Curr Cardiol Rep (2015) 17:121DOI 10.1007/s11886-015-0673-x PUBLIC HEALTH POLICY (TA GAZIANO, SECTION EDITOR) Polypill: Progress and Challenges to Global Use—Update on the Trials and Policy Implementation Ruth Webster 1 & Anthony Rodgers 2 # Springer Science+Business Media New York 2015 Abstract Cardiovascular disease (CVD) is the leading cause Keywords Polypill . Cardiovascular disease . Prevention . of mortality globally. Most people with cardiovascular disease Policy do not take long-term cholesterol-lowering, anti-platelet and blood pressure-lowering medications despite proven benefits. Fixed-dose combination pills (‘polypills’) have been shown to Introduction improve adherence to these recommended medications with corresponding improvements in risk factors such as blood Despite large-scale randomised trial evidence demonstrating pressure and low-density lipoprotein (LDL) cholesterol. substantial reductions in cardiovascular events with anti- Among patients not taking the full complement of recom- platelet [1], blood pressure lowering [2] and cholesterol low- mended CVD preventive therapies, use of a polypill-based ering therapy [3] among patients with established cardiovas- strategy (i.e. initiating treatment with single-pill combination cular disease (CVD) and those at high CVD risk, treatment medication then titrating further therapy as needed) has large gaps among this patient group are very large. Despite many potential benefits in reducing global morbidity and mortality. people with established CVD in high-income countries being Despite this, few polypills are available on the market due to started on recommended medications, significant numbers of market failure in the funding of research and development for such individuals do not remain adherent to these treatments affordable non-communicable disease medicines. long-term [4–6]. The large majority of CVD patients in low- Additionally, defining a path to market has been problematic and middle-income countries do not either receive or remain in that fixed-dose combinations with multiple different drug adherent to these treatments long-term [7–9]. classes included are quite novel, and regulatory processes to review these types of applications are not well established. History of the Polypill Despite these delays, progress is slowly being made. The concept of combining multiple classes of cardiovascular medications into a single pill with the aim of improving ad- herence has a long history—the term ‘asp-olol’ was coined for a potential aspirin and atenolol combination in the 1970s. The This article is part of the Topical Collection on Public Health Policy first major scientific meeting on the concept of a fixed-dose * Ruth Webster combination pill for CVD control was held in 2001, when the
[email protected] World Health Organization and The Wellcome Trust con- Anthony Rodgers vened a meeting of experts to discuss evidence-based and
[email protected] affordable interventions for non-communicable diseases 1 The George Institute for Global Health, University of Sydney, Level [10]. A major outcome for the meeting was in relation the 10, KGV Building, 83-117 Missenden Rd, potential for fixed-dose combination pills containing aspirin, Camperdown, NSW 2050, Australia statin and BP-lowering agents, noting ‘the use of a single pill 2 The George Institute for Global Health, University of Sydney, Level could well encourage patients to adhere to treatment as well as 13, 321 Kent St, Sydney, NSW 2000, Australia seriously reduce the cost of the drugs’. In the medical 121 Page 2 of 8 Curr Cardiol Rep (2015) 17:121 literature, the concept of a fixed-dosed combination pill was Long-Term Trials of Polypills in Primary Prevention discussed by Yusuf in a Lancet editorial in 2002 [11] and of CVD Events in Patients at Low or Moderate Risk effectiveness and cost-effectiveness analyses were conducted of CVD in the 2002 World Health Report [12]. The term ‘polypill’ itself was introduced with the publication of Wald and Law’s One of the key areas of potential and also of controversy, is seminal paper in 2003 [13]. As well as recommending use in primary prevention of CVD events. Proponents have advocat- people with established vascular disease, which had been the ed widespread use of a polypill (combined with other focus up to that time, Wald and Law estimated that the use of a population-based strategies), with simple targeting strate- single pill (containing aspirin, a statin, three BP-lowering gies—ranging from absolute CVD risk, to age+1 CV risk drugs and folic acid) in all people aged over 55 years would factor through to just age alone [19]. However, there are cur- reduce cardiovascular disease by more than 80 %. They ar- rently no data on the long-term safety and clinical benefits of gued for a simple age-based prescription strategy on the basis use of a polypill in this setting. that age is the most significant determinant of risk. This con- Three large-scale placebo-controlled or minimal care com- cept provoked much discussion and controversy. The potential parison clinical trials are underway to address the outstanding benefits were large—as Wald and Law stated ‘a formulation questions around use of a polypill in primary prevention that prevented all cancer and was safe would undoubtedly be (Table 2). widely used, and one that prevented over 80 % of cardiovas- These trials are studying the primary prevention of cardio- cular disease would be even more important, because such vascular disease events in patients at moderate risk of CVD deaths are more common than cancer deaths’. However, resis- who have neither a clear indication for or against included tance to widespread use of preventive medications was highly medications (with the exception of Poly-Iran which also has prevalent and deeply felt. One unanticipated consequence was a secondary prevention component). a distraction from the initial, far less controversial use of polypills as a strategy to increase uptake and adherence in The Polypill in Secondary Prevention and High-Risk people with unequivocal indications for all the component Primary Prevention of CVD Events medications. More than a decade on from the initial widespread discus- The population in which there is perhaps the least controversy sion on the topic, several clinical trials have provided evidence about the potential role of a polypill is patients with on the feasibility and efficacy of polypills in clinical practice. established disease or who are at high risk of cardiovascular The polypills used in these trials vary in their components, disease (at least 15 % over 5 years) and have established although all include aspirin, statin and blood pressure lower- indications for anti-hypertensives, cholesterol-lowering and ing medications. anti-platelet drugs. There are currently six trials completed or active in this area, three of which (UMPIRE, Kanyini-GAP and IMPACT) Short-Term Effects of Polypills on Cardiovascular Risk are part of the Single Pill to Avert Cardiovascular Events Factors and Tolerability (SPACE) Collaboration (www.spacecollaboration.org) (Table 3). All completed trials have shown significant im- Several trials have been completed comparing polypills pre- provements in adherence to CVD preventive medication with dominantly to placebo or no treatment with the aim of use of a polypill. The UMPIRE trial also showed a significant assessing short-term effects on risk factors such as BP and improvement in systolic blood pressure (SBP) and low- cholesterol, as well as side effects [14, 15, 16•, 17•, 18] density lipoprotein (LDL)-C likely due to the better power (Table 1). from having the largest number of patients included. In summary, most of these trials found short-term risk In all three of the SPACE Collaboration trials, there was no factor reductions consistent with the expected size of ef- need to stabilise patients on polypill component drugs at spe- fect from components, taking into account the baseline cific doses prior to randomisation. To be eligible, participants risk factor levels, number of BP-lowering agents included, had to have indications for all the polypill components, but not and adherence observed within the study. Available data necessarily to be currently taking them, since the overarching from these studies on side effects and tolerability also issue that provides the rationale for polypill development is indicate effects consistent with those expected from the that despite such indications large numbers of patients do not individual components. One study [14] showed very small actually take recommended medications long term. Relative risk factor reductions with the polypill compared with risk for adherence to combination therapy at end of study in placebo; however, there were concerns about low and dif- those who were already taking all component medications at ferential follow-up and imbalances in baseline risk fac- baseline ranged from 1.04 (1.01–1.08) in the UMPIRE [23••] tors, suggesting flawed randomisation. trial to 1.08 (0.97–1.21) in Kanyini-GAP [24•]. However, the Table 1 Trials assessing the impact of a polypill on risk factor levels Study Study population Drugs in the polypill Comparison group Results Notes characteristics (daily dose) Number of patients Duration of follow-up Observed mean Observed difference in control-adjusted SBP (mmHg) reduction in LDL (mmol/L) Curr Cardiol Rep (2015) 17:121 Malekzadeh et al. Primary prevention (no previous Aspirin (81 mg), enalapril Placebo −2.4 (−6.81 to −0.45 (−0.59 to Imbalance in baseline [14] cardiovascular disease). (2.5 mg), atorvastatin (20 mg), n=468 2.01) −0.31) characteristics suggests Inclusion criteria—>50 years hydrochlorothiazide (12.5 mg) 12 months possible inadequacy of (no previous cardiovascular randomisation. Differential disease); not on active blood follow-up rate, 68 % in pressure or lipid-lowering interventionand 78 % in drugs. No exclusion for diabetes control Pill Collaborative Primary prevention (no previous Aspirin (75 mg), lisinopril Placebo −9.9 (−13.2 to −0.75 (−0.94 to 99 % follow-up [15] cardiovascular disease). (10 mg), hydrochlorothiazide n=378 −6.6) −0.56) Inclusion criteria—5-year (12.5 mg), simvastatin (20 mg) 12 weeks cardiovascular disease risk at >7.5 % (based on Framingham risk score) or 5–7.5 % and 2 cardiovascular disease risk factors. No exclusion for diabetes Wald [16•] Primary prevention (no previous Amlodipine (2.5 mg), losartan Placebo −17.9 (−21.9 to −1.4 (−1.68 to 98 % follow-up cardiovascular disease). (25 mg), hydrochlorothiazide n=86 −13.9) −1.12) Inclusion criteria—over (12.5 mg), simvastatin (40 mg) 12 weeks 50 years of age (cross-over randomised control trial) The Indian Polycap Primary prevention (no previous Hydrochlorothiazide (12.5 mg), n=2053 −7.4 (−9.1 to −0.72 (−0.86 to 85 % follow-up in these 3 Study BTIPS^ [18] cardiovascular disease). atenolol (50 mg), ramipril 12 weeks −5.7) −1.58) arms Inclusion criteria—at least 1 (5 mg), simvastatin (20 mg), multi-armed study (some cardiovascular risk factor aspirin (100 mg) 8–12 weeks) (including diabetes) The Second Indian Secondary prevention (established Hydrochlorothiazide (25 mg), Hydrochlorothiazide −2.8 (−4.7 to −0.17 (−0.29 to 93 % follow-up Polycap Study CVD) or high-risk diabetes atenolol (100 mg), ramipril (12.5 mg), atenolol −1.0) −0.05) (TIPS-2) [17•] (HbA1c <7.5 %, with (10 mg), simvastatin (40 mg), (50 mg), ramipril (5 mg), microalbuminuria or BP >140/ aspirin (200 mg), plus simvastatin (20 mg), 90 mmHg) potassium supplementation aspirin (100 mg), n=518 (8-week study) SBP systolic blood pressure, LDL low-density lipoprotein Page 3 of 8 121 121 Page 4 of 8 Curr Cardiol Rep (2015) 17:121 Table 2 Three large-scale placebo-controlled or minimal care comparison clinical trials are underway to address the outstanding questions around use of a polypill in primary prevention Study Study population characteristics Drugs in the polypill (daily dose) Comparison Results Number of patients due Duration of follow-up Prevention of Age 50 to 79 years, excluding Aspirin (81 mg), enalapril (5 mg; or Usual care N=7000 (5 years) 2018 Cardiovascular Disease previous history of stroke valsartan, 40 mg), atorvastatin in Middle-aged and (20 mg) and hydrochlorothiazide Elderly Iranians Using a (12.5 mg) Single PolyPill–Poly- Iran [20] Heart Outcomes Prevention (1) Women aged >60 years and men 10 mg rosuvastatin, 16/12.5 mg 2×2 factorial design of 10 mg 2015 Evaluation-3 – HOPE-3 aged >55 years. (2) At least 1 candesartan/HCT (note rosuvastatin, 16/12.5 mg [21] additional CV risk factor rosuvastatin and candesartan/ candesartan/HCT and placebo including: waist/hip ratio ≥0.90 in HCT are given as individual N=12,705 (5.7 years) men and ≥0.85 in women. (3) tablets, i.e. polypill concept of History of current or recent multi-modal therapy, but not co- smoking (regular tobacco use packaged) within 5 years). (4) Low HDL cholesterol. (5) Dysglycemia. (6) Renal dysfunction. (7) Family history of premature CHD in first- degree relatives The International Polycap (1) Men aged ≥55 years and women Thiazide (25 mg), atenolol 2×2×2 factorial of polypill 2019 Study 3–TIPS-3 [22]. aged ≥60 years with an (100 mg), ramipril (10 mg), containing thiazide (25 mg), INTERHEART risk score of 10 simvastatin (40 mg) atenolol (100 mg), ramipril or greater (10 mg), simvastatin (40 mg), vitamin D, aspirin and placebo). N=5000 (5 years) relative risks for adherence in those who were not taking all medication components in those who are under-treated at base- recommended treatment at baseline were 3.35 (2.74–4.09) for line (Fig. 1). A fundamental aim of this treatment strategy is to UMPIRE [23••], 3.7 (2.48–5.53) for Kanyini-GAP [24•] and improve uptake and adherence to indicated medicines, and pa- 5.09 (3.40–7.63) for IMPACT [25•]. Hence, the primary value tients who have challenges in this area are, almost by definition, of the polypill seems to lie in improving coverage of all those least likely to be stabilised on specific drugs at specific Table 3 Results from polypills trials in secondary or high-risk primary prevention Trial Location Polypill components Comparator Design/duration Number Summary results UMPIRE UK, Ireland, 75 mg aspirin, 10 mg Usual care Randomised, 2004 Improved adherence (86 vs. 65 %), SBP [23••] Nether- lisinopril, 40 mg parallel group (−2.6 mmHg, 95 % CI, −4.0, −1.1), lands, simvastatin, either 12.5 mg 15 months and LDL (−0.11 mmol/L, 95 % CI, India hydrochlorothiazide or median treatment −0.17, −0.05). All p≤0.0005 50 mg atenolol and follow-up Kanyini- Australia 75 mg aspirin, 10 mg Usual care Randomised, 623 Improved adherence (70 vs. 47 %, GAP lisinopril, 40 mg parallel group p<0.0001). No significant difference in [24•] simvastatin, either 12.5 mg 18 months SBP (−1.5, 95 % CI, −4.0, −1.0) or hydrochlorothiazide or median treatment LDL (0.00, 95 % CI, 0.12, −0.11) 50 mg atenolol and follow-up IMPACT NZ 75 mg aspirin, 10 mg Usual care Randomised, 513 Improved adherence (64 vs. 43 %, [25•] lisinopril, 40 mg parallel group p<0.001), no significant difference in simvastatin, either 12.5 mg 18 months SBP (−2.1, 95 % CI, −6.5, 2.3) or LDL hydrochlorothiazide or median treatment (−0.11, 95 % CI, −.24, 0.02) 50 mg atenolol and follow-up FOCUS Argentina, 100 mg aspirin, 40 mg Individual Randomised, 695 Improved adherence (50.8 vs. 41 %, [26•] Brazil, simvastatin, 2.5, 5 or 10 mg medication parallel group p=0.019). No difference in SBP (0.88 Italy, ramipril compo- 9 months follow- vs. −0.32 mmHg, p=0.32) or LDL-C Paraguay, nents of the up (2.17 vs. 5.27 mg/dL p=0.34) Spain polypill Curr Cardiol Rep (2015) 17:121 Page 5 of 8 121 Fig. 1 Adherence to combination therapy at end of study. Adherence defined as taking anti- platelet, statin and ≥2 BP- lowering drugs at least 4 days of the last 7 at end of study in UMPIRE, Kanyini-GAP and IMPACT. Adherence in the FOCUS trial was defined as pill count between 80 and 110 % at end of study plus a score of 20/20 on the Morisky-Green questionnaire doses. The safety and efficacy of the approach of not requiring doses as contained in the polypill—hence, this is a more prior stabilisation has now been confirmed in these trials. direct comparison of a fixed-dose combination vs. sepa- It is also worth noting that usual care in the SPACE rate pills, rather than a treatment based on use of fixed- trials was at a better level than normally seen in the dose combination therapy vs. usual care. general population. For example, in high-income coun- Two trials are ongoing including the Poly-Iran trial (as tries approximately 40 % of patients with prior CHD or mentioned previously), which includes both secondary and stroke do not receive anti-platelet, statin and BP- primary prevention population groups, and The Heart lowering long term [9]; whereas in these trials, about Outcomes Prevention and Evaluation-4 (HOPE-4) trial [27]. 85 % of such patients were receiving all three treatment HOPE-4 is an open label cluster randomised controlled trial modalities. Also, in at least one of the studies [24•] two being conducted in Asia, North America, South America and thirds of statin prescriptions in the usual care arm were sub-Saharan Africa which aims to develop and test a pro- for atorvastatin or rosuvastatin (personal communica- gramme for cardiovascular disease risk assessment and treat- tion), which is considerably higher than average com- ment involving simple screening and treatment guidelines im- pared with the Australian general population. plemented by non-physician health workers (NPHW), Furthermore, in contrast to general population observa- polypill-based therapy and family or friends and mobile phone tions, treatment rates rose slightly initially in the usual technology to help participants comply with the treatment care group and remained higher than baseline throughout regimen. Recruitment commenced in 2014 and results are the trials. Since patients most in need of strategies to not expected for another 5 years. improve treatment uptake and adherence are under- represented in these clinical trials, the overall results Acceptability from the trials will underestimate the population level impact of the introduction of such treatments. Acceptability of the polypill-based strategy will play a key The Fixed-Dose Combination Drug for Secondary role in implementation of this concept into routine prac- Cardiovascular Prevention (FOCUS) trial was conducted tice. Each study within the SPACE Collaboration also col- in Spain, Argentina, Brazil and Paraguay [26•]. Six hun- lected data from patients and physicians about their views dred and ninety-five patients were randomised to either a on the polypill. All trials concluded that the polypill con- polypill (containing aspirin (100 mg), simvastatin cept was highly acceptable to patients. Acceptability was (40 mg) and ramipril (2.5, 5 or 10 mg)) or individual also high for treating physicians (although this potentially therapies. The primary endpoint of adherence showed is due to selection bias with these physicians agreeing to an absolute improvement of 10 % (50.8 vs. 41 %, p= take part in the study). In general, there was a preference 0.019) in those taking the polypill. No difference was for additional versions to provide more flexibility. Other seen in mean SBP (129.6 vs. 128.6 mmHg) or LDL studies conducted in physicians in the USA and GPs in cholesterol (90 vs. 92 mg/dL). In this trial, all partici- the UK have also confirmed these findings with evidence pants were provided the same component drugs and of increasing acceptability of the polypill concept 121 Page 6 of 8 Curr Cardiol Rep (2015) 17:121 particularly in patients with established disease or other- Why Has Progress Been so Slow? wise indicated for all component medications (e.g. calcu- lated high-risk primary patients) [28, 29]. The 2001 WHO/Wellcome meeting [10] made a number of recommendations for future research, stating ‘such an evalu- Current Availability of Polypills on the Market ation could take 5 years or more to complete and would re- quire careful assessment of the following: Several polypills are in development globally, however few have marketing approval. Each polypill is slightly different in (a) Stability testing terms of number and type of BP-lowering drugs, type of statin (b) Bio-availability testing and dose of aspirin. Trinomia™ (aspirin (100 mg), simvastatin (c) Assessment of the short-term effects of the drugs on (40 mg) and ramipril (2.5, 5 or 10 mg)) is a polypill developed blood pressure, LDL cholesterol and platelet aggregation by Ferrer Pharmaceuticals which has been approved by the (d) Assessment of safety and short-term symptomatic side local regulatory authorities in Spain, Sweden, Argentina, effects Mexico, Guatemala, Dominican Republic, Nicaragua, (e) Study of the interactions and effects of a combination of Honduras and El Salvador and is the only polypill with mar- drugs on physiological mechanisms keting approval in a high-income country. The POLYCAP™ (f) Studies on adherence to treatment’ (Cadila Pharmaceuticals) is the only other polypill developed through public-private partnership that currently has market- The timeframes have been far longer than anticipated. ing approval and is only available in India (where it is Regulatory uncertainty as noted above has no doubt played manufactured) and Zambia. a major role. Also of great importance is the market failure in The necessity for defining a path to market is that fixed- the funding of R&D for affordable NCD medicines. Big dose combinations with multiple different drug classes includ- Pharma focus on high-margin, on patent new chemical/ ed are quite novel, and regulatory processes to review these biological entities; generics pharma do not have major R&D types of applications are not well established. Regulatory budgets; government funding agencies typically do not have guidelines from tend to focus on fixed-dose combinations of the budgets required for drug approval studies (in this instance the same classes of drugs (e.g. anti-hypertensives) or at most $5–15 m per product); and the major NGOs and charities two classes of drugs. Approved indications of fixed-dose com- typically focus on communicable diseases. The progress that bination medications are only possible for established indica- has been made has been a result of public-private partnerships tions of the individual components (e.g. lowering of choles- between academic groups and generics companies, and more terol, for treatment of hypertension) rather than a higher level recently also by alliances with health payors, e.g. AETNA indication such as ‘prevention of cardiovascular disease’. This [30], with clinical trials funded by public funding agencies has led to significant barriers to registration of the various such as Wellcome Trust, European Union and National polypills that have been developed globally. For example, Health and Medical Research Council of Australia. Clearly, the most straightforward path to obtaining marketing approval one barrier for industry is the challenge in ensuring a return on of polypills is for ‘straight substitution’ in patients who are investment, given that reimbursements for FDCs are typically stabilised on the individual components, at the same doses. around the sum of the costs of the component generics (which However, trials have clearly demonstrated that the benefit in are now very low cost). this population is quite small [23••, 24•, 25•] and a more useful indication would be for patients who should be taking these Implications for Global Health drugs long term. This would allow ‘step-up substitution’ with the polypill. Tailoring could occur with other drugs added on The ‘low-hanging fruit’ of CVD prevention is increased up- top and/or different polypill dose versions. There are positive take and adherence to recommended medications in those signs that the major regulatory agencies realise the need to who people have had a symptomatic event. The vast majority change traditional practice to facilitate regulatory applications of this population globally is under-treated and these for polypills. The Federal Drug Administration in the USA evidence-practice gaps exist in both high-income and low/ convened a meeting of its Cardiovascular and Renal middle-income countries [9]. Data now available from com- Advisory committee on 10 September 2014 to discuss approv- pleted clinical trials have demonstrated that the polypill has al pathways for polypills in secondary prevention. The panel significant potential to move people in one step from being was overall supportive of a potential role for the polypill in under-treated (not receiving some or all recommended treat- this setting, initially aimed at population groups with chal- ment classes) to receiving all recommended treatment classes. lenges in long-term follow-up and adherence. The recent Making an affordable polypill available in low- and middle- European Union approvals for the Ferrer polypill are also income countries has the capacity to contribute significantly to indicative that regulatory pathways are opening up. the WHO 25×25 goals in a cost-effective manner and most Curr Cardiol Rep (2015) 17:121 Page 7 of 8 121 significantly will assist in meeting the goal for coverage of containing metformin); and integration with other adherence preventive medications in at least 50 % of the population improving strategies such as education, behavioural econom- [31, 32]. ics, IT solutions and increased involvement of allied health Ensuring uptake of the polypill into low- and middle- professionals. income countries requires further consideration of other issues including drug cost, drug supply, physician acceptability and health system infrastructure and resources. Cost of the polypill Conclusions could be minimised with utilisation of medications that are off patent and minimising manufacturing, distribution and inter- Polypills have been shown to improve adherence to recom- mediary costs. Pricing in the open market will need to be ultra- mended, proven-effective CVD-preventive medications, with competitive for this to be scalable and feasible in low-income particular effect in those under-treated with these drugs. Use settings. of a polypill-based strategy has the capacity to contribute sig- Traditional pharmaceutical models focus on high profit nificantly to reducing the current epidemic of CVD, in both margins, which in part support a dedicated and expansive high- and low/middle-income countries. sales and marketing force that promotes the new product. Once the product has been established and patents expire, Acknowledgements The authors have received grants from several genericisation leads to lower prices and higher volumes. research charities and national funding agencies for research on cardio- This model is untenable in low-income settings and cannot vascular fixed-dose combination medications and from Dr. Reddys Ltd work for the polypill in any markets. A key challenge for the for co-ordination of the SPACE programme. The George Institute for Global Health obtained an exclusive global license in Dec 2012 for the next decade will be developing novel, affordable ways of in- fixed-dose combinations used in the SPACE trials following a decision by troducing this comparatively new treatment strategy. A num- Dr. Reddy’s Ltd not to proceed with taking the products to market be- ber of such strategies have been implemented in health sys- cause of uncertainty in regulatory requirements. tems in recent years, often to ensure the most cost-effective use of generic medicines, such as prescribing targets, national Compliance with Ethical Standards formularies, preferred medicines lists, physician-focused fi- Conflict of Interest Anthony Rodgers is supported by an NHMRC nancial incentives for appropriate prescribing, national guide- Principle Research Fellowship. Ruth Webster is supported by a Heart lines and academic detailing/educational outreach. Foundation of Australia post-doctoral fellowship. Future Directions Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. Although the efficacy of a polypill-based strategy has been confirmed there are still outstanding questions raised by this research that merit further attention. Firstly, although risk fac- tor benefits have been demonstrated in meta-analysis, debate has already begun as to whether trials demonstrating reduction References in hard outcomes are needed. We would suggest this question should be parsed in to two-patient populations for whom only Papers of particular interest, published recently, have been some or even none of the medications are currently recom- highlighted as: mended, and patient groups for whom there is a clear indica- • Of importance tion for all the component medicines. In the former group, •• Of major importance hard outcome trials are likely to be required. For the latter group, there is a compelling argument that endpoint trials are 1. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and not necessary, as the individual component medications are secondary prevention of vascular disease: collaborative meta- proven. Re-requiring endpoint proof would imply doubt of analysis of individual participant data from randomised trials. that evidence. Rather, intermediate outcomes of improved Lancet. 2009;373:1849–60. 2. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering medicine uptake should be sufficient. If medications drugs in the prevention of cardiovascular disease: meta-analysis contained in the polypill are shown to be no different than of 147 randomised trials in the context of expectations from pro- separate pills via bioequivalence studies of the polypill vs. spective epidemiological studies. BMJ. 2009;338:b1665. individual medications, and polypills increase uptake, then 3. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of this should be sufficient. In these populations, future research more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. should include trials of uptake in under-treated populations; 2010;376:1670–81. next-generation polypills containing other combinations of 4. Kotseva K, Wood D, De Backer G, et al. EUROASPIRE III: a drugs or drug classes (e.g. perhaps a diabetes polypill survey on the lifestyle, risk factors and use of cardioprotective drug 121 Page 8 of 8 Curr Cardiol Rep (2015) 17:121 therapies in coronary patients from 22 European countries. Eur J 19. Lonn E, Bosch J, Teo KK, et al. The polypill in the prevention of Cardiovasc Prev Rehabil. 2009;16:121–37. cardiovascular diseases: key concepts, current status, challenges, 5. Kumar A, Fonarow GC, Eagle KA, et al. Regional and practice and future directions. Circulation. 2010;122:2078–88. variation in adherence to guideline recommendations for secondary 20. PolyIran. Available at http://clinicaltrials.gov/ct2/show/ and primary prevention among outpatients with atherothrombosis NCT01271985?term=polyiran&rank=1. Accessed July 2013 or risk factors in the United States: a report from the REACH 21. HOPE 3. Available at http://clinicaltrials.gov/ct2/show/ registry. Crit Pathways Cardiol. 2009;8:104–11. NCT00468923?term=hope+3&rank=1. Accessed July 2013 6. Webster RJ, Heeley EL, Peiris DP, et al. Gaps in cardiovascular 22. TIPS 3. Available at http://clinicaltrials.gov/ct2/show/ disease risk management in Australian general practice. Med J NCT01646437?term=tips+3&rank=1. Accessed July 2013 Austr. 2009;191:324–9. 23.•• Thom S, Poulter N, Field J, et al. Effects of a fixed-dose combina- 7. Mendis S, Abegunde D, Yusuf S, et al. WHO study on prevention tion strategy on adherence and risk factors in patients with or at high of recurrences of myocardial infarction and stroke (WHO- risk of CVD: the UMPIRE randomized clinical trial. JAMA J Am PREMISE). B World Health Organ. 2005;83:820–9. Med Assoc. 2013;310:918–29. First large scale RCT of polypill 8. Sharma KK, Gupta R, Agrawal A, et al. Low use of statins and vs usual care in secondary prevention of 2004 patients from other coronary secondary prevention therapies in primary and sec- Western Europe and India. Showed improvement in adherence, ondary care in India. Vasc Health Risk Manage. 2009;5:1007–14. systolic blood pressure and LDL-cholesterol. 9. Yusuf S, Islam S, Chow CK, et al. Use of secondary prevention 24.• Patel A, Cass A, Peiris D et al. A pragmatic randomized trial of a drugs for cardiovascular disease in the community in high-income, polypill-based strategy to improve use of indicated preventive treat- middle-income, and low-income countries (the PURE study): a ments in people at high cardiovascular disease risk. Eur J Prevent prospective epidemiological survey. Lancet. 2011;378:1231–43. Cardiol. 2014. Randomised trial of polypill vs usual care in 623 Australian patients, including 50 % indigenous participants. 10. World Health Organization. Secondary prevention of non- Showed improvement in adherence to recommended CVD communicable disease in low and middle income countries through therapy. community-based and health service interventions. World Health 25.• Selak V, Elley CR, Bullen C et al. Effect of fixed dose combination Organization-Wellcome trust meeting report. Geneva; 2002. treatment on adherence and risk factor control among patients at 11. Yusuf S. Two decades of progress in preventing vascular disease. high risk of cardiovascular disease: randomised controlled trial in Lancet. 2002;360:2–3. primary care. BMJ 2014;348. Randomised trial of polypill vs 12. World Health Organization. The World Health Report 2002: usual care in 513 New Zealand patients, including 50 % Reducing risks, promoting healthy life. Edited by: World Health Maori participants. Showed improvement in adherence to rec- Organization. Geneva; 2002. ommended CVD therapy. 13. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by 26.• Castellano JM, Sanz G, Penalvo JL et al. A polypill strategy to more than 80 %. Br Med J. 2003;326:1419. improve adherence: results from FOCUS (Fixed-dose 14. Malekzadeh F, Marshall T, Pourshams A, et al. A pilot double-blind Combination Drug for Secondary Cardiovascular Prevention) randomised placebo-controlled trial of the effects of fixed-dose Project. J Am Coll Cardiol. 2014. Randomised trial of polypill combination therapy (‘polypill’) on cardiovascular risk factors. Int vs components taken as individual medications. Showed im- J Clin Pract. 2010;64:1220–7. provement in adherence. 15. Pill Collaborative Group, Rodgers A, Patel A, et al. An international 27. HOPE 4. Available at http://clinicaltrials.gov/ct2/show/ randomised placebo-controlled trial of a four-component combina- NCT01826019?term=hope+4&rank=1. Accessed 10 October tion pill (Bpolypill^) in people with raised cardiovascular risk. PLoS 2014 One. 2011;6:e19857. 28. Virdee SK, Greenfield SM, Fletcher K, et al. Would primary 16.• Wald DS, Morris JK, Wald NJ. Randomized polypill crossover trial healthcare professionals prescribe a polypill to manage cardiovas- in people aged 50 and over. PLoS One. 2012;7:e41297. Results cular risk? A qualitative interview study. BMJ Open. 2013. doi:10. from a 12 week cross over RCT of polypill vs placebo in prima- 1136/bmjopen-2012-002498. ry prevention. 29. Viera AJ, Sheridan SL, Edwards T, et al. Acceptance of a polypill 17.• Yusuf S, Pais P, Sigamani A, et al. Comparison of risk factor reduc- approach to prevent cardiovascular disease among a sample of U.S. tion and tolerability of a full-dose polypill (with potassium) versus physicians. Prev Med. 2011;52:10–5. low-dose polypill (Polycap) in individuals at high risk of cardiovas- 30. Steinberg G. Polypills: a new solution to help improve medication cular diseases: the Second Indian Polycap Study (TIPS-2) investi- adherence. 2015. Available at https://news.aetna.com//polypills- gators. Circulation. Cardiovasc Qual Outcome. 2012;5:463–71. new-solution-help-improve-medication-adherence/. Accessed 19th Showed incremental improvement in risk factor reduction June 2015 when full-dose polypill was used in patients at high CVD risk 31. Lim SS, Gaziano TA, Gakidou E, et al. Prevention of cardiovascular compared to low-dose polypill. disease in high-risk individuals in low-income and middle-income 18. Indian Polycap S, Yusuf S, Pais P, et al. Effects of a polypill countries: health effects and costs. Lancet. 2007;370:2054–62. (Polycap) on risk factors in middle-aged individuals without car- 32. World Health Organisation. Global action plan for the prevention diovascular disease (TIPS): a phase II, double-blind, randomised and control of noncommunicable diseases. Geneva: World Health trial.[see comment]. Lancet. 2009;373:1341–51. Organization; 2013.