado engañoso, falsificados o de imitación; proporcionar la información necesaria a los profesionales de la salud y los pacientes para que puedan usar los medicamentos de una manera racional; y procurar que el acceso a los medicamentos no se vea obstaculizado por marcos regulatorios poco eficientes. Por consiguiente, el desarrollo de un sistema regulatorio nacional sólido constituye un componente fundamental de un sistema nacional de salud. En este contexto, nos complace presentar el primer número especial que se publica en la Revista Panamericana de Salud Pública sobre el fortalecimiento de los sistemas regulatorios de los medicamentos y otras tecnologías. Este número especial es una expresión de la determinación de los Estados Miembros de la Región de las Américas de aplicar la resolución CD50.R9 del Consejo Directivo de la Organización Panamericana de la Salud (2010) sobre el Fortalecimiento de las autoridades reguladoras nacionales de medicamentos y productos biológicos y, más recientemente, de los Estados Miembros de la Organización Mundial de la Salud al aprobar la resolución WHA67.20 (2014), Fortalecimiento del sistema de reglamentación de los productos médicos...En este número se recogen artículos de expertos en regulación de la Región de las Américas así como de expertos mundiales, que ponen en primer plano una amplia variedad de experiencias. Estos expertos presentan los fundamentos esenciales científicos y regulatorios que permiten que lleguen al mercado productos innovadores que salvan vidas; las contribuciones clave de los foros internacionales y las colaboraciones entre el sector público y el privado que pueden realizar aportaciones a la ciencia de la regulación y al desarrollo de buenas prácticas regulatorias; y los retos en continuo cambio que enfrentan las instancias regulatorias para establecer sistemas de regulación interconectados y convergentes dentro de un contexto de capacidad y recursos humanos y económicos limitados, a nivel nacional y mundial.

Strengthening of regulatory systems for medicines in the Americas / Fortalecimiento de los sistemas regulatorios de los medicamentos en la Región de las Américas

Health regulation is regarded as one of public health’s basic functions. Effective regulation of medicines promotes and protects the public’s health by guaranteeing medicines quality, safety, and efficacy; promoting the adequate manufacture, storage, and distribution of medicines; facilitating the fight against substandard, spurious, falsely labeled, falsified, or counterfeit medical products; providing the necessary information to health professionals and patients so they can use medicines rationally; and ensuring that access to medicines is not hindered by inefficient regulatory frameworks. Developing a strong national regulatory system is, therefore, a critical component of a national health system. In this context, we are pleased to present the first ever special issue of the Pan American Journal of Public Health to focus on strengthening of regulatory systems for medicines and other technologies. This special issue is an expression of the resolve of the governments of the Americas in implementing the Pan American Health Organization Directing Council Resolution CD50.R9 (2010) “Strengthening National Regulatory Authorities for Medicines and Biologicals,” and more recently of the Member States of the World Health Organization in the adoption of resolution WHA67.20 (2014), “Regulatory system strengthening for medical products.”...The journal brings together articles from regulatory experts within the Region of the Americas as well as from global experts, who bring an array of experiences to the fore. They present the essential underpinning of science and regulation that bring life-saving and innovative products to the marketplace; analysis of key contributions from international fora and public-private coalitions that can add to regulatory science and the development of good regulatory practices; and the ever-evolving challenges that regulators face to build inter-linked and convergent regulatory systems within the context of limited capacity, human and financial resources, nationally and globally.

Venous thromboembolism and cardiovascular risk: results from the NAVIGATOR trial.

BACKGROUND: Contemporary studies suggest an association between venous thromboembolism and a higher incidence of major cardiovascular events, mostly attributed to arterial atherothrombosis. Using data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, we assessed the association of venous thromboembolism with major cardiovascular events. METHODS: In NAVIGATOR, patients with impaired glucose tolerance were randomly allocated to receive valsartan or placebo and nateglinide or placebo in addition to lifestyle modification. Baseline characteristics and prior history of venous thromboembolism were assessed. After adjusting for important baseline covariates, Cox proportional hazards regression models were used to assess the association between venous thromboembolism and major cardiovascular outcomes. RESULTS: Of the 9306 patients enrolled, 129 (1.4%) had a history of venous thromboembolism. Patients with venous thromboembolism were older, more frequently white and female, and had a higher body mass index. Patients with venous thromboembolism had higher 5-year event rates for the composite of death, myocardial infarction, and stroke, as compared with patients without venous thromboembolism (10.7% vs 5.9%; P < .001; adjusted hazard ratio 2.12; 95% confidence interval, 1.36-3.31; P = .001). CONCLUSION: In patients with impaired glucose tolerance at high risk for cardiovascular events, the prevalence of venous thromboembolism was rare but associated with worse long-term cardiovascular outcomes, including arterial events. Venous thromboembolism is a marker of risk, and attention should be paid to this high-risk group of patients.

Prevalence, characteristics, and predictors of early termination of cardiovascular clinical trials due to low recruitment: insights from the ClinicalTrials.gov registry.

BACKGROUND: Early termination of clinical trials due to low recruitment represents an understudied challenge for clinical research. We aimed to describe characteristics of cardiovascular trials terminated because of low recruitment and identify the major predictors of such early termination. METHODS: We reviewed all cardiovascular clinical trials (7,042 studies) registered in ClinicalTrials.gov from February 29, 2000, to January 17, 2013, and assessed information about trials that were completed and those that were terminated early. Logistic regression models were developed to identify independent predictors of early termination due to low recruitment. RESULTS: Our search strategy identified 6,279 cardiovascular clinical trials, of which 684 (10.9%) were terminated prematurely. Of these halted trials, the main reason for termination was lower than expected recruitment (278 trials; 53.6%). When comparing trials that terminated early because of low recruitment with those that were completed, we found that studies funded by the National Institutes of Health or other US federal agencies (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.14-0.89), studies of behavior/diet intervention (OR 0.35, 95% CI 0.19-0.65), and single-arm design studies (OR 0.57, 95% CI 0.42-0.78) were associated with a lower risk of early termination. University/hospital-funded (OR 1.52, 95% CI 1.10-2.10) and mixed-source-funded studies (OR 2.14, 95% CI 1.52-3.01) were associated with a higher likelihood of early termination due to lower than expected recruitment rates. CONCLUSIONS: Low recruitment represents the main cause of early termination of cardiovascular clinical trials. Funding source, type of intervention, and study design are factors associated with early termination due to low recruitment and might be good targets for improving enrollment into cardiovascular clinical trials.

Impact of global geographic region on time in therapeutic range on warfarin anticoagulant therapy: data from the ROCKET AF clinical trial.

BACKGROUND: Vitamin K antagonist (VKA) therapy remains the most common method of stroke prevention in patients with atrial fibrillation. Time in therapeutic range (TTR) is a widely cited measure of the quality of VKA therapy. We sought to identify factors associated with TTR in a large, international clinical trial. METHODS AND RESULTS: TTR (international normalized ratio [INR] 2.0 to 3.0) was determined using standard linear interpolation in patients randomized to warfarin in the ROCKET AF trial. Factors associated with TTR at the individual patient level (i-TTR) were determined via multivariable linear regression. Among 6983 patients taking warfarin, recruited from 45 countries grouped into 7 regions, the mean i-TTR was 55.2% (SD 21.3%) and the median i-TTR was 57.9% (interquartile range 43.0% to 70.6%). The mean time with INR <2 was 29.1% and the mean time with an INR >3 was 15.7%. While multiple clinical features were associated with i-TTR, dominant determinants were previous warfarin use (mean i-TTR of 61.1% for warfarin-experienced versus 47.4% in VKA-naïve patients) and geographic region where patients were managed (mean i-TTR varied from 64.1% to 35.9%). These effects persisted in multivariable analysis. Regions with the lowest i-TTRs had INR distributions shifted toward lower INR values and had longer inter-INR test intervals. CONCLUSIONS: Independent of patient clinical features, the regional location of medical care is a dominant determinant of variation in i-TTR in global studies of warfarin. Regional differences in mean i-TTR are heavily influenced by subtherapeutic INR values and are associated with reduced frequency of INR testing. CLINICAL TRIAL REGISTRATION: URL: ClinicalTrials.gov. Unique identifier: NCT00403767.

Highlights from the III International Symposium of Thrombosis and Anticoagulation (ISTA), October 14-16, 2010, São Paulo, Brazil.

To discuss and share knowledge around advances in the care of patients with thrombotic disorders, the Third International Symposium of Thrombosis and Anticoagulation was held in São Paulo, Brazil, from October 14-16, 2010. This scientific program was developed by clinicians for clinicians, and was promoted by four major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, the Canadian VIGOUR Centre, and the Uppsala Clinical Research Center. Comprising 3 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

Outcomes of patients in clinical trials with ST-segment elevation myocardial infarction among countries with different gross national incomes.

AIMS: To evaluate whether there is an association between 30-day mortality in patients with ST-segment elevation myocardial infarction (STEMI) included in clinical trials and country gross national income (GNI). METHODS AND RESULTS: A retrospective analysis of the databases of five randomized trials including 50 310 patients with STEMI (COBALT 7169, GIK-2 2931, HERO-2 17,089, ASSENT-2 17,005, and ASSENT-3 6116 patients) from 53 countries was performed. Countries were divided into three groups according to their GNI based on the World Bank data: low (less than 2900 US dollars), medium (between 2900 US dollars and 9000 US dollars), and high GNI (more than 9000 US dollars per capita). Baseline characteristics, in-hospital management variables, and 30-day outcomes were evaluated. A previously defined logistic regression model was used to adjust for differences in baseline characteristics and to predict mortality. The observed mortality was higher than the predicted mortality in the low (12.1 vs. 11.8%) and in the medium income groups (9.4 vs. 7.9%), whereas it was lower in the high income group (4.9 vs. 5.6%). CONCLUSION: An inverse relationship between mortality and GNI was observed in STEMI clinical trials. Most of the variability in mortality can be explained by differences in baseline characteristics; however, after adjustment, lower income countries have higher mortality than the expected.

Electrocardiographic infarct size assessment after thrombolysis: insights from the Acute Myocardial Infarction STudy ADenosine (AMISTAD) trial.

BACKGROUND: Noninvasive methods are needed to evaluate reperfusion success in patients with acute myocardial infarction (MI). The AMISTAD trial was analyzed to compare MI size and myocardial salvage determined by electrocardiogram (ECG) with technetium Tc 99m sestamibi single-photon emission computerized tomography (SPECT) imaging. METHODS: Of 236 patients enrolled in AMISTAD, 166 (70 %) with no ECG confounding factors and no prior MI were included in this analysis. Of these, group 1 (126 patients, 53%) had final infarct size (FIS) available by both ECG and SPECT. Group 2 (56 patients, 24%) had myocardium at risk, FIS, and salvage index (SI) assessed by both SPECT and ECG techniques. Aldrich/Clemmensen scores for myocardium at risk and the Selvester QRS score for final MI size were used. Salvage index was calculated as follows: SI = (myocardium at risk-FIS)/(myocardium at risk). RESULTS: In group 1, FIS was 15% (6, 24) as measured by ECG and 11% (2, 27) as measured by SPECT. In the adenosine group, FIS was 12% (6, 21) and 11% (2, 22). In the placebo group, FIS was 16.5% (7.5, 24) and 11.5% (3.0, 38.5) by ECG and SPECT, respectively. The overall correlation between SPECT and ECG for FIS was 0.58 (P = .0001): 0.60 in the placebo group (P = .0001) and 0.54 (P = .0001) in the adenosine group. In group 2, myocardium at risk was 23% (17, 30) and 26% (10, 50) with ECG and SPECT, respectively (P = .0066). Final infarct size was 17% (6, 21) and 12% (1, 24) (P < .0001). The SI was 29% (-7, 57) and 46% (15, 79) with ECG and SPECT, respectively (P = .0510). CONCLUSIONS: The ECG measurement of infarct size has a moderate relationship with SPECT infarct size measurements in the population with available assessments. This ECG algorithm must further be validated on clinical outcomes.

Prognostic value of predischarge electrocardiographic measurement of infarct size after thrombolysis: insights from GUSTO I Economics and Quality of Life substudy.

BACKGROUND: Current methods for risk stratification after acute myocardial infarction (MI) include several noninvasive studies. In this cost-containment era, the development of low-cost means should be encouraged. We assessed the ability of an electrocardiogram (ECG) MI-sizing score to predict outcomes in patients enrolled in the Economics and Quality of Life (EQOL) sub study of the Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries -I (GUSTO-I) trial. METHODS: We classified patients by electrocardiographic Selvester QRS score at hospital discharge: those with a score 0-9 versus > or =10. Endpoints were 30-day and 1-year mortality, resource use, and quality-of-life measures. RESULTS: Patients with a QRS score <10 were well-matched with those with QRS score > or =10 with the exception of a trend to more anterior MI in the higher scored group. Patients with QRS score > or =10 had increased risk of death at 30-days (8.9% vs. 2.9% P < .001), and this difference persisted at 1 year (12.6% vs. 5.4%, P = .001). Recurrent chest pain, use of angiography, and angioplasty were similar during follow-up. However, there was a trend toward less coronary bypass surgery in patients with a QRS score > or =10. Readmission rates were higher at 30 days but similar at 1 year. CONCLUSIONS: Stratification of patients after acute MI by a simple measure of MI size identifies populations with different long-term prognoses; patients with a QRS score > or =10 (approximately 30% of the left ventricle infarcted) at discharge have poorer outcomes in both the short- and long-term. The standard 12-lead ECG provides a simple, economical means of risk stratification at discharge.

International variation in the use of evidence-based medicines for acute coronary syndromes

Aims We sought to evaluate international patterns of use and factors influencing use of evidence-based medications early after ACS. Methods and results Using a database of 15 904 ACS patients enrolled in the SYMPHONY and 2nd SYMPHONY trials in 37 countries, we performed descriptive and logistic regression analyses. After controlling for other factors, region was significantly associated with the use of every class of evidence-based medication, most pronounced for intravenous unfractionated heparin (IV UFH), low- molecular-weight heparin (LMWH), angiotensin II converting enzyme inhibitors (ACEI) and discharge use of lipid-lowering agents. Latin America and Eastern Europe were among the highest users of early ACEI, yet the lowest users of discharge lipid-lowering therapy. Relative to the United States, all regions except Canada had greater use of LMWH and lower use of IV UFH. Compared with patients with acute myocardial infarction, those with unstable angina less often received aspirin, beta-blockers, ACEI, or IV UFH. Older age was associated with lower use of aspirin, beta-blockers, IV UFH, and lipid-lowering agents. Conclusion Use of evidence-based therapies for management of ACS patients is strongly associated with region. To improve patient outcomes, more research is needed to understand this variation, and to institute appropriate solutions.