Cost-effectiveness of ultra-low-dose quadruple combination therapy for high blood pressure.

OBJECTIVE: To determine the cost-effectiveness and cost-utility of a quadpill containing irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg and bisoprolol 2.5 mg in comparison with irbesartan 150 mg for people with hypertension who are either untreated or receiving monotherapy. METHODS: We conducted a within-trial and modelled economic evaluation of the Quadruple UltrA-low-dose tReaTment for hypErTension trial. The analysis was preplanned, and medications and health service use captured during the trial. The main outcomes were incremental cost-effectiveness ratios (ICERs) for cost per mm Hg systolic blood pressure (BP) reduction at 3 months, and modelled cost per quality-adjusted life year (QALY) over a lifetime. RESULTS: The within-trial analysis showed no clear difference in cost per mm Hg BP lowering between randomised treatments at 3 months ($A10 (95% uncertainty interval (UI) $A -18 to $A37) per mm Hg per person) for quadpill versus monotherapy. The modelled cost-utility over a lifetime projected a mean incremental cost of $A265 (95% UI $A166 to $A357) and a mean 0.02 QALYs gained (95% UI 0.01 to 0.03) per person with quadpill therapy compared with monotherapy. Quadpill therapy was cost-effective in the base case (ICER of $A14 006 per QALY), and the result was sensitive to the quadpill cost in one-way sensitivity analysis. CONCLUSIONS: Quadpill in comparison with monotherapy is comparably cost-effective for short-term BP lowering. In the long-term, quadpill therapy is likely to be cost-effective. TRIAL REGISTRATION NUMBER: ANZCTRN12616001144404.

Can old drugs learn new tricks? Achieving registration and public subsidy listing for off-patent medicines with novel therapeutic applications.

With the increasing costs of drug development, repurposing of low-cost medicines for new indications has never been more important. However, there are multiple barriers to repurposing, particularly for off-patent medicines, and limited incentives for the pharmaceutical industry to sponsor registration and public subsidy listing. Here, we explore these barriers and their consequences and provide examples of successful repurposing strategies.

Cost-effectiveness analysis of initial treatment with single-pill combination antihypertensive medications.

Hypertension guidelines recommend initiating treatment with single pill combination (SPC) antihypertensive medications, but SPCs are used by only one-third of treated hypertensive US adults. This analysis estimated the cost-effectiveness of initial treatment with SPC dual antihypertensive medications compared with usual care monotherapy in hypertensive US adults.The validated BP Control Model-Cardiovascular Disease (CVD) Policy Model simulated initial SPC dual therapy (two half-standard doses in a single pill) compared with initial usual care monotherapy (half-standard dose when baseline systolic BP < 20 mmHg above goal and one standard dose when ≥20 mmHg above goal). Secondary analyses examined equivalent dose monotherapy (one standard dose) and equivalent dose dual therapy as separate pills (two half-standard doses). The primary outcomes were direct healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) over 10 years from a US healthcare sector perspective.At 10 years, initial dual drug SPC was projected to yield 0.028 (95%UI 0.008 to 0.051) more QALYs at no greater cost ($73, 95%UI -$1 983 to $1 629) than usual care monotherapy. In secondary analysis, SPC dual therapy was cost-effective vs. equivalent dose monotherapy (ICER $8 000/QALY gained) and equivalent dose dual therapy as separate pills (ICER $57 000/QALY gained). At average drug prices, initiating antihypertensive treatment with SPC dual therapy is more effective at no greater cost than usual care initial monotherapy and has the potential to improve BP control rates and reduce the burden of CVD in the US.

Two-drug fixed-dose combinations of blood pressure-lowering drugs as WHO essential medicines: An overview of efficacy, safety, and cost.

Cardiovascular diseases (CVD) are the world's leading cause of death. High blood pressure (BP) is the leading global risk factor for all-cause preventable morbidity and mortality. Globally, only about 14% of patients achieve BP control to systolic BP <140 mm Hg and diastolic BP <90 mm Hg. Most patients (>60%) require two or more drugs to achieve BP control, yet poor adherence to therapy is a major barrier to achieving this control. Fixed-dose combinations (FDCs) of BP-lowering drugs are one means to improve BP control through greater adherence and efficacy, with favorable safety and cost profiles. The authors present a review of the supporting data from a successful application to the World Health Organization (WHO) for the inclusion of FDCs of two BP-lowering drugs on the 21st WHO Essential Medicines List. The authors discuss the efficacy and safety of FDCs of two BP-lowering drugs for the management of hypertension in adults, relevant hypertension guideline recommendations, and the estimated cost of such therapies.

Does splitting a tablet obtain the accurate dose?: A systematic review protocol.

BACKGROUND: Physical manipulation of the manufactured dose form is a common practice, with almost a quarter of all drugs administered in primary care having their dose altered. Splitting a tablet can be advantageous as it facilitates swallowing, allows for dose flexibility and provides cost reductions. However, there are concerns these physical changes can lead to inaccurate portions resulting in significant variations from the prescribed dose. Thus, the review described in this protocol aims to summarise the literature assessing the effect of tablet splitting on dose accuracy. METHODS: Relevant studies will be identified through electronic searches in databases including EMBASE, MEDLINE, CINAHL, and the Cochrane Library, from the beginning of databases until January 2020. Studies investigating any drug, where the tablet was split, will be potentially eligible. Two reviewers will independently screen studies and extract data using standardised forms. Data extracted will include general study information, characteristics of the study, intervention characteristics and outcomes. Primary outcome is to assess dose accuracy of a split tablet measured by drug content or weight variability. Assessment of risk of bias will be dependent upon study design. If deemed feasible, meta-analysis will be performed. RESULTS: The study described within this protocol will provide a synthesis of current evidence assessing the effect of tablet splitting on dose accuracy. CONCLUSION: The conclusion of our study will provide evidence to judge whether splitting a tablet results in an accurate half dose. ETHICS AND DISSEMINATION: Ethics approval was not required for this study. The results of the systematic review described will be published in a peer-reviewed journal. REGISTRATION DETAILS: PROSPERO CRD42018106252.

Fixed-combination, low-dose, triple-pill antihypertensive medication versus usual care in patients with mild-to-moderate hypertension in Sri Lanka: a within-trial and modelled economic evaluation of the TRIUMPH trial.

BACKGROUND: Elevated blood pressure incurs a major health and economic burden, particularly in low-income and middle-income countries. The Triple Pill versus Usual Care Management for Patients with Mild-to-Moderate Hypertension (TRIUMPH) trial showed a greater reduction in blood pressure in patients using fixed-combination, low-dose, triple-pill antihypertensive therapy (consisting of amlodipine, telmisartan, and chlorthalidone) than in those receiving usual care in Sri Lanka. We aimed to assess the cost-effectiveness of the triple-pill strategy. METHODS: We did a within-trial (6-month) and modelled (10-year) economic evaluation of the TRIUMPH trial, using the health system perspective. Health-care costs, reported in 2017 US dollars, were determined from trial records and published literature. A discrete-time simulation model was developed, extrapolating trial findings of reduced systolic blood pressure to 10-year health-care costs, cardiovascular disease events, and mortality. The primary outcomes were the proportion of people reaching blood pressure targets (at 6 months from baseline) and disability-adjusted life-years (DALYs) averted (at 10 years from baseline). Incremental cost-effectiveness ratios were calculated to estimate the cost per additional participant achieving target blood pressure at 6 months and cost per DALY averted over 10 years. FINDINGS: The triple-pill strategy, compared with usual care, cost an additional US$9·63 (95% CI 5·29 to 13·97) per person in the within-trial analysis and $347·75 (285·55 to 412·54) per person in the modelled analysis. Incremental cost-effectiveness ratios were estimated at $7·93 (95% CI 6·59 to 11·84) per participant reaching blood pressure targets at 6 months and $2842·79 (-28·67 to 5714·24) per DALY averted over a 10-year period. INTERPRETATION: Compared with usual care, the triple-pill strategy is cost-effective for patients with mild-to-moderate hypertension. Scaled up investment in the triple pill for hypertension management in Sri Lanka should be supported to address the high population burden of cardiovascular disease. FUNDING: Australian National Health and Medical Research Council.

Modeling the cost effectiveness and budgetary impact of Polypills for secondary prevention of cardiovascular disease in the United States.

BACKGROUND: There is underutilization of appropriate medications for secondary prevention of cardiovascular disease (CVD). METHODS: Usual care (UC) was compared to polypill-based care with 3 versions using a validated micro-simulation model in the NHANES population with prior CVD. UC included individual prescription of up to 4 drug classes (antiplatelet agents, beta-blockers, renin-angiotensin-aldosterone inhibitors and statins). The polypills modeled were aspirin 81 mg, atenolol 50 mg, ramipril 5 mg, and either simvastatin 40 mg (Polypill I), atorvastatin 80 mg (Polypill II), or rosuvastatin 40 mg (Polypill III). Baseline medication use and adherence came from United Healthcare claims data. RESULTS: When compared to UC, there were annual reductions of 130,000 to 178,000 myocardial infarctions and 54,000 to 74,000 strokes using Polypill I and II, respectively. From a health sector perspective, in incremental analysis the ICERs for Polypill I and II were $20,073/QALY and $21,818/QALY respectively; Polypill III was dominated but had a similar cost-effectiveness ratio to Polypill II when compared directly to usual care. From a societal perspective, Polypill II was cost-saving and dominated all strategies. Over a 5-year period, those taking Polypill I and II compared to UC saved approximately $12 and $6 per-patient-per-year alive, respectively. Polypill II was the preferred strategy in 98% of runs at a willingness to pay of $50,000 in the probability sensitivity analysis. CONCLUSIONS: Use of a polypill has a favorable cost profile for secondary CVD prevention in the United States. Reductions in CVD-related healthcare costs outweighed medication cost increases on a per-patient-per-year basis, suggesting that a polypill would be economically advantageous to both patients and payers.

Acute Increases in Serum Creatinine After Starting Angiotensin-Converting Enzyme Inhibitor-Based Therapy and Effects of its Continuation on Major Clinical Outcomes in Type 2 Diabetes Mellitus.

Discontinuation of angiotensin-converting enzyme (ACE) inhibitor is recommended if patients experience ≥30% acute increase in serum creatinine after starting this therapy. However, the long-term effects of its continuation or discontinuation on major clinical outcomes after increases in serum creatinine are unclear. In the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation), 11 140 diabetes mellitus patients were randomly assigned to perindopril-indapamide or placebo after a 6-week active run-in period. The current study included 11 066 participants with 2 serum creatinine measurements recorded before and during the active run-in period (3 weeks apart). Acute increase in creatinine was determined using these 2 measurements and classified into 4 groups: increases in serum creatinine of <10%, 10% to 19%, 20% to 29%, and ≥30%. The primary study outcome was the composite of major macrovascular events, new or worsening nephropathy, and all-cause mortality. An acute increase in serum creatinine was associated with an elevated risk of the primary outcome ( P for trend <0.001). The hazard ratios were 1.11 (95% CI, 0.97-1.28) for those with an increase of 10% to 19%, 1.34 (1.07-1.66) for 20% to 29%, and 1.44 (1.15-1.81) for ≥30%, compared with <10%. However, there was no evidence of heterogeneity in the benefit of randomized treatment effects on the outcome across subgroups defined by acute serum creatinine increase ( P for heterogeneity=0.94). Acute increases in serum creatinine after starting perindopril-indapamide were associated with greater risks of subsequent major clinical outcomes. However, the continuation of angiotensin-converting enzyme inhibitor-based therapy reduced the long-term risk of major clinical outcomes, irrespective of acute increase in creatinine. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00145925.

Cost-effectiveness of a fixed dose combination (polypill) in secondary prevention of cardiovascular diseases in India: Within-trial cost-effectiveness analysis of the UMPIRE trial.

BACKGROUND: The Use of Multidrug Pill In Reducing cardiovascular Events (UMPIRE) trial, showed that access to a cardiovascular polypill (aspirin, statin and two blood pressure lowering drugs) significantly improved adherence, lowered systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDLc) in patients with or at high risk of cardiovascular disease (CVD). We aimed to analyze the within-trial cost-effectiveness of the polypill strategy versus usual care in India. METHODS: Relative effectiveness and costs of polypill versus usual care groups in UMPIRE were estimated from the health sector perspective. Only direct medical costs were considered. The effectiveness of the polypill was reported as a percentage increase in adherence and mean reductions in SBP, and LDL-c, over the 15-month trial period. Healthcare resource utilization and costs were collected for each patient during the trial. Polypill price was constructed using a range of scenarios: $0.06-$0.94/day. The cost-effectiveness of the polypill was measured as the additional cost for 10% increase in adherence, and per unit reduction in SBP and LDL-c. RESULTS: Overall, the mean cost per patient was significantly lower with the polypill strategy (-$203 per person, (95% CI: -286, -119, p < 0.01). In scenario analyses that varied polypill price assumptions, incremental cost-effectiveness ratios for a polypill strategy ranged between cost-saving to $75 per 10% increase in adherence for polypill price of $0.94 per day. CONCLUSIONS: The polypill strategy was cost-saving compared to usual care among patients with or at high risk of CVD in India.

A protocol for an economic evaluation of a polypill in patients with established or at high risk of cardiovascular disease in a UK NHS setting: RUPEE (NHS) study.

INTRODUCTION: The 'Use of a Multi-drug Pill in Reducing cardiovascular Events' (UMPIRE) trial was a randomised controlled clinical trial evaluating the impact of a polypill strategy on adherence to indicated medication in a population with established cardiovascular disease (CVD) of or at high risk thereof. The aim of Researching the UMPIRE Processes for Economic Evaluation in the National Health Service (RUPEE NHS) is to estimate the potential health economic impact of a polypill strategy for CVD prevention within the NHS using UMPIRE trial and other relevant data. This paper describes the design of a modelled economic evaluation of the impact of increased adherence to the polypill versus usual care among the UK UMPIRE participants. METHODS AND ANALYSIS: As recommended by the International Society for Pharmacoeconomics and Outcomes Research and the Society for Medical Decision Making modelling guidelines, a review of published CVD models was undertaken to identify the most appropriate modelling approach and structure. The review was carried out in the electronic databases, MEDLINE and EMBASE. 40 CVD models were identified from 57 studies, the majority of economic models were health state transition cohort models and individual-level simulation models. The findings were discussed with clinical experts to confirm the approach and structure. An individual simulation approach was identified as the most suitable method to capture the heterogeneity in the population at CVD risk. RUPEE-NHS will use UMPIRE trial data on adherence to estimate the long-term cost-effectiveness of the polypill strategy. DISSEMINATION: The evaluation findings will be presented in open-access scientific and healthcare policy journals and at national and international conferences. We will also present findings to NHS policy makers and pharmaceutical companies.

Efficacy and Safety of Quarter-Dose Blood Pressure-Lowering Agents: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

There is a critical need for blood pressure-lowering strategies that have greater efficacy and minimal side effects. Low-dose combinations hold promise in this regard, but there are few data on very-low-dose therapy. We, therefore, conducted a systematic review and meta-analysis of randomized controlled trials with at least one quarter-dose and one placebo and standard-dose monotherapy arm. A search was conducted of Medline, Embase, Cochrane Registry, Food and Drug Administration, and European Medicinal Agency websites. Data on blood pressure and adverse events were pooled using a fixed-effect model, and bias was assessed using Cochrane risk of bias. The review included 42 trials involving 20 284 participants. Thirty-six comparisons evaluated quarter-dose with placebo and indicated a blood pressure reduction of -4.7/-2.4 mm Hg (P<0.001). Six comparisons were of dual quarter-dose therapy versus placebo, observing a -6.7/ -4.4 mm Hg (P<0.001) blood pressure reduction. There were no trials of triple quarter-dose combination versus placebo, but one quadruple quarter-dose study observed a blood pressure reduction of -22.4/-13.1 mm Hg versus placebo (P<0.001). Compared with standard-dose monotherapy, the blood pressure differences achieved by single (37 comparisons), dual (7 comparisons), and quadruple (1 trial) quarter-dose combinations were +3.7/+2.6 (P<0.001), +1.3/-0.3 (NS), and -13.1/-7.9 (P<0.001) mm Hg, respectively. In terms of adverse events, single and dual quarter-dose therapy was not significantly different from placebo and had significantly fewer adverse events compared with standard-dose monotherapy. Quarter-dose combinations could provide improvements in efficacy and tolerability of blood pressure-lowering therapy.

Cost-effectiveness of a text message programme for the prevention of recurrent cardiovascular events.

OBJECTIVE: To estimate the cost-effectiveness of Tobacco, Exercise and Diet Messages (TEXT ME), a text message-based intervention that provides advice, motivation, information and support to improve health-related behaviours. METHODS: A lifetime Markov model was used to estimate major vascular events (myocardial infarctions and strokes) avoided, quality-adjusted life years (QALYs) gained, costs to the health system and the incremental cost per QALY gained. The model was informed by data from a randomised controlled trial of TEXT ME, with evidence from systematic reviews and meta-analyses used to estimate the effects of changes in risk factors on the risk of major vascular events. Expected costs and health outcomes were estimated with uncertainty surrounding these characterised using probabilistic sensitivity analysis and a number of scenario analyses. RESULTS: For a target population of 50 000 patients with documented coronary heart disease, the intervention is expected to lead to 563 fewer myocardial infarctions, 361 fewer strokes and 1143 additional QALYs. TEXT ME is expected to lead to an overall saving of $10.56 million for the health system over the patients' lifetimes. The intervention can therefore be considered cost-saving and health-improving. Neither parameter nor structural uncertainty had a significant impact on the conclusion that TEXT ME is cost-effective. CONCLUSIONS: The provision of TEXT ME is predicted to lead to better health outcomes and an overall saving in costs for the health system. TRIAL REGISTRATION NUMBER: anzctr.org.au identifier: ACTRN12611000161921.

Comparative Cost-Effectiveness of Conservative or Intensive Blood Pressure Treatment Guidelines in Adults Aged 35-74 Years: The Cardiovascular Disease Policy Model.

The population health effect and cost-effectiveness of implementing intensive blood pressure goals in high-cardiovascular disease (CVD) risk adults have not been described. Using the CVD Policy Model, CVD events, treatment costs, quality-adjusted life years, and drug and monitoring costs were simulated over 2016 to 2026 for hypertensive patients aged 35 to 74 years. We projected the effectiveness and costs of hypertension treatment according to the 2003 Joint National Committee (JNC)-7 or 2014 JNC8 guidelines, and then for adults aged ≥50 years, we assessed the cost-effectiveness of adding an intensive goal of systolic blood pressure <120 mm Hg for patients with CVD, chronic kidney disease, or 10-year CVD risk ≥15%. Incremental cost-effectiveness ratios <$50 000 per quality-adjusted life years gained were considered cost-effective. JNC7 strategies treat more patients and are more costly to implement compared with JNC8 strategies. Adding intensive systolic blood pressure goals for high-risk patients prevents an estimated 43 000 and 35 000 annual CVD events incremental to JNC8 and JNC7, respectively. Intensive strategies save costs in men and are cost-effective in women compared with JNC8 alone. At a willingness-to-pay threshold of $50 000 per quality-adjusted life years gained, JNC8+intensive had the highest probability of cost-effectiveness in women (82%) and JNC7+intensive the highest probability of cost-effectiveness in men (100%). Assuming higher drug and monitoring costs, adding intensive goals for high-risk patients remained consistently cost-effective in men, but not always in women. Among patients aged 35 to 74 years, adding intensive blood pressure goals for high-risk groups to current national hypertension treatment guidelines prevents additional CVD deaths while saving costs provided that medication costs are controlled.

Polypill treatments for cardiovascular diseases.

Cardiovascular disease (CVD) is the leading cause of mortality globally. Effective CVD preventive medications are available including statin, blood pressure-lowering and antiplatelet medications; however most people do not take these drugs long term. Fixed-dose combination pills ("polypills") have been shown, in several clinical trials, to improve adherence to these recommended medications, with corresponding improvements in risk factors such as blood pressure and LDL-cholesterol. In patients not taking all modalities of recommended CVD preventive therapies, polypill-based strategies could importantly contribute to global CVD control strategies. The largest benefits are seen in those who are under-treated at baseline, rather than those who are already taking the individual components separately: simplified step-up is more important than pill count reduction. Despite the potential benefits for patients and payers, only a few polypills are available due to market failure in the funding of research and development for affordable non-communicable disease medicines. Regulatory paradigms have focused on substitution indications among patients already taking component medications; however, this is the population that is likely to receive the least benefit from a polypill-based strategy. Greater health impact is likely if focus is given to patients who have indications for all polypill components, but currently do not receive the benefits of recommended medicines long term.

An economic case for a cardiovascular polypill? A cost analysis of the Kanyini GAP trial.

OBJECTIVE: To measure the costs of a polypill strategy and compare them with those of usual care in people with established cardiovascular disease (CVD) or at similarly high cardiovascular risk. DESIGN: A within-trial cost analysis of polypill-based care versus usual care with separate medications, using data from the Kanyini Guidelines Adherence with the Polypill (GAP) trial and linked health service and medication administrative claims data. PARTICIPANTS: Kanyini GAP participants who consented to Australian Medicare record access. MAIN OUTCOME MEASURES: Mean health service and pharmaceutical expenditure per patient per year, estimated with generalised linear models. Costs during the trial (randomisation January 2010 - May 2012, median follow-up 19 months, maximum follow-up 36 months) were inflated to 2012 costs. RESULTS: Our analysis showed a statistically significantly lower mean pharmaceutical expenditure of $989 (95% CI, $648-$1331) per patient per year in the polypill arm compared with usual care (P < 0.001; adjusted, excluding polypill cost). No significant difference was shown in health service expenditure. CONCLUSIONS: This study provides evidence of significant cost savings to the taxpayer and Australian Government through the introduction of a CVD polypill strategy. The savings will be less now than during the trial due to subsequent reductions in the costs of usual care. Nonetheless, given the prevalence of CVD in Australia, the introduction of this polypill could increase considerably the efficiency of health care expenditure in Australia. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN126080005833347.

Applying a 3.0 transformation framework to guide large-scale health system reform.

Implementation of the Affordable Care Act is unleashing historic new efforts aimed at reforming the US health system. Many important incremental improvements are under way, yet there is a growing recognition that more transformative changes are necessary if the health care system is to do a better job of optimizing population health. While the concept of the Triple Aim-dedicated to improving the experience of care, the health of populations, and lowering per capita costs of care-has been used to help health care providers and health care systems focus their efforts on costs, quality, and outcomes, it does not provide a roadmap for a new system. In this article we describe the 3.0 Transformation Framework we developed to stimulate thinking and support the planning and development of the new roadmap for the next generation of the US health care system. With a focus on optimizing population health over the life span, the framework suggests how a system designed to better manage chronic disease care could evolve into a system designed to enhance population health. We describe how the 3.0 Transformation Framework has been used and applied in national, state, and local settings, and we suggest potential next steps for its wider application and use.

The effect of active video games by ethnicity, sex and fitness: subgroup analysis from a randomised controlled trial.

BACKGROUND: The prevention and treatment of childhood obesity is a key public health challenge. However, certain groups within populations have markedly different risk profiles for obesity and related health behaviours. Well-designed subgroup analysis can identify potential differential effects of obesity interventions, which may be important for reducing health inequalities. The study aim was to evaluate the consistency of the effects of active video games across important subgroups in a randomised controlled trial (RCT). FINDINGS: A two-arm, parallel RCT was conducted in overweight or obese children (n=322; aged 10-14 years) to determine the effect of active video games on body composition. Statistically significant overall treatment effects favouring the intervention group were found for body mass index, body mass index z-score and percentage body fat at 24 weeks. For these outcomes, pre-specified subgroup analyses were conducted among important baseline demographic (ethnicity, sex) and prognostic (cardiovascular fitness) groups. No statistically significant interaction effects were found between the treatment and subgroup terms in the main regression model (p=0.36 to 0.93), indicating a consistent treatment effect across these groups. CONCLUSIONS: Preliminary evidence suggests an active video games intervention had a consistent positive effect on body composition among important subgroups. This may support the use of these games as a pragmatic public health intervention to displace sedentary behaviour with physical activity in young people.

Combination pharmacotherapy to prevent cardiovascular disease: present status and challenges.

Combination pills containing aspirin, multiple blood pressure (BP) lowering drugs, and a statin have demonstrated safety, substantial risk factor reductions, and improved medication adherence in the prevention of cardiovascular disease (CVD). The individual medications in combination pills are already recommended for use together in secondary CVD prevention. Therefore, current information on their pharmacokinetics, impact on the risk factors, and tolerability should be sufficient to persuade regulators and clinicians to use fixed-dose combination pills in high-risk individuals, such as in secondary prevention. Long-term use of these medicines, in a polypill or otherwise, is expected to reduce CVD risk by at least 50-60% in such groups. This risk reduction needs confirmation in prospective randomized trials for populations for whom concomitant use of the medications is not currently recommended (e.g. primary prevention). Given their additive benefits, the combined estimated relative risk reduction (RRR) in CVD from both lifestyle modification and a combination pill is expected to be 70-80%. The first of several barriers to the widespread use of combination therapy in CVD prevention is physician reluctance to use combination pills. This reluctance may originate from the belief that lifestyle modification should take precedence, and that medications should be introduced one drug at a time, instead of regarding combination pills and lifestyle modification as complementary and additive. Second, widespread availability of combination pills is also impeded by the reluctance of large pharmaceutical companies to invest in development of novel co-formulations of generic (or 'mature') drugs. A business model based on 'mass approaches' to drug production, packaging, marketing, and distribution could make the combination pill available at an affordable price, while at the same time providing a viable profit for the manufacturers. A third barrier is regulatory approval for novel multidrug combination pills, as there are few precedents for the approval of combination products with four or more components for CVD. Acceptance of combination therapy in other settings suggests that with concerted efforts by academics, international health agencies, research funding bodies, governments, regulators, and pharmaceutical manufacturers, combination pills for prevention of CVD in those with disease or at high risk (e.g. those with multiple risk factors) can be made available worldwide at affordable prices. It is anticipated that widespread use of combination pills with lifestyle modifications can lead to substantial risk reductions (as much as an 80% estimated RRR) in CVD. Heath care systems need to deploy these strategies widely, effectively, and efficiently. If implemented, these strategies could avoid several millions of fatal and non-fatal CVD events every year worldwide.