Importance Most patients with cardiovascular disease (CVD) do not take recommended medications long-term. The use of fixed-dose combinations (FDCs) improves adherence in several clinical areas. Previous trials of cardiovascular FDCs have assessed short-term effects compared with placebo or no treatment. Objective To assess whether FDC delivery of aspirin, statin, and 2 blood pressure–lowering agents vs usual care improves long-term adherence to indicated therapy and 2 major CVD risk factors, systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C). Design, Setting, and Participants The UMPIRE trial, a randomized, open-label, blinded-end-point trial among 2004 participants with established CVD or at risk of CVD enrolled July 2010–July 2011 in India and Europe. The trial follow-up concluded in July 2012. Interventions Participants were randomly assigned (1:1) to an FDC-based strategy (n=1002) containing either (1) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 50 mg atenolol or (2) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 12.5 mg hydrochlorothiazide or to usual care (n=1002). Main Outcomes and Measures Adherence to medication (defined as self-reported use of antiplatelet, statin, and ≥2 BP-lowering medications) and changes in SBP and LDL-C from baseline. Results At baseline, mean BP was 137/78 mm Hg, LDL-C was 91.5 mg/dL, and 1233 (61.5%) of 2004 participants reported use of antiplatelet, statin, and 2 or more BP-lowering medications. Median follow-up was 15 months (interquartile range, 12-18 months). The FDC group had improved adherence vs usual care (86% vs 65%; relative risk [RR] of being adherent, 1.33; 95% CI, 1.26-1.41; P P P P P  = .01 for interaction), and LDL-C was reduced by 6.7 mg/dL (95% CI, 10.5-2.8 mg/dL; P  = .11 for interaction). There were no significant differences in serious adverse events or cardiovascular events (50 [5%] in the FDC group and 35 [3.5%] in the usual care group; RR, 1.45; 95% CI, 0.94-2.24; P =.09) between the groups. Conclusions and Relevance Among patients with or at high risk of CVD, use of an FDC strategy for blood pressure, cholesterol, and platelet control vs usual care resulted in significantly improved medication adherence at 15 months and statistically significant but small improvements in SBP and LDL-C. Trial Registration clinicaltrials.gov Identifier:NCT01057537

https://jamanetwork.com/journals/jama/articlepdf/1734704/joi130052.pdf

Effects of a Fixed-Dose Combination Strategy on Adherence and Risk Factors in Patients With or at High Risk of CVD: The UMPIRE Randomized Clinical Trial

Summary Patterns of cancer incidence across the world have undergone substantial changes as a result of industrialisation and economic development. However, the economies of most countries remain at an early or intermediate stage of development—these stages are characterised by poverty, too few health-care providers, weak health systems, and poor access to education, modern technology, and health care because of scattered rural populations. Low-income and middle-income countries also have younger populations and therefore a larger proportion of children with cancer than high-income countries. Most of these children die from the disease. Chronic infections, which remain the most common causes of disease-related death in all except high-income countries, can also be major risk factors for childhood cancer in poorer regions. We discuss childhood cancer in relation to global development and propose strategies that could result in improved survival. Education of the public, more and better-trained health professionals, strengthened cancer services, locally relevant research, regional hospital networks, international collaboration, and health insurance are all essential components of an enhanced model of care.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(13)70008-1.pdf

Paediatric cancer in low-income and middle-income countries

https://academiccommons.columbia.edu/doi/10.7916/D8RB7GHG/download

Adherence to cardiovascular medications: lessons learned and future directions.

https://spiral.imperial.ac.uk/bitstream/10044/1/30542/2/SPACE_mainresults_IJC_revised.pdf

Effectiveness of fixed dose combination medication ('polypills') compared with usual care in patients with cardiovascular disease or at high risk: A prospective, individual patient data meta-analysis of 3140 patients in six countries☆ , ☆☆

Background:
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability worldwide, yet ASCVD risk factor control and secondary prevention rates remain low. A fixed-dose combination of blood pressure- and cholesterol-lowering and antiplatelet treatments into a single pill, or polypill, has been proposed as one strategy to reduce the global burden of ASCVD.

Objectives:
To determine the effect of fixed-dose combination therapy on all-cause mortality, fatal and non-fatal ASCVD events, and adverse events. We also sought to determine the effect of fixed-dose combination therapy on blood pressure, lipids, adherence, discontinuation rates, health-related quality of life, and costs.

Search methods:
We updated our previous searches in September 2016 of CENTRAL, MEDLINE, Embase, ISI Web of Science, and DARE, HTA, and HEED. We also searched two clinical trials registers in September 2016. We used no language restrictions.

Selection criteria:
We included randomised controlled trials of a fixed-dose combination therapy including at least one blood pressure-lowering and one lipid-lowering component versus usual care, placebo, or an active drug comparator for any treatment duration in adults 18 years old or older, with no restrictions on presence or absence of pre-existing ASCVD.

Data collection and analysis:
Three review authors independently selected studies for inclusion and extracted the data for this update. We evaluated risk of bias using the Cochrane 'Risk of bias' assessment tool. We calculated risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI) using fixed-effect models when heterogeneity was low (I2 < 50%) and random-effects models when heterogeneity was high (I2 ≥ 50%). We used the GRADE approach to evaluate the quality of evidence.

Main results:
In the initial review, we identified nine randomised controlled trials with a total of 7047 participants and four additional trials (n = 2012 participants; mean age range 62 to 63 years; 30% to 37% women) were included in this update. Eight of the 13 trials evaluated the effects of fixed-dose combination (FDC) therapy in populations without prevalent ASCVD, and the median follow-up ranged from six weeks to 23 months. More recent trials were generally larger with longer follow-up and lower risk of bias. The main risk of bias was related to lack of blinding of participants and personnel, which was inherent to the intervention. Compared with the comparator groups (placebo, usual care, or active drug comparator), the effects of the fixed-dose combination treatment on mortality (FDC = 1.0% versus control = 1.0%, RR 1.10, 95% CI 0.64 to 1.89, I2 = 0%, 5 studies, N = 5300) and fatal and non-fatal ASCVD events (FDC = 4.7% versus control = 3.7%, RR 1.26, 95% CI 0.95 to 1.66, I2 = 0%, 6 studies, N = 4517) were uncertain (low-quality evidence). The low event rates for these outcomes and indirectness of evidence for comparing fixed-dose combination to usual care versus individual drugs suggest that these results should be viewed with caution. Adverse events were common in both the intervention (32%) and comparator (27%) groups, with participants randomised to fixed-dose combination therapy being 16% (RR 1.16, 95% CI 1.09 to 1.25, 11 studies, 6906 participants, moderate-quality evidence) more likely to report an adverse event . The mean differences in systolic blood pressure between the intervention and control arms was -6.34 mmHg (95% CI -9.03 to -3.64, 13 trials, 7638 participants, moderate-quality evidence). The mean differences (95% CI) in total and LDL cholesterol between the intervention and control arms were -0.61 mmol/L (95% CI -0.88 to -0.35, 11 trials, 6565 participants, low-quality evidence) and -0.70 mmol/L (95% CI -0.98 to -0.41, 12 trials, 7153 participants, moderate-quality evidence), respectively. There was a high degree of statistical heterogeneity in comparisons of blood pressure and lipids (I2 ≥ 80% for all) that could not be explained, so these results should be viewed with caution. Fixed-dose combination therapy improved adherence to a multidrug strategy by 44% (26% to 65%) compared with usual care (4 trials, 3835 participants, moderate-quality evidence).

Authors' conclusions:
The effects of fixed-dose combination therapy on all-cause mortality or ASCVD events are uncertain. A limited number of trials reported these outcomes, and the included trials were primarily designed to observe changes in ASCVD risk factor levels rather than clinical events, which may partially explain the observed differences in risk factors that were not translated into differences in clinical outcomes among the included trials. Fixed-dose combination therapy is associated with modest increases in adverse events compared with placebo, active comparator, or usual care but may be associated with improved adherence to a multidrug regimen. Ongoing, longer-term trials of fixed-dose combination therapy will help demonstrate whether short-term changes in risk factors might be maintained and lead to expected differences in clinical events based on these changes.

Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular diseases.

Atherosclerotic cardiovascular diseases remain the leading cause of morbidity and mortality in both developed and developing countries. Adequate treatment of vascular risk factors, such as low-dens...

The cardiovascular polypill in high-risk patients:

Although modern clinical trials are traditionally conducted in Western countries, currently there is a shift to involve developing countries, particularly China and India. For these trials, the large population size of India and China means that substantial numbers of individuals affected by rare diseases may be found, increasing the likelihood of successfully completing enrollment in a clinical trial. Furthermore, the increasing involvement of Asian countries in global clinical trials is likely to lead to greater appreciation of the value of evidence-based treatment decisions in the region. These sites are more cost-effective, although this advantage is being eroded over time. Asian participants in clinical trials are also typically more likely to complete study follow-up and procedures, and to adhere to their randomized treatment allocation than individuals from Western countries. Challenges include relevance of the proposed trial to the region, capacity limitations because of undeveloped training, and ensuring research implementation quality and different intellectual property practices. There are specific challenges to conducting clinical trials in India, such as the status of ethics committees, health insurance and coverage for participants, and variability in languages and record-keeping. Challenges in both countries are substantial but are able to be managed with appropriate planning.

Vinodvenkatesh Patil

Papers

The cardiovascular polypill in high-risk patients:

Global randomized trials: the promise of India and China.