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Combination pharmacotherapy to prevent cardiovascular disease: present status and challenges

DOI: http://dx.doi.org/10.1093/eurheartj/eht407 353-364 First published online: 27 November 2013

Abstract

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.

  • Polypill
  • CVD
  • Hypertension

Introduction

The use of a combination pill consisting of aspirin, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and statins to prevent cardiovascular disease (CVD) in high-risk individuals was proposed over a decade ago.1 The main rationale of a combination pill was to improve access and adherence to multiple drugs. This approach to CV drug delivery would help address the large gaps in secondary prevention that exist globally,2 despite clear evidence that these drugs prevent recurrent myocardial infarction, stroke, and death.35 The potential cumulative benefit is considerable; for example, Yusuf in 20026 calculated that a combination pill containing these four classes of medication would have an estimated RRR in CVD events of 75% in those with prior CVD. The term ‘polypill’ was coined in 2003 by Wald and Law,7 who proposed several additional strategies, including adding folic acid to lower homocysteine, using three blood pressure (BP) lowering drugs at half-dose to reduce side effects and not basing treatment on risk factor levels. As well as recommending treatment among patients with vascular disease, they recommended treatment for all individuals older than 55 years. They estimated that there would be an 80% RRR of CVD with the use of such a polypill. These ideas were novel but controversial, especially the suggestion that treatment could be initiated simply based on the age. Some regarded this as a bold concept that could substantially reduce CVD at a population level, particularly in developing countries.8 Others argued that this approach represented suboptimal treatment for many individuals or would ‘medicalize’ entire communities while ignoring the benefits of lifestyle modification.9,10

There is precedent for the use of combination therapy in other conditions and settings (particularly in resource-constrained settings), such as in tuberculosis (TB), human immunodeficiency virus (HIV) infection and cancer treatment. Such approaches can be adapted for secondary prevention of CVD based on existing evidence confirming that aspirin, ACE inhibitors, beta-blockers and statins reduce the risk of CVD and death.35 Further, a case can be made to consider the use of both lipid-lowering and BP-lowering medications in certain high-risk (but not yet with prevalent CVD) groups such as those with diabetes or hypertension. Several drugs from each class are generic (‘mature’) and a combination pill of these medications would likely be affordable in resource-constrained settings. In addition, the effects of lifestyle modification and appropriate drug treatment are additive, allowing both approaches to be used simultaneously.11 Recognizing the potential of combination pills but also the need for research to resolve uncertainties, the World Health Organization (WHO), Centers for Disease Control (USA), the Wellcome Trust (UK), European Union, and funding agencies in several countries have called for and supported research in this field.

This review summarizes the current research, potential benefits, barriers, and challenges of combination-pill development and use in CVD prevention.

The need for cardiovascular disease prevention combination pills

Evidence-practice gaps in primary and secondary prevention

Significant evidence-practice gaps exist in the primary prevention of CVD. For example, in the Prospective Urban Rural Epidemiology (PURE) study2,12 involving 154 000 individuals from 628 communities and 17 countries, 41% of participants had hypertension. Of those with hypertension, only 46% were aware of having elevated BP and only 41% were on pharmacological treatment (Figure 1). As a consequence, merely 13% of all hypertensives had their BP controlled to recommended values.35 Among those treated, only 31% (or 12.5% of all with hypertension) were taking two or more drugs, likely explaining the poor control in these communities, as use of two or three BP-lowering drugs control BP to a greater degree.12

Figure 1

Percent prevalence, awareness, treatment, and control of hypertension in urban and rural communities from high-, middle-, and low-income countries. Results are shown stratified by country economic status. Hypertension prevalence is defined as self-reported hypertension on treatment OR blood pressure ≥140/90 mmHg. Hypertension aware is the proportion of participants with hypertension reporting a medical diagnosis of hypertension. Hypertension treated is the proportion of participants with hypertension reporting taking blood pressure lowering medication. Hypertension controlled is defined as the proportion of participants with hypertension with SBP < 140 and DBP < 90 mmHg. HIC, high-income countries; UMIC, upper middle-income countries; LMIC, lower middle-income countries; LIC, low-income countries; HT, hypertension. Adapted from Chow et al.12

Large global treatment gaps in the secondary prevention of CVD were also observed in the PURE study. For example, ∼8000 participants had coronary heart disease (CHD) or stroke, and among this group, only 25% were taking anti-platelet drugs, 17% were taking beta-blockers, 20% were taking ACE inhibitors or angiotensin II receptor blockers (ARBs) and 15% were taking statins, at a mean time of ∼5 years after their event. In participating low-income countries (Bangladesh, India, Pakistan, and Zimbabwe), the use of these drugs was very low (3–9%), but only moderate rates of use (40–67%) were observed even in the high-income countries (Canada, Sweden, and United Arab Emirates) in the study (Figure 2).

Figure 2

Use of Medication in Secondary Prevention. Percent use of antiplatelet medications, beta blockers, angiotensin-converting enzyme inhibitors or ARBs, and statins in participants with coronary heart disease or stroke, by urban or rural locations stratified by country economic status. HIC, high-income countries; UMIC, upper middle-income countries; LMIC, lower middle-income countries; LIC, low-income countries; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blockers. Adapted from Yusuf et al.2

Combination therapy and the barriers to evidence-based cardiovascular disease management

Global evidence-practice gaps in primary and secondary CVD care may be explained by barriers at the patient, healthcare provider, and health system level.13 At the patient level, stopping therapy (discontinuation) and not consistently taking the recommended regimen (non-adherence) have been identified as significant barriers to achieve optimal population outcomes. For secondary prevention, therapy discontinuation has been found to begin within 30 days, rising to as high as 25–50% at 1 year with further worsening over time.1418 Even in studies of selected patients where lower rates of therapy discontinuation are reported (e.g. EUROASPIRE III), control of BP and cholesterol is poor.19 This may be explained by the observation that among patients who do not permanently discontinue treatment, ∼50% are non-adherent to their daily pill regimen.20 For example, an analysis of electronic dosing monitor records found that half of the patients starting antihypertensive therapy discontinue treatment within the first year, and of those persisting with therapy about half have at least one ‘drug holiday’(omitting ≥3 days in sequence) per year.21 For primary prevention, discontinuation, and non-adherence rates are likely even worse.20

Discontinuation and non-adherence have repeatedly been shown to be associated with an increased risk for CVD events and mortality in both primary and secondary prevention.2228 Discontinuation and non-adherence are therefore important issues, and the reasons appear to be complex.2931 The multitude of patient-level barriers contributing to this decline may include high drug costs, dislike of taking multiple drugs, complexity of regimens, no noticeable benefits of taking medications while side effects are apparent, lack of knowledge about the importance of adhering to the prescribed regimen, forgetfulness, or absence of systematic follow-up programmes.3234 Although overcoming these barriers is difficult, the combination pill has the potential to address many (but not all) of these barriers through substantially simplifying treatment and follow-up regimens with low-cost medications.35 In this way, the combination pill could be an important advance.

Low-cost and accessible combination pills may also help to overcome barriers relating to health care providers and the health system. Providers may prefer to add medications and titrate doses individually over many visits, or they may attempt lifestyle counselling before starting medication. However, most physicians have little time to screen individuals without CVD to assess their eligibility for preventive strategies.3639 The use of combination pills could simplify treatment initiation and follow-up with evidence-based drugs used at fixed dosages. At the health system level, there can be issues with affordability, difficult access to health care providers, poor communication between specialized and community care providers, or absence of structural provider incentives to prescribe therapy or follow patients for the long term. In this regard, combination pills have the potential to improve affordability,40 transfer screening and treatment initiation with simple and safe medications to non-physician health workers (NPHW) due to the regimen's simplicity41 and reduce inefficiencies in communication between specialists and primary care physicians regarding medication changes.

Completed studies of combination pills

Several studies to test the efficacy, safety, affordability, and implementation of combination pills for CVD have been completed (Table 1). These studies focused on individuals with no CVD but risk factors (primary prevention) and individuals with existing CVD (secondary prevention).

View this table:
Table 1

Completed, ongoing, and planned trials of multidrug combination therapy

Trial/referenceSize/populationDesign/duration of treatmentPolypill compositionResults/current status
Studies primarily assessing impact on risk factors, safety, and tolerability
 Completed studies
  TIPS/ NCT00443794/Ref.42n = 2053/45–80 y without CVD and with at least 1 CV risk factor in IndiaDouble-blind RCT of polypill vs. individual components/12 weeksAspirin 100 mg, simvastatin 20 mg, ramipril 5 mg, hydrochlorothiazide 12.5 mg, atenolol 50 mgPolypill reduced SBP by 7.4 mmHg, LDL by 0.70 mmol/L and heart rate by 7.0 bpm vs. groups not receiving individual components.
  Poly-Iran Pilot Study/NCT00603590/Ref.45n = 475/Men 50–79 years and women 55–80 years without CVD in IranDouble-blind RCT vs. placebo/12 monthsEnalapril 2.5 mg, hydrochlorothiazide 12.5 mg, atorvastatin 20 mg and aspirin 81 mgReductions in SBP/DBP of 4.5/1.6 mmHg and LDL of 0.46 mmol/L.
  PILL Collaborative Group Study/ACTRN12607000099426/Ref.43n = 378/≥18 years with 5-year CVD risk ≥7.5% in Australia, Brazil, India, Netherlands, New Zealand, UK, USDouble-blind RCT vs. placebo/12 weeksAspirin 75 mg, lisinopril 10 mg, hydrochlorothiazide 12.5 mg, simvastatin 20 mgSBP reduced by 9.9 mmHg and LDL by 0.8 mmol/L. Discontinuation rates in the polypill group vs. placebo were 23% vs. 18%.
  TIPS-2/ CTRI/2010/091/000054/Ref.47n = 518/≥40 years with CVD or diabetes in IndiaDouble-blind RCT of half vs. standard dose polypill/8 weeksHalf-dose (one capsule) vs. standard-dose (two capsules) of Aspirin 100 mg, simvastatin 20 mg, ramipril 5 mg, hydrochlorothiazide 12.5 mg, atenolol 50 mgStandard dose (two capsules) reduced SBP by additional 2.8 mmHg and LDL by an additional 0.17 mmol/L vs. half-dose (1 capsule). Higher rates of dyspepsia with higher dose of aspirin.
  Polypill Prevention Trial 1/ISRCTN36672232/Ref.44n = 86/≥50 years without history of CVD in the UKDouble-blind crossover RCT of polypill vs. placebo/12 weeks per treatmentAmlodipine 2.5 mg, losartan 25 mg, hydrochlorothiazide 12.5 mg and simvastatin 40 mgSBP reduced by 17.9 mmHg, DBP by 9.8 mmHg, and LDL by 1.4 mmol/L.
  UMPIRE/ NCT01057537/Refs.48,49n = 2004/≥18 years with CVD or 5-year CVD risk ≥15% in India, Netherlands, England, IrelandOpen-label RCT of choice of 2 polypill formulations vs. usual care/mean follow-up 15 monthsAspirin 75 mg, atenolol 50 mg, simvastatin 40 mg, lisinopril 10 mg; or aspirin 75 mg, hydrochlorothiazide 12.5 mg, simvastatin 40 mg, lisinopril 10 mgCombination pill improved adherence vs. usual care (86% vs. 65%); reduced SBP (−2.6 mmHg) and LDL (−4.2 mg/dL).
 On-going studies (results not yet published)
  Kanyini-GAP/ACTRN12608000583347/Ref.55,64n = 623/≥18 years with CVD or 5-year CVD risk ≥15% among indigenous and non-indigenous people in AustraliaOpen-label RCT of choice of 2 polypill formulations vs. usual care/18–24 monthsAspirin 75 mg, atenolol 50 mg, simvastatin 40 mg, lisinopril 10 mg; or aspirin 75 mg, hydrochlorothiazide 12.5 mg, simvastatin 40 mg, lisinopril 10 mgStudy completed. Results expected in 2013.
  FOCUS/ NCT01321255/Ref.53n = 1340/≥40 years post- myocardial infarction patients in Argentina, Brazil, Italy, Paraguay, SpainRCT of polypill vs. individual component drugs/9 monthsAspirin 100 mg, simvastatin 40 mg, and ramipril 2.5, 5, or 10 mgExpected completion 2013.
  IMPACT/ACTRN12606000067572/Ref.56n = 513/≥18–79 years with CVD or 5-year CVD risk ≥15% in indigenous Māori and non-indigenous people in New ZealandOpen-label RCT of choice of two polypill formulations vs. usual care/12–30 monthsAspirin 75 mg, atenolol 50 mg, simvastatin 40 mg, lisinopril 10 mg or aspirin 75 mg, hydrochlorothiazide 12.5 mg, Simvastatin 40 mg, lisinopril 10 mgExpected completion 2014.
  TEMPUS/ ISRCTN36672232/Ref.54n = 75 (target)/≥18 years with CVD or 5-year CVD risk ≥10% in the NetherlandsPROBE crossover trial of evening vs. morning polypill vs. individual components with 6–8 weeks per treatmentAspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg, and hydrochlorothiazide 12.5 mgExpected completion 2013.
Studies Assessing Impact on Cardiovascular Events
 On-going Studies (Results not yet published)
  HOPE-3/ NCT0046892350n = 12,705/Men ≥55 years and women ≥60 years with at least 1 CV risk factor and with average BP and cholesterol levels in 22 countries.2 × 2 factorial design rosuvastatin vs. placebo and candesartan/hydrochlorothiazide vs. placebo/6 yearsFixed dose candesartan 16 mg and hydrochlorothiazide 12.5 mg or placebo with rosuvastatin 10 mg or placeboCompleted recruitment. Results expected in 2016.
  TIPS-3/ NCT0164643751n = >5500 (target)/Men ≥ 55 years and women ≥ 60 years with an INTERHEART risk score of ≥10 in India, Philippines, Canada, China, Brazil, Argentina, Chile, and Columbia2 × 2 × 2 factorial of polypill vs. placebo; 75 mg aspirin vs. placebo; vitamin D (60 000 IU monthly) vs. placebo/5 yearsHydrochlorothiazide 25 mg, atenolol 100 mg, ramipril 10 mg, simvastatin 40 mgExpected completion 2018
  PolyIran/ NCT0127198558n = 7000 (target)/50–79 years and enrolled in the Golestan Cohort Study in IranOpen cluster RCT of polypill and minimal care vs. minimal care alone vs. usual primary care/5 yearsAspirin 81 mg, enalapril 5 mg (or valsartan 40 mg), atorvastatin 20 mg and hydrochlorothiazide 12.5 mgExpected completion 2018
  HOPE-4/ NCT0182601957n = 190 communities and 9500 participants (target)/≥50 years with HT or history of CV risk factors in Colombia, Malaysia, Philippines, India, Argentina, South Africa, Tanzania, and Rwanda.Cluster RCT with NPHW intervention of education and lifestyle counselling; three polypill formulations; treatment supporters/text-messaging vs. usual care/6 yearsStandard dose of simvastatin (40 mg), Atenolol (100 mg), Ramipril (10 mg), hydrochlorothiazide (25 mg) with and without ASA (100 mg) as well as half-dose of this formulation with and without ASA (100 mg)Recruitment to pilot hypertension phase to start in 2014.
  • ACTRN, Australian Clinical Trials Registry Number; AHA, American Heart Association; ASA, Acetylsalicylic acid; BP, blood pressure; BPM, beats per minute; CTRI, Clinical Trials Registry India; CV, cardiovascular; CVD, cardiovascular disease; DBP, diastolic blood pressure; FOCUS, Fixed-Dose Combination Drug for Secondary Cardiovascular Prevention; HOPE, Heart Outcomes Prevention Evaluation; HT, hypertension; IMPACT, Improving adherence using combination therapy; IU, International Unit; Kanyini-GAP, Kanyini Guidelines Adherence with the Polypill ; LDL, low density lipoprotein; MG, milligram; mmHG, millimetre of mercury; mmol/L, millimole per litre; NCT, National clinical trial; NPHW, non-physician health worker; PILL, Program to Improve Life and Longevity; PROBE, prospective, randomized, open, blinded endpoint; RCT, randomized controlled trial; SBP, systolic blood pressure; TEMPUS, The Evening vs. Morning Polypill Utilization Study; TIPS, Indian Polycap Study; UK, United Kingdom; UMPIRE, Use of a Multidrug Pill In Reducing cardiovascular events.

Primary prevention

The Indian Polycap Study (TIPS-1)42 was the first randomized controlled trial (RCT) to document the physiological effects and tolerability of a five-drug combination pill (see Table 1 for formulations) compared with each single drug and combinations of two, three or four drugs using a partial factorial design in 2053 Indian subjects without CVD but with at least one risk factor (mean baseline characteristics: age 54.0 years, SBP 134.4 mmHg, DBP 85 mmHg, LDL cholesterol 3.0 mmol/L, % current smokers 13%). The 12-week study demonstrated good tolerability, and adherence of approximately 85%. The combination pill, when compared with arms not containing BP lowering drugs, reduced systolic BP by 7.4 mmHg and diastolic BP by 5.6 mmHg (Figure 3). The combination pill reduced LDL cholesterol by 0.70 mmol/L, which was less than that with simvastatin alone (0.83 mmol/L, P = 0.04); both reductions were greater than for groups without simvastatin (P < 0.0001). These reductions in risk factors were less than initially hypothesized but nevertheless substantial. It was estimated that the degree of risk factor modification could lead to a 62% RRR in CHD events and estimated 48% RRR in stroke (Table 2).

View this table:
Table 2

Estimated relative risk reductions in cardiovascular disease with a combination pill based on impact on risk factors from four trials

Parallel-group RCTsCrossover RCT
Half standard-dose Polycap (based on TIPS-1)Standard-dose Polycap (based on TIPS-1 and TIPS-2)PILL collaborative groupWald 2012b
Risk factor ReductioneRRR in eventsRisk factor ReductioneRRR in eventsRisk factor ReductioneRRR in eventsRisk factor ReductioneRRR in events
CHDStrokeCHDStrokeCHDStrokeCHDStroke
LDL-C(mg/dL)−27.027%8%−33.633%10%−30.935%23%−54.154%16%
DBP(mmHg)−5.624%33%−7.332%43%−5.322%41%−9.842%58%
LDL-C and BPNA44%33%NA54%49%NANANANANANA
Aspirin onlyaNA32%16%NA32%16%NA20%17%NA32%16%
LDL-C and BP and Aspirin (e.g. secondary prevention)62%48%69%57%60%56%72%64%
  • Combination-pill constituents: TIPS-1 (half standard-dose Polycap) = aspirin 100 mg, simvastatin 20 mg, ramipril 5 mg, hydrochlorothiazide 12.5 mg, atenolol 50 mg; TIPS-2 (standard-dose Polycap) = aspirin 200 mg, simvastatin 40 mg, ramipril 10 mg, hydrochlorothiazide 25.mg, atenolol 100 mg; PILL collaborative polypill = aspirin 75 mg, lisinopril 10 mg, hydrochlorothiazide 12.5 mg, simvastatin 20 mg; Wald 2012 = amlodipine 2.5 mg, losartan 25 mg, hydrochlorothiazide 12.5 mg, simvastatin 40 mg.

  • TIPS, The Indian Polycap Study; PILL, Programme to Improve Life and Longevity; LDL-C, LDL cholesterol; DBP, diastolic blood pressure; eRRR, estimated relative risk reduction.

  • aAs projected by Wald and Law, which is higher than that observed in the antithrombotic trialists meta-analyses.

  • bParticipants had already received the medications for a prolonged period prior to randomization, due to high CVD risk and had higher baseline LDL-C and BP levels than other studies. Therefore, the data are not comparable.

Figure 3

Effect of one, two, and three drugs used at low doses in combinations in the Indian Polycap Study-1 and full/double dose Polycap in the Indian Polycap Study-2 on (A) blood pressure control in participants with hypertension†, and (B) on estimated cardiovascular disease relative risk reduction ‡ in participants with hypertension† in the Indian Polycap Study-1 and the Indian Polycap Study-2. BP, blood pressure; CVD, cardiovascular disease. *P < 0.05; **P < 0.01; ***P < 0.001. Hypertension at baseline defined as systolic blood pressure >140 mmHg. ‡ Estimates derived from Framingham Score corresponding to 10-year CVD relative risk reduction (National Cholesterol Education Programme). From: Mente A, Pais P, Xavier D, Teo K, Yusuf S. Antihypertensive therapy: Polypill concept. In: Berbari AE, Mancia G, eds. Special Issues in Hypertension. Milan: Springer; 2012: 279–294.77

The international Programme to Improve Life and Longevity (PILL) Collaborative Group43 performed an RCT to evaluate a combination pill for primary prevention in 378 moderate risk individuals (mean BP 134/81, LDL cholesterol 3.7 mmol/L) over 12 weeks. Systolic BP was reduced by 9.9 mmHg and LDL by 0.80 mmol/L compared with placebo. Discontinuations in the combination pill and placebo groups were 23 and 18%, respectively (P = 0.2). The investigators calculated that the combination pill had an estimated RRR for a major CV event of 46% in a moderate-risk population and 53% in a high-risk population.

Wald et al.44 conducted a cross-over RCT in 86 people older than 50 years without a history of CVD and who had been enrolled in a CVD prevention programme due to a high-risk profile (age 59 years, SBP of 143 mmHg, DBP of 86 mmHg, LDL cholesterol of 3.7 mmol/L, % current smokers 9%). Participants were randomized to receive the combination-pill or placebo for 12 weeks, following which they crossed over to the other arm. Overall, there was a high level of adherence (98% took >85% pills) and no participants stopped medications due to side effects. Systolic BP was reduced by 17.9 mmHg, diastolic BP by 9.8 mmHg and LDL by 1.40 mmol/L. The estimated RRR in ischemic heart disease events was 72% and in stroke 64%. While this projection is close to the theoretical estimates,6,7 such large benefits may not be observed in clinical practice because participants in this study were highly motivated individuals, had elevated risk factors, and were known to tolerate the individual components of the combination pill.

Malekzadeh45 investigated a combination pill vs. placebo over 12 months in 475 participants without elevated BP or lipids. The investigators reported significant but modest reductions in BP (4.5/1.6 mmHg) and LDL cholesterol (0.46 mmol/L). However, there were imbalances in baseline characteristics at randomization, and a high rate of drug discontinuation (44% in the combination-pill group and 33% in the placebo group at 12 weeks), which could partially explain the relatively modest risk factor reductions reported.

To assess acceptability of a combination pill in primary care in a developing country, investigators in Sri Lanka46 allocated 216 people without CVD to a combination pill or standard practice for 3 months. While there were no significant differences in BP or lipids observed, there was high acceptability among participants and physicians of the combination pill.

Secondary prevention and high-risk primary prevention

The TIPS-247 was a RCT in 518 patients with stable CVD or diabetes from 27 sites in India. The aim was to estimate the incremental effect and tolerability of standard daily doses of the five drugs used in TIPS-1 compared with low doses of a combination pill of the same drugs. Participants were randomized to either take one combination-pill capsule (half-dose) or 2 capsules (standard dose). The standard dose reduced BP by a further 2.8 mmHg systolic (P = 0.003), 1.7 mmHg diastolic (P < 0.001), total cholesterol by 0.19 mmol/L (P = 0.014) and LDL cholesterol by 0.17 mmol/L (P = 0.006) compared with the half-dose. The rates of drug discontinuation during 8 weeks were similar in the two groups (6.9% vs. 7.8%). These results suggest that aspirin 100 mg with standard doses of three BP lowering drugs and simvastatin would be well tolerated and reduce both BP and lipids substantially, translating to an estimated 60% RRR in CVD risk (Table 2). For hypertension specifically, an analysis of TIPS-1and TIPS-2 found that BP control consistently increased with increasing number of drugs and doses, from 58% controlled with one half standard-dose drug to 80% with a combination of three standard-dose drugs (P for trend < 0.0001). The latter also yielded a 3.84-point reduction in the Framingham score, translating to an estimated 64% RRR in CVD risk (Figure 3).

The Use of a Multidrug Pill In Reducing cardiovascular Events (UMPIRE) trial48 conducted in the UK, Ireland, Netherlands, and India has recently been completed.49 The trial included 2004 participants with clear indications for the components of a combination-pill, including those with established CVD or a calculated 5-year CVD risk of ≥15% (a high-risk primary prevention population). Patients were randomized to a fixed-dose combination pill strategy or to usual care, and followed for a median follow-up of 15 months. The combination pill group was found to have improved adherence vs. usual care (86% vs. 65%, P < 0.001) with concurrent reductions in SBP (−2.6 mmHg, P < 0.001) and LDL cholesterol (−4.2 mg/dL, P < 0.001). Predefined subgroup analyses found larger benefits in 727 participants (36%) not receiving all recommended treatments at baseline, with an adherence in this subgroup at the end of the study of 77% vs. 23%, and larger reductions in SBP (−4.9 mmHg) and LDL cholesterol (−6.7 mg/dL). No significant differences in serious adverse events or cardiovascular events were observed between groups.

A meta-analysis of adverse events in completed RCTs (Figure 4) showed that tolerability of combination therapy was similar to that of controls. In particular, there was no significant increase in the rates of most side effects (other than cough; 2.0% vs. 0.7%, P = 0.003), and the proportion of individuals stopping combination therapy ( vs. control) was not importantly dissimilar to the proportion of individuals stopping the control treatment (12% vs. 9%, P = 0.04). Moreover, since participants enrolled in these trials were moderate- or high-risk individuals, the adherence rates in both the combination therapy and control groups were high (93.0% vs. 92.8%, P = 0.94).

Figure 4

Meta-analysis of selected adverse effects with Polypill vs. controls in completed multidrug combination therapy trials. Polypill formulations and control groups vary in accordance with the study design. *P value equals 0.04 for permanent discontinuation; and P = 0.003 for cough. Data taken from the following studies: the Indian Polycap Study-142; the Indian Polycap Study-247; Poly-Iran Pilot Study45; Pill Collaborative Group Study43; and Polypill Prevention Trial 1.44

The completed trials of combination-pill vs. placebo or no treatment demonstrated good short-term safety and tolerability and short-term risk factor reductions that were of approximately the size expected from the additive effects of the individual agents. Based on these CV risk factor improvements, most trials supported the theoretical RRR of more than 50% in the overall trial populations, and larger potential benefits might be achieved among higher risk individuals and those who are adherent to the combination-pill. However, these studies did not assess CV events and had too few events for even a meta-analysis of all trials to provide reliable information. Therefore, larger and longer term trials assessing clinical CV outcomes and safety are needed, especially in high-risk primary prevention.

Ongoing studies

Primary prevention

Several studies are underway in selected moderate or high-risk primary prevention populations (Table 1). The Heart Outcomes Prevention Evaluation (HOPE)-3 trial50 is evaluating the concept of combined BP and cholesterol lowering for 6 years in 12 705 individuals from five continents without vascular disease but at moderate CVD risk. All participants receive structured lifestyle advice, and the primary outcomes are CVD events and secondary outcomes are cognitive and renal function, with results expected in 2016. The TIPS-3 trial51 will include >5 500 individuals from India, the Philippines, Canada, China, Brazil, Argentina, Chile and Colombia and additional countries. The aim of the study is to estimate the impact on major CVD events of a four drug combination-pill vs. placebo in a primary prevention population over five years. The participants are men over 55 years and women over 60 years without vascular disease and with an elevated INTERHEART risk score52 of ≥10 (which corresponds to a projected annual CV event rate in the control group of >1%). Recruitment has commenced (>1200 individuals have been enrolled as of September 2013) and the results are expected in 2018.

Large trials are needed in a range of moderate-to-high-risk participants to assess the balance of benefits and risks in primary prevention. If these studies indicate large reductions in CVD (e.g. >35–50% RRR), and that use of a combination pill is safe and cost-effective, population trials in lower risk individuals can be considered.

Secondary prevention

The Fixed Dose Combination Drug for Secondary Cardiovascular Prevention (FOCUS) trial53 is a 1340 patient randomized controlled trial of the effects of a combination pill on adherence, BP and lipids at 9 months in participants post-myocardial infarction. The Evening vs. Morning Polypill Utilization Study (TEMPUS) study54 is a prospective, randomized, open, blinded endpoint (PROBE) cross-over trial of evening vs. morning combination pill vs. individual component medications throughout the day in 75 participants ≥18 y with CVD or 5-year CVD risk ≥10% in the Netherlands. The Kanyini Guidelines Adherence with the Polypill (Kanyini-GAP) study55 is a recently-completed Australian randomized trial involving 623 indigenous and non-indigenous patients with established CVD or a ≥15% 5-year risk of a CV event, who are randomized to a combination pill or to usual care. Outcomes of interest include adherence, systolic BP (SBP), and total cholesterol and the results are expected shortly. The Improving Adherence using Combination Therapy (IMPACT) trial56 is a randomized trial of 516 participants from New Zealand indigenous Māori and non-indigenous populations with established CVD or 5-year CVD risk of at least 15%. This open randomized trial investigates the impact of a combination pill vs. usual care on adherence, SBP, and LDL cholesterol. The study has completed recruitment and the results are expected in 2013. The UMPIRE, Kanyini-GAP, and IMPACT trials are all being conducted utilizing similar protocols and a prospective individual participant data meta-analysis is planned (www.spacecollaboration.org).

Community implementation

The Heart Outcomes Prevention Evaluation-4 (HOPE-4) community cluster randomized trial57 will evaluate an evidence-based programme for CVD risk assessment, treatment, and control involving simplified screening and treatment algorithms implemented by non-physician health workers (often public health nurses or nursing assistants) coupled with lifestyle counselling and combination-pill therapy. The initial risk factor phase of the study will assess BP and cholesterol changes in Colombia and Malaysia (50 communities), with plans to expand to 190 communities in eight countries to evaluate CVD events over 6 years. The PolyIran58 open-label cluster RCT aims at determining the effects of a combination-pill vs. minimal care in primary and secondary prevention of CVD in 7000 adults 50–79 years old from Iran. The primary outcome at 5 years is the time to first major CV event, and the results are expected in 2018 or 2019.

Ongoing studies will elucidate the benefit of combination pills for primary prevention of CVD events in moderate- to high-risk patients. In addition, the collaboration of research groups in secondary prevention will provide useful data on risk factor reduction and medication adherence. To implement proven effective and safe combination-pills in ‘real world’ populations will require re-engineering health systems using existing resources. Employing NPHWs for routine screening and initiation of combination drug therapy, as well as on-going treatment and lifestyle education and reminders, is a strategy that has great potential.59

Benefits of combination therapy plus lifestyle modification

Table 3 depicts estimated cumulative RRR for lifestyle modification and combination pills at half and standard doses. The potential CVD risk reductions were derived from estimates in longitudinal studies of lifestyle modifications (including smoking cessation 30%; healthy diet 30%, and physical activity 20% assuming ‘full adherence’)6063 and the TIPS-1 and TIPS-2 trial results that translated to an estimated RRR of 50 and 60%, respectively, from the Polycap alone. Models of a range of combination-pill adherence rates from 50-90% for these interventions are estimated. The cumulative estimated RRR for a combination of lifestyle modification and combination drugs ranges from 63 to 88%. Moreover, the benefits of the combination pill and lifestyle modification are additive and employing them together is the preferred approach, and could prevent several millions of premature deaths and hospitalizations every year from CVD worldwide.

View this table:
Table 3

Estimated cumulative risk reductions for cardiovascular disease with lifestyle modifications in combination with Polypill therapy

InterventionPotential CVD risk reductions of individual componentsCumulative risk reductions at differing levels of adherencec
50%75%90%
Lifestyle cumulative risk reductiona
 Smoking cessation30%6015%23%27%
 Healthy diet30%.6115%23%27%
 Physical activity20%.6310%15%18%
 Combined lifestyle (smoking + diet + physical activity) modification50%.6226%37%43%
Polypill cumulative risk reductionb
 Polypill , half standard dose50%25%38%45%
 Polypill, standard dose60%30%45%54%
Lifestyle (shown at 50–90% levels of adherence) + polypill (included at constant 75% adherence in all columns) estimated cumulative risk reduction
 Polypill (half dose with 75% adherence) + smoking cessation53%60%65%
 Polypill (half dose with 75% adherence) + combined lifestyle modification63%75%81%
 Polypill (full dose with 75% adherence) + smoking cessation60%68%72%
 Polypill (full dose with 75% adherence) + combined lifestyle modification71%82%88%
  • CVD, cardiovascular disease; mg, milligram.

  • aCumulative relative risk reductions for lifestyle are calculated for smoking cessation, healthy diet, and physical activity separately and in combination.

  • bCumulative risk reduction for the Polypill is derived from half and standard polypill dose, using results from TIPS-1 and TIPS-2. Half-dose polypill is defined as Aspirin 100 mg, simvastatin 20 mg, ramipril 5 mg, hydrochlorothiazide 12.5 mg, atenolol 50 mg. Standard-dose polypill is defined here as aspirin 200 mg, simvastatin 40 mg, ramipril 10 mg, hydrochlorothiazide 25 mg, and atenolol 100 mg.

  • cRisk reduction values at different levels of adherence for lifestyle factors and the Polypill are extrapolated from the risk reduction estimate multiplied by the adherence rates (e.g. 30% risk reduction × 0.90 adherence = 27% risk reduction). To account for different scenarios in real life, we modeled adherence rates for the interventions from 50 to 90% based on the results from TIPS-1 and TIPS-2.

  • ¶ Assuming 75% adherence to the polypill.

A global summit on combination polypharmacy

A Global Summit on Combination Polypharmacy for CVD was held on September 25–26, 2012 at the Population Health Research Institute (PHRI), Hamilton, Canada64 with researchers, regulators, and industry representatives participating. The Summit deliberated on the global challenges in CVD prevention, and reviewed completed and ongoing trials, knowledge and attitudes of clinicians, regulatory issues, and how to increase access to combination therapy. The Summit concluded that considerable progress has been made to generate data on short-term safety and efficacy of several combination-pill formulations and identified three areas needing advancement.

First, regulatory guidelines should be updated and clarified. While a handful of three-drug combinations have been approved for use in HIV, cancer, and hypertension, there are no four or five-drug combinations currently approved. An overview of current regulatory guidelines and constraints in the cardiovascular area was provided at the Summit by senior staff from the US Food and Drug Administration and the European Medicines Agency. Topics included the need to reference approved indications for component medications, the requirement to show the therapeutic contributions of each component, and the challenges posed if there are only limited fixed-dose versions available. The second area requiring progress was the need for novel business models, so that industry can commit the necessary funds for development, manufacturing, and sales while keeping costs affordable for use in developing countries and increasingly cost-constrained developed countries. Major health organization such as national health departments, foundations, and large health insurance companies could assist in this area by making advanced commitment to purchasing combination pills, if made available at large scale and affordable costs. Third, the Summit noted the need for further research funding to support trials testing effects of the combination pill on clinical outcomes in specific patient groups (such as in high-risk primary prevention) and to test expansion of the concept to other patient groups who are at high risk for CVD such as those with diabetes or HIV/AIDS. A Second Global Summit will be held on May 8 2014, following the World Congress of Cardiology.

Conceptual issues

The combination pill as a complement to lifestyle modification

A concern related to the use of combination therapy is that it would replace efforts to promote healthy lifestyles and that entire populations may be unnecessarily ‘medicalized’.65 The UMPIRE trial provides direct randomized data demonstrating that people who knew they were taking a polypill had no adverse effect on lifestyle measures, such as weight, exercise or smoking.48 Lifestyle modification should remain an integral and primary component in the armamentarium of CVD prevention, but the reality is that successful and sustained lifestyle modification is achieved in only a small proportion of patients.66 Waiting to assess the effects of lifestyle counselling before resorting to evidence-based drug therapy in high-risk individuals delays effective care. Instead, it is appropriate to initiate lifestyle modification simultaneously with drug therapy as the benefits are complementary and additive for CVD prevention (Table 3).11

Additionally, it is a difficult and lengthy process to undertake effective societal reforms which favourably shape individual health behaviours. For example, it has taken more than 50 years since the discovery that tobacco is harmful to develop the Framework Convention for Tobacco Control (which is one of the few legal frameworks to enhance public policy), and will likely take several more decades before it is fully implemented worldwide. It will likely take a prolonged period before similar appropriate societal or legislative mechanisms to promote healthy lifestyles (e.g. taxes on unhealthy foods and subsidies on healthy foods, or changing the structure of cities and transportation modes) can be implemented. In most countries such legal innovations are at a very early stage of development or are held back by controversy—which is all the more reason to enhance efforts on pharmacotherapy.

Simplifying treatment without compromising safety

A second concern regarding the use of combination pills stems from the belief of some physicians that they should individually select and tailor dosages of medications rather than prescribe a fixed-dose, fixed-component combination pill.65,67,68 While some obvious contraindications exist for each drug (e.g. dyspepsia and bleeding for aspirin, asthma for a beta-blocker), the number of individuals with these conditions are relatively few (likely <10% in total)69 and an alternative formulation could be made to accommodate these situations. In secondary prevention, the benefits of the typical combination-pill components are clear and consistent in all subgroups examined irrespective of the level of individual risk factors. For example, in secondary prevention, a statin is effective irrespective of the initial lipid level70 and an ACE inhibitor and/or beta-blocker is effective irrespective of the BP level.71, 72 Physicians accept combination therapy in other conditions and settings; it is time for a similar approach in CVD prevention, at least in high-risk groups. In the majority of such individuals, a combination-pill (perhaps available in low and standard doses) can be used without the need for further customization.

Selection of drug components

A third concern related to combination therapy is the choice of drugs to be included in the combination pill. The main tenets of a combination-pill are simplicity, ease of administration and modest cost. Use of generic or mature compounds is likely required in order to keep costs low. Current supplier wholesale cost estimates are $0.088 USD/€ 0.066 per tablet to purchase the individual components in a typical polypill (20 mg simvastatin, 5 mg ramipril, 50 mg atenolol, 12.5 hydrochlorothiazide and 100 mg aspirin).73 Few combination-pills are currently approved for sale, however in India the Polycap™ is available to consumers for ∼INR 461 ($8.90 USD/€ 6.67) per month and Trinomia® is available in Latin America for €14–17 ($18–$22 USD) per month.74

Eventually, there will need to be several formulations of the combination pill available to meet the needs of different clinical populations. In hypertensives, a combination pill could contain higher doses of several anti-hypertensive agents. In individuals with asthma and hypertension, beta-blockers may be replaced by a CCB. If a few different combination-pills were available, most patients could likely find one that is suitable as first-line therapy.

Commercial and Regulatory Constraints

In addition to conceptual issues, there are other issues that may impede the widespread use of the combination-pill, for which we will discuss potential solutions.

Business model

The first constraint is the understandable lack of interest among large pharmaceutical companies. A common pharmaceutical company business model is based on developing innovative drugs at great cost, and then selling them at considerable profit during the period in which the company has intellectual property protection. By contrast, the key appeal in a combination pill is the use of low-cost mature drugs. However, it may be possible to develop innovative and commercially attractive business models whereby there are profits to be made from high volumes but low unit prices, with a reduction in ancillary costs related to marketing and distribution. Further, governments and large health maintenance organizations and health insurance companies could provide advanced purchase commitments, making the investment in developing a combination pill lower risk. This has been done successfully for other conditions like malaria and HIV/AIDS in developing countries. In malaria, innovative partnerships including academia, governments, non-governmental organizations, and commercial partners have played a role in the development of affordable fixed dose combination therapy.75 In HIV/AIDS, the majority of antiretroviral drugs are off-patent and first-line therapy is generally offered in the form of co-formulations of several generic medicines.76 While there are many patents that potentially apply to the co-formulation process and technology (rather than to the active pharmaceutical ingredients), these patents do not appear to have impeded the rollout of co-formulations for other conditions, and could be licensed if necessary. Governments, foundations, and insurance companies could consider purchasing the combination pill in bulk and providing it free or at a locally sensitive low cost in resource-constrained settings, thereby increasing both access to treatment and volume of pills purchased from manufacturers.

Simple guidelines for regulatory approval

An additional constraint to the widespread availability of combination therapy is a clear and practical pathway for regulatory approvals. In secondary prevention where the benefit of the individual drugs has been well established, demonstrating pharmacologic stability, bioequivalence and tolerability of the combination pill in short-term trials should be considered adequate for regulatory approvals.1 Such an approach has led to the approval of the Polycap™ in India and of Trinomia/Sincronium™ in Guatemala and Argentina. For primary prevention, trials demonstrating that the combination pill as a whole is safe and significantly reduces CVD events should be adequate, instead of being required to conduct trials to identify the relative contribution of each component drug. It is hoped that major regulatory authorities like the U.S. Food and Drug Administration and the European Medicines Agency will work with academics, industry, and other arms of the government to develop simple, practical, and rational guidelines that will facilitate the availability of combination pills. Such guidelines would be a model to be used by regulatory authorities globally.

Conclusions

Combination drug therapy along with appropriate lifestyle changes can lead to a large estimated reduction in CVD (70–80%) and can benefit many individuals globally. Therefore, this strategy should be adopted for CVD prevention worldwide. While there are currently many barriers to widespread use of combination therapy, they are surmountable.

Funding

The Global Summit on Combination Polypharmacy for Cardiovascular Disease received unrestricted funding for the symposium from the World Heart Federation, UnitedHealth, Ferrer Grupo, Cadila Pharmaceuticals, the Institute of Circulatory and Respiratory Health - Canadian Institutes for Health Research, and the Population Health Research Institute.

Conflict of interest: A.A., J.B., P.J., E.L., T.M., A.M., R.N., P.P., A.R., J.-D.S., K.T.D.X., and S.Y. report that their institutions have received research support from granting agencies and pharmaceutical companies for polypill/combination therapy projects. A.R. reports that his institution has obtained a license for combination therapy medications from the manufacturer. P.P., D.X., and S.Y. report receiving support for travel from pharmaceutical companies. R.S. reports being a long-standing enthusiast for the polypill and the editor of the BMJ when it published the papers that popularized the word polypill, and he reports taking a polypill and participating in a trial of a polypill. He also reports working for and holding stock in the UnitedHealth Group, which was one of the sponsors of the Combination Polypharmacy meeting.

Footnotes

  • The Writing Group included Salim Yusuf1 (Chair) and Amir Attaran2, Jackie Bosch1, Philip Joseph1, Eva Lonn1, Tara McCready1, Andrew Mente1, Robby Nieuwlaat1, Prem Pais3, Anthony Rodgers4, J-D Schwalm1, Richard Smith5, Koon Teo,1 and Denis Xavier3.1. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada.2. Faculties of Law and Medicine, University of Ottawa, Ottawa, ON, Canada.3. St. John's Medical College and Research Institute, Bangalore, India.4. The George Institute for Global Health, University of Sydney, Sydney, Australia.5. UnitedHealth Chronic Disease Initiative, London, UK.This manuscript incorporates many of the discussions that took place at the Global Summit on Combination Polypharmacy for Cardiovascular Disease, held September 25–26, 2012 at the Population Health Research Institute, McMaster University and Hamilton Health Sciences. Lists of speakers, participants, and slides are available at www.cannectin.ca. However, the opinions expressed in this paper reflect the views of only the named authors.

References

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