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Polypill: Can Its Potential Enhancement of Efficacy Trigger New Interest? Jennifer Chao, Sameer Bansilal New York, NY, USA

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Polypill: Can Its Potential Enhancement of Efficacy Trigger New Interest? Jennifer Chao, Sameer Bansilal New York, NY, USA j VIEWPOINT gOPINION Polypill: Can its Potential Enhancement of Efficacy Trigger New Interest? Jennifer Chao, Sameer Bansilal New York, NY, USA Heralded as “one of the boldest claims for a new appropriate use decreased linearly with diminishing eco- intervention” [1], the concept of the polypill was first nomic status, with 66.5% of the population adherent to introduced in 2003 by Professors Nicholas Wald and statin in high-income countries compared to 3.3% in low- Malcolm Law [2]. Conceived as a pill containing 3 blood income countries. Furthermore, in all countries, rural set- pressureelowering drugs from various classes, aspirin, tings had the lowest rates of appropriate medication used; statin, and folic acid, the polypill was designed for 2 medication costs, inadequate health care systems, and poor population types: all individuals with established cardio- infrastructure were posited as key factors in the disparate vascular disease (CVD), and because the relative risk for treatment results [5]. cardiovascular (CV) events increases linearly with age, all individuals without CVD but older than age 55 years. At its POLYPILL AND ADHERENCE inception, the polypill was projected to safely reduce Several studies have found improvement in medication ischemic heart disease events by 88% and strokes by 80% adherence with the polypill [6e8]. In UMPIRE (Use of a [3]. Multidrug Pill In Reducing cardiovascular Events), 2,004 As chronic diseases, such as hypertension, diabetes patients with established CVD or calculated 5-year CVD mellitus, and hyperlipidemia, and a more sedentary risk >15% were randomized to a polypill or usual medical lifestyle become more widely prevalent in low- and middle- therapy; adherence improved 33% in the polypill cohort, income countries, CVD is now shifting to become a major accompanied by a significant reduction in systolic blood global burden. Over the last decade, many polypills have pressure and low-density lipoprotein [6]. FOCUS (Fixed- been created and studied in various populations of Dose Combination Drug for Secondary Cardiovascular different socioeconomic status. Many of the already pub- Prevention), a 5-country cohort of 2,118 patients, found lished studies, although limited by scope and power, have that complexity of treatment contributed significantly to shown promising results for preserved pharmacokinetic/ medication nonadherence. Access to the polypill improved pharmacodynamic properties while significantly improving adherence significantly by 22%, with low and similar patient adherence to the polypill versus its separate adverse effects [9]. components. With the initiation of large cardiovascular outcomes studies, there is now a new resurgence and optimism to the concept of the polypill largely for COST BENEFIT secondary, but also for primary prevention. A single polypill could simplify and streamline the treat- ment algorithms and increase the ease of providing MEDICATION ADHERENCE GAP appropriate medical therapy. It also has reduced costs, which is important for the low- to middle-income coun- Individually, aspirin, statins, beta-blockers, and tries but also to high-income countries with rising health angiotensin-converting enzyme inhibitors (ACEIs) are care costs. It can be prescribed by nonphysician health care proven to reduce CVD in secondary prevention cohorts. The authors report no re- workers with little or no monitoring. If using generic lationships that could be However, several studies have shown a large treatment gap components, the cost of a polypill is estimated at w$1/day construed as a conflict of in all aspects of medication delivery from lack of interest. in developed and <20 cents in developing countries due to prescription to medication nonadherence. EUROASPIRE From the Icahn School of reduced packaging, distribution, and marketing costs and III (European Action on Secondary and Primary Prevention Medicine at Mount Sinai, fewer physician visits and laboratory tests. An observa- New York, NY, USA. Corre- by Intervention to Reduce Events III), a study of 76 centers tional study of 170,024 Kaiser Permanente members with spondence: S. Bansilal in 22 European countries, found that the use of statins and diabetes, CAD, or both showed that a pill of statin and an (Sameer.bansilal@ ACEI remains suboptimal in patients with established mountsinai.org). ACEI/angiotensin receptor blocker was delivered with ischemic heart disease and CV risk factors [4]. The PURE minimal physician visit and laboratory tests and reduced GLOBAL HEART (Prospective Urban Rural Epidemiological) study found the risk of hospitalization for myocardial infarction (MI) or © 2016 World Heart that in 153,996 surveyed adults with a history of coronary stroke [10]. Federation (Geneva). Pub- heart disease or stroke in high-, medium-, and low-income lished by Elsevier Ltd. All countries, overall use of appropriate medications was rights reserved. < CV OUTCOMES TRIALS VOL. 11, NO. 4, 2016 suboptimal, with 20% of the surveyed cohort in low- ISSN 2211-8160/$36.00. income countries taking antiplatelet drugs, beta-blockers, For primary prevention, studies vary in either adopting an http://dx.doi.org/10.1016/ ACEIs/angiotensin receptor blockers, or a statin. Notably, “individual” approach, which encompasses people with j.gheart.2016.10.020 GLOBAL HEART, VOL. 11, NO. 4, 2016 469 December 2016: 469-472 j 470 TABLE 1. The polypill landscape Company Polypill Name Active Components Countries Approved Clinical Trial Status gOPINION Polypills approved Cadila Pharmaceuticals Polycap Aspirin (100 mg), atenolol (50 mg), India and Zambia TIPS (Indian Polycap Study) (Ahmedabad, Gujarat, India) hydrochlorothiazide (12.5 mg), ramipril (5 mg) Zydus Cadila Healthcare Zycad-4 Aspirin (75 mg), atorvastatin (10 mg), India None (Ahmedabad, Gujarat, India) metoprolol (50 mg), ramipril (5 mg) Ramitorva Aspirin (75 mg), atorvastatin (10 mg), India None ramipril (5 mg) USV (Mumbai, India) Polytorva Aspirin (75 mg), atorvastatin (5 mg), ramipril India None (10 mg) Ferrer Internacional (Barcelona, Trinomia Aspirin (100 mg), ramipril (2.5, 5, or 10 mg), 15 European countries (Austria, FOCUS (Fixed-dose Spain) simvastatin (40 mg) Belgium, Bulgaria, Czech Combination drug for Republic, Finland, France, Secondary Cardiovascular Germany, Greece, Ireland, Italy, Prevention), SECURE Poland, Portugal, Romania, Spain, (Secondary Prevention of Sweden) and Chile Cardiovascular Disease in the Elderly) trial underway Polypills in development Dr. Reddy’s Laboratories Red Heart Pill Aspirin (75 mg), atenolol (50 mg), lisinopril UMPIRE (Use of a Multidrug (Hyderabad, India) 1TM (10 mg), simvastatin (40 mg) Pill In Reducing cardiovascular Events), SPACE trial underway Red Heart Pill Aspirin (75 mg), hydrochlorothiazide (12.5 2TM mg), lisinopril (10 mg), simvastatin (40 mg) Cadila Pharmaceuticals Polycap DS Atenolol (100 mg), hydrochlorothiazide (25 TIPS-3 (The International (Ahmedabad, Gujarat, India) mg), ramipril (10 mg), simvastatin (40 Polycap Study 3) mg) Alborz Darou Pharmaceutical PolyIran1TM Aspirin (81 mg), atorvastatin (20 mg), PolyIran (Prevention of Company (Tehran, Iran) enalapril (5 mg), hydrochlorothiazide (25 Cardiovascular Disease in mg) Middle-aged and Elderly Iranians Using a Single Polypill) PolyIran2TM Aspirin (81 mg), atorvastatin (20 mg), GLOBAL HEART, VOL. 11, NO. 4, 2016 hydrochlorothiazide (25 mg), valsartan (40 mg) Hypermarcas SA (Sao Paulo, Polypill Atorvastatin (10 mg), lisinopril (50 mg), Clinical Assessment of December 2016: 469-472 Brazil) hydrochlorothiazide (12.5 mg) Association Pharmacokinetics In Healthy Subjects AstraZeneca (Molndal, Sweden) Candesartan (16 mg), hydrochlorothiazide HOPE-3 (Heart Outcomes (12.5 mg) or placebo with rosuvastatin Prevention Evaluation-3) 10 mg j gOPINION risk factors, versus a “population” approach, which for secondary prevention. TIPS-3 evaluates the Polycap involves lowering risk factor levels in entire populations. without aspirin (simvastatin/hydrochlorothiazide/atenolol/ The Indian Polycap Study is a randomized controlled trial ramipril) versus placebo over 5 years in 5,000 individuals of Polycap (simvastatin/aspirin/hydrochlorothiazide/ateno- without CVD in India and China. The study is expected to lol/ramipril; Cadila Pharmaceuticals Limited, Ahmedabad, report results in 2020. SECURE evaluates the polypill India) versus individual drugs in 2,053 individuals in combination of aspirin/ramipril/simvastatin in 3,600 India. The selected participants included men and women elderly (age >65 years) post-MI patients in several Euro- age 45 to 80 years without previous cardiac disease but pean countries. The study is also expected to report results with at least 1 cardiovascular risk factor: hypertension, in 2020. obesity, hypercholesterolemia, diabetes, or smoking [11]. Polycap was noninferior to individual components in lowering blood pressure and heart rate. Notably, although PUBLIC AVAILABILITY it showed reduction of each individual risk factor, the In 1977, the World Health Organization developed its first study was not designed to study a reduction in death, MI, Model List of Essential Medications to guide countries in or stroke. Interestingly, the absolute rate of drug discon- the creation of national formularies of cost-effective med- tinuation was low, but surprisingly was not different across ications. In November 2012, an application was submitted the treatment groups (16% in Polycap vs. 14.8% overall). for the inclusion of the polypill into that list; the updated The most common reason for
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