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An Application to Recommend That Fixed-Dose Combination Therapy AN APPLICATION TO RECOMMEND THAT FIXED-DOSE COMBINATION THERAPY BE ADDED TO THE WHO MODEL LIST OF ESSENTIAL MEDICINES FOR SECONDARY PREVENTION OF CARDIOVASCULAR DISEASE (ISCHEMIC HEART DISEASE AND ISCHEMIC STROKE) (12) Mark D. Huffman, MD, MPH, Northwestern University Feinberg School of Medicine, Chicago, USA Pablo Perel, MD, MSc, PhD, London School of Hygiene and Tropical Medicine, London UK José Maria Castellano, MD, PhD, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain Valentin Fuster, MD, PhD, Icahn School of Medicine at Mount Sinai, New York, USA Anthony Rodgers, MD, PhD, The George Institute for Global Health, Sydney, Australia Ruth Webster, PhD, The George Institute for Global Health, Sydney Australia Sidney C. Smith, Jr., MD, University of North Carolina, Chapel Hill, USA Salim Yusuf, MD, DPhil, MRCP, Population Health Research Institute, McMaster University, Hamilton, Canada 1 1. Summary statement of the proposal for inclusion In recognition of their integral role in management of cardiovascular diseases (CVD), aspirin, statins, and blood pressure lowering drugs such as beta-blockers, hydrochlorothiazide, and ACE inhibitors have been included in the WHO Essential Medicines List for many years. The first year of listing for aspirin was 1990, for a beta- blocker was 1997, for an ACE inhibitor was 2003, for a statin was 2007, and for hydrochlorothiazide was 2009. Aspirin, simvastatin, hydrochlorothiazide, bisoprolol, and enalapril are all included on the core list, with the latter four having a “square box” annotation (i.e., recognition of similar clinical performance within a pharmacological class). There is consensus among guidelines internationally that patients with atherothrombotic CVD, such as previous heart attack or ischemic stroke, should take an antiplatelet agent, statin, and blood pressure lowering drugs long-term to reduce the risk of a recurrent non-fatal of fatal CVD event. The World Health Organization (WHO) aims to reduce the premature mortality from non-communicable, chronic diseases, including CVD, by 25% by 2025. One key strategy to achieve this goal will be to increase the proportion of people with established atherothrombotic CVD who receive an antiplatelet agent, statin, and blood pressure lowering drugs as recommended by WHO guidelines and all other major guidelines. However, this goal will not be achieved unless current treatment rates are increased substantially, and the aim of this application is to reduce this gap. Ischemic heart disease and stroke are the leading causes of death worldwide, with more than 80% of premature deaths from these conditions occurring in low- and middle-income countries. However, less than 20% patients with prior disease take all recommended medication classes for CVD secondary prevention and control in these regions. The burden of CVD is disproportionately greater in low- and middle-income countries, both in terms of age-adjusted rates and total number of individuals dying from CVD. A 2014 Cochrane systematic review of nine trials including 7,047 participants and an updated meta-analysis of four trials of multiple fixed-dose combinations including 3,338 participants included in this application demonstrate a 44% (95% CI: 26% to 65%) increase in adherence to drug therapy with fixed-dose combination therapy for CVD prevention compared with usual care. There is a robust and consistent effect on improving adherence with different formulations across diverse settings, with a consistently greater effect among individuals with low baseline adherence. The fixed- dose combinations of aspirin + simvastatin + ramipril and aspirin + atorvastatin + ramipril (trade name: Trinomia for both) have received regulatory approval from European, South American, and Central American country regulatory authorities. The fixed-dose combination of aspirin + simvastatin + atenolol + hydrochlorothiazide + ramipril (trade name: Polycap) has received regulatory approval from India and Zambia. The fixed-dose combinations of aspirin + simvastatin + atenolol + lisinopril (trade name: Red Heart Pill 1c) and aspirin + simvastatin + hydrochlorothiazide + lisinopril (trade name: Red Heart Pill 2c) have yet to receive regulatory approval but have been widely tested in four randomized controlled clinical trials to help support the concept of fixed- dose combination therapy for CVD prevention. Using the GRADE approach, both the overall body and quality of evidence and strength of recommendation are strong 2 to support fixed-dose combination therapy to improve adherence for secondary CVD prevention. Fixed-dose combination therapy has been advocated by the WHO for CVD secondary prevention since 2001 given the benefits in terms of efficacy, adherence, scalability, and cost-effectiveness and receives strong support from leadership within major cardiovascular professional organizations, such as the World Heart Federation. Therefore, we propose the inclusion of fixed-dose combination for improved adherence to CVD secondary preventive drug therapy in the WHO Model List of Essential Medicines. 2. Name of the focal point in WHO submitting or supporting the application Dr. Shanthi Mendis, Coordinator, Chronic Disease Prevention and Management. 3. Name of the organizations consulted and/or supporting the application To be submitted after the application has been posted to the World Health Organization’s Model List of Essential Medicines website. 4. International Proprietary Names (INN) a) Acetylsalicylic acid (non-INN. The WHO establishes that aspirin does not have INN because this name was already in wide use when the INN system began, and it was a well-established name). b) Simvastatin c) Atorvastatin d) Atenolol e) Hydrochlorothiazide f) Ramipril 5. Formulations proposed for inclusion We propose one or more of the following formulations: Aspirin 100 mg + simvastatin 40 mg + ramipril 2.5 mg, 5 mg, or 10 mg as a fixed-dose combination. This formulation is currently available as “Trinomia”. Aspirin 100 mg + atorvastatin 20 mg + ramipril 2.5 mg, 5 mg, or 10 mg as a fixed-dose combination. This formulation is currently available as “Trinomia”. Aspirin 100 mg + simvastatin 20 mg + atenolol 50 mg + hydrochlorothiazide 12.5 mg + ramipril 5 mg. This formulation is currently available as “Polycap”. 6. International availability - sources, of possible manufacturers and trade names Ferrer Internacional, S.A. of Spain manufactures both formulations of Trinomia. Cadila Pharmaceuticals, Ltd. of India manufactures the Polycap. A list of countries where each formulation is currently available and is scheduled to be available in 2015 is listed in Table 1. Table 1. List of countries where fixed-dose combinations formulations are currently 3 available and are scheduled to be available in 2015. Currently available Available in 2015 Aspirin + simvastatin + ramipril, fixed- Guatemala, dose combination in formulation of Nicaragua, Trinomia Dominican Republic, Honduras, El Salvador, México and Argentina Aspirin + simvastatin + ramipril, fixed- Spain, Sweden, dose combination in formulation of Romania, Greece, Trinomia Austria, Belgium, Bulgaria, Czech Republic, Finland, France, Germany, Italy, Poland, Portugal and Ireland Aspirin + simvastatin + atenolol + India, Zambia hydrochlorothiazide + ramipril in formulation of Polycap 7. Whether listing is requested as an individual medicine or as an example of a therapeutic group We propose listing under the “square box” substitutable category. Trinomia and Polycap are examples of the class of product. Therapeutic alternatives would include combinations with aspirin + statin + at least one blood pressure lowering drug such as aspirin + simvastatin + atenolol + lisinopril or ramipril, aspirin + simvastatin + hydrochlorothiazide + lisinopril or ramipril, or other similar formulations. 8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population) The World Health Organization (WHO) has recently announced targets for reducing the number of premature deaths (>30 and <70 years) due to non- communicable, chronic diseases (NCDs) by 25% by the year 2025.(1) These targets have been preceded by other WHO goals of reducing the burden of not only premature death but also disability from NCDs,(2) which were formalized as a result of the resulting Political Declaration from the 2011 United Nations High Level Meeting on NCDs. Since cardiovascular diseases (CVD) are the leading causes of overall and premature mortality in the world and since more than 80% of CVD deaths occur in low- and middle-income countries,(3) CVD treatment and control are crucial to reaching these WHO targets. If current trends continue over the next decade, the “25 x 25” goal will not be achieved, and the absolute burden of CVD morbidity and mortality will increase substantially due to population growth and ageing.(4) 4 One specific target within the WHO’s “25 x 25” goal that this application specifically addresses is global NCD target #8: “At least 50% of eligible people receive drug therapy and counseling (including glycemic control) to prevent heart attacks and strokes. The indicator for monitoring this target in the global monitoring framework is the proportion of eligible persons receiving drug therapy and counseling (including glycemic control) to prevent heart attacks and strokes. Eligible persons are those aged 40 years and older with a 10-year CVD risk ≥30% (based on WHO/ISH risk prediction charts),
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