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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

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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

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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

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available and are scheduled to be available in 2015. Currently available Available in 2015 Aspirin + simvastatin + ramipril, fixed-dose combination in formulation of Trinomia

Guatemala, Nicaragua,

Dominican Republic, Honduras, El

Salvador, México and Argentina

Aspirin + simvastatin + ramipril, fixed-dose combination in formulation of Trinomia

Spain, Sweden, Romania, Greece, Austria, Belgium, Bulgaria, Czech

Republic, Finland, France, Germany,

Italy, Poland, Portugal and

Ireland Aspirin + simvastatin + atenolol + hydrochlorothiazide + ramipril in formulation of Polycap

India, Zambia

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)

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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), including those with existing CVD. Drug therapy is defined as taking medications for primary and secondary prevention of heart attacks and strokes based on WHO recommendations.”(1) WHO Member States are setting national targets consistent with global targets, including this global target related to secondary prevention and high-risk primary prevention. Widespread availability of fixed-dose combination therapy is an important strategy towards achieving this goal.

A large amount of evidence supports the use of pharmacological treatment for the secondary prevention of fatal and non-fatal cardiovascular events in patients with prior CVD events. Drugs including antiplatelet agents,(5) lipid-lowering agents,(6) beta-blockers,(7) and angiotensin-converting-enzyme inhibitors(8) have all demonstrated improvements in mortality and morbidity individually and are recommended for secondary prevention of CVD by a diverse group of professional organizations. However, substantial gaps in coverage of CVD secondary prevention are widespread globally.(9) More than half of patients with prior ischemic heart disease or stroke receive no secondary medications, with statin prevalence rate as low as 3% in low-income country settings; yet, the WHO’s recent indicators to reach its “25 x 25” target include provision that 50% of eligible people receive drugs to prevent heart attacks and strokes. Reasons for these substantial gaps include lack of availability (stock-outs), poor adherence, unaffordable cost, and inadequate prescription of medicines. Fixed-dose combination therapy that combines CVD secondary preventive medicines overcomes many of these barriers and has been proposed as a potential strategy by the WHO(10) and organizations such as the NCD Alliance(11) given its efficacy, adherence, scalability and cost-effectiveness.

Recent studies have shown that fixed-dose combination therapy improves

adherence by 44% (95% CI: 26% to 65%; Section 10, Table 5) compared with usual care in CVD secondary prevention, thus meeting the Model List’s recommendation that fixed-dose combination therapies should have “a proven advantage in therapeutic effect, safety or compliance over single compounds administered separately.”(12-16) These recent trials indicate that fixed-dose combination therapy reduces lipids (through which statins exert their beneficial effects) and blood pressure (a marker of the effects of blood pressure lowering drugs) to the same extent as giving each one of them separately (an additive effect on the surrogate markers of efficacy), if not more so, and that they are well tolerated.(12) Similar or improved efficacy, tolerance, and adherence have been demonstrated both in individuals with prior CVD (compared against the individual components given separately) and in individuals without prior CVD (compared against placebo). Further, the efficacy of fixed-dose combination therapy with other medicines has been

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demonstrated in populations of patients with other conditions such as HIV/AIDS, tuberculosis and hypertension,(17) thereby supporting the general concept that using drugs in combination improves adherence.

Each individual component of fixed-dose combination therapy has been proven to reduce death, myocardial infarction, or stroke in those with ischemic heart disease or stroke and each drug class is already included in the 18th Model List of Essential Medicines. Existing data on fixed-dose combination therapy shows the combined formulation reduces risk factors to the extent expected if the individual components were given individually. The effects of giving all of the individual components together is expected to be substantial and may lead to as much as a 75% RRR in recurrent CVD events.(18) Therefore, the current consensus is that the fixed-dose combination therapy should be considered for use in CVD secondary prevention. This conclusion is based on the existing data and the high-risk profile for CVD events in this group. Different expert panels, including the WHO(10) and the Combination Pharmacotherapy and Public Health Research Working Group,(19) have recognized the potential value of applying the fixed-dose combination therapy concept for secondary prevention of CVD.

There is precedent for including fixed-dose combination therapy in the WHO Model List. Section 6.5.3.1 of the 17th Model List of Essential Medicines includes fixed-dose combination therapy for curative treatment of Plasmodium falciparum malaria. The section states, “The list currently recommends combinations according to treatment guidelines. The Committee recognizes that not all of these FDCs exist and encourages their development and rigorous testing.” Further, the 18th Model List of Essential Medicines states that the, “WHO recommends and endorses the use of fixed-dose combinations and the development of appropriate new fixed-dose combinations” for both HIV and tuberculosis treatment. The 18th Model List includes five different fixed-dose combinations for treatment of HIV in section 6.4.2:

1) Efavirenz + emtricitabine + tenofovir 2) Emtricitabine + tenofovir 3) Lamivudine + nevirapine + stavudine 4) Lamivudine + nevirapine + zidovudine 5) Lamivudine + zidovudine

The 18th Model List also includes five different fixed-dose combinations for treatment of tuberculosis in section 6.2.4:

1) Ethambutol + isoniazid 2) Ethambutol + isoniazid + pyrazinamide + rifampicin 3) Ethambutol + isoniazid + rifampicin 4) Isoniazid + pyrazinamide + rifampicin 5) Isoniazid + rifampicin

A similar argument can be made for including multiple fixed-dose combination

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formulations for CVD secondary prevention based on the available evidence, current regulatory status, indication, and patient and physician preference. Overall, fixed-dose combination therapy has an immense potential public health benefit as a low cost and readily available form that combines several proven treatments to reduce the burden of CVD. 9. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostics, treatment or monitoring facilities and skills)

Cardiovascular disease secondary prevention includes treatment with aspirin, statin, beta-blocker, and an ACE-inhibitor following a myocardial infarction and treatment with antiplatelet agent, statin, and blood pressure lowering drugs following an ischemic stroke. These medications are typically to be used lifelong. Numerous professional organizations including the American Heart Association, American College of Cardiology,(20) European Society of Cardiology,(21) and United Kingdom’s National Institute of Health and Clinical Excellence(22) recommend that these drugs for CVD secondary prevention should be used concomitantly given their efficacy and favorable risk-benefit profile.

The WHO has recommended fixed-dose combination therapy for secondary CVD prevention.(10) The WHO’s recent announcement of voluntary targets for Member States includes the goal of treating at least 50% of patients with CVD with medications. The 2012 European Society of Cardiology Guidelines on Cardiovascular Disease Prevention in Clinical Practice states that, “reducing dosage demands is the most effective single approach toward enhancing adherence.”(21) Fixed-dose combination therapy is one such strategy to reduce dosage demands. Treatment or monitoring facilities and skills:

Treatment or monitoring facilities and skills for fixed-dose combination therapy are as for the individual components. 10. Summary of comparative effectiveness in a variety of clinical settings

The 2002 joint report by the World Health Organization and Wellcome Trust recommended that evaluation of these products in the secondary prevention setting be principally based on bioequivalence (i.e., studies showing that the fixed-dose combination is bioequivalent to the separate components) and evidence of improved adherence (such as improved risk factor control, as seen in different trials given the extensive evidence of clinical event reduction with the component medicines and drug classes, which has increased in the ensuing decade.(10) A 2014 Cochrane systematic review on fixed-dose combination therapy for CVD prevention included all combinations with at least one lipid lowering medication and one blood pressure lowering medication and included trials of both primary and secondary CVD prevention.(12) The end of the literature search for this review was July 19, 2013. This review identified nine randomized trials that included 7,047 participants. The results of this systematic review are summarized in Table 2. In brief, the trials were not designed to evaluate differences in morbidity or mortality, and there was substantial heterogeneity, suggesting that

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pooled results should be viewed with caution. Further, the comparator groups among the trials differed among inactive placebo to active comparator to usual care, which likely influenced results such as adverse events and discontinuation rates.

Table 2. Summary of findings of fixed-dose combination therapy for CVD prevention.(12)

Because an antiplatelet medication, statin, and blood pressure lowering

medications are recommended for individuals with prevalent atherothrombotic cardiovascular disease, we will report individual trial level and summary data on fixed-dose combination formulations with aspirin, statin, and blood pressure lowering drugs, such as:

1. Aspirin 100 mg + simvastatin 40 mg + ramipril 2.5 mg, 5 mg, or 10 mg 2. Aspirin 100 mg + atorvastatin 20 mg + ramipril 2.5 mg, 5 mg, or 10 mg 3. Aspirin 100mg + simvastatin 20 mg + atenolol 50 mg + hydrochlorothiazide

12.5 mg + ramipril 5 mg 4. Aspirin 75 mg + simvastatin 40 mg + atenolol 50 mg + lisinopril 10 mg 5. Aspirin 75 mg + simvastatin 40 mg + hydrochlorothiazide 12.5 mg + lisinopril

10 mg

Outcomes Event rates (categorical outcomes) or mean changes (continuous outcomes), by group

Relative effect or weighted mean

difference (95% CI)

No. of participants (studies)

Standard practice or placebo

Fixed-dose combination therapy

All-cause mortality %

1.0% 17 events, n=1684

1.2% 22 events; n=1781

RR = 1.26 (0.67, 2.38)

3465 (2 studies)

CVD event %

2.9% 36 events; n=1236

4.0% 50 events; n=1243

RR = 1.38 (0.91, 2.10)

2479 (2 studies)

Any adverse event 6 weeks to 15 months

24.2% 576 events; n=2379

29.7% 739 events; n=2485

RR = 1.19 (1.09, 1.30)

4864 (7 studies)

Systolic blood pressure (SBP) mmHg

-6.3 (range: 0 to -26.9)

n=2837

-13.4 (range: -3.7 to -28.8)

n=2950

-7.02 (-10.18, -3.87)

5787 (9 studies)

Total cholesterol (TC) mg/dl

-4.3 (range: 7.0 to -38.7)

n=2636

-33.3 (range: -3.9 to -56.8)

n=2933

-0.75 (-1.05, -0.46)

5569 (9 studies)

LDL cholesterol mg/dl

-1.2 (range: 5.0 to -7.0)

n=2531

-32.1 (range: -5.8 to -54.1)

n=2834

-0.81 (-1.09, -0.53)

5365 (8 studies)

Discontinuation for any reason 6 weeks to 15 months, %

11.5% 150 events; n=1307

14.0% 156 events; n=1116

RR = 1.26 (1.02, 1.55)

2423 (6 studies)

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Since the end of the Cochrane systematic review literature search in July 2013,

the results of the FOCUS,(13) Kanyini GAP,(14) and IMPACT(15) trials have been reported, the results of which are also included in this application. Bioequivalence for Trinomia formulation

Safety and efficacy of the concomitant administration of the components of cardiovascular fixed-dose combination therapy has been demonstrated. These claims are applicable to fixed-dose combinations provided they meet bioequivalence criteria for the active components. As an example, the following is a summary of the bioequivalence study conducted for the fixed-dose combination containing acetyl salicylic acid 100 mg + atorvastatin 20 mg + ramipril 10 mg that served as the basis for approval of this formulation by the European Medicines Agency.(23)

The aim of the study was to assess bioequivalence of the acetylsalicylic acid, atorvastatin, and ramipril fixed-dose combination (Test [T]) versus equal doses of the co-administered reference (R) formulations (Aspirin + Cardyl + Acovil), administered to healthy male and female volunteers in fasting conditions. The assessment was based on plasma drug levels of acetylsalicylic acid, atorvastatin, and ramipril, which were determined by high performance liquid chromatography–mass spectrometry. A total of 104 volunteers were enrolled, and 101 per-protocol completers were included in the statistical analysis, which was the standard bioequivalence ANOVA model. Bioequivalence can be claimed if the 90% confidence intervals for the intra-individual ratios of Cmax and AUC0-t fall within 80-125%. The following is an overview of the key study results: Table 3a. The 90% confidence intervals acetylsalicylic acid mean treatment T/R ratios were:

Test name Parameter Test value (T/R)

Lower 90% CI

Upper 90% CI

Classic 90% CI AUC0-t 100.625 96.924 104.467 Classic 90% CI Cmax 89.973 84.511 95.787 If the lower and upper CI lie within accepted CI (80-125%), then equivalence can be concluded. Table 3b. The 90% confidence intervals atorvastatin mean treatment T/R ratios were:

Test name Parameter Test value (T/R)

Lower 90% CI

Upper 90% CI

Classic 90% CI AUC0-t 100.577 95.495 105.929 Classic 90% CI Cmax 104.811 94.584 116.143 If the lower and upper CI lie within accepted CI (80-125%), then equivalence can be concluded. Table 3c. The 90% confidence intervals ramipril mean treatment T/R ratios were:

Test name Parameter Test value (T/R)

Lower 90% CI

Upper 90% CI

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Test name Parameter Test value (T/R)

Lower 90% CI

Upper 90% CI

Classic 90% CI AUC0-t 113.958 108.126 120.105 Classic 90% CI Cmax 101.517 91.508 112.621 If the lower and upper CI lie within accepted CI (80-125%), then equivalence can be concluded.

The statistical analysis of the pharmacokinetic data obtained in this study shows that the cardiovascular fixed-dose combination is bioequivalent to aspirin, atorvastatin (Cardyl), and ramipril (Acovil) administered concomitantly. Test and reference formulations were well tolerated by all participants. Clinical trial data assessing adherence improvement with Trinomia formulation

The Fixed-Dose Combination Drug for Secondary Cardiovascular Prevention (FOCUS) randomized controlled trial evaluated the effect of aspirin 100 mg + simvastatin 40 mg + ramipril 2.5, 5, 10 mg (trade name: Trinomia) compared with these three drugs given separately on adherence at 9 months among 695 participants were >40 years old with a prior history of myocardial infarction.(13) The combination of Morisky-Green Medication Adherence Questionnaire (MAQ) score=20 and pill counts between 80 and 110 was used to adherence to aspirin, statin, and blood pressure lowering drugs. Both groups received free medications throughout the study period to minimize performance bias. The study was conducted in Spain, Italy, Argentina, Brazil, and Paraguay from 2011 to 2014. At the end of 9 months, the proportion of adherent patients was 51% in the group randomized to Trinomia and 41% in the group randomized to the control arm. There was no evidence of any differences in systolic blood pressure, diastolic blood pressure, or lipids between the two groups. Bioequivalence for Polycap formulation The bioequivalence results of Polycap compared with its mono-components are shown below in Table 4.(24) In brief, 196 healthy male and female volunteers were enrolled into a five-arm, randomized, single-dose, two-period, two-treatment, two-sequence crossover study. Plasma drug levels were analyzed in liquid chromatography-tandem mass spectrometry, excluding aspirin, which was analyzed by ultra-performance liquid chromatography. The statistical analysis of the pharmacokinetic data obtained in this study shows that the Polycap fixed-dose combination is bioequivalent to aspirin, simvastatin (Zocor), atenolol (Tenormin), hydrochlorothiazide (Microzide), and ramipril (Altace) administered concomitantly, based on point estimates of the Test/Reference ratio of the geometric means falling within 80-125% for Cmax, AUC0-t, and AUC∞. Table 4. Pharmacokinetic parameters (mean ± standard deviation) of the different analytes as calculated from evaluable participants receiving either the test formulation (Polycap) or the individual reference preparations.(24)

Test name Cmax (ng/ml) AUC0-t (ng · h/mL) AUC∞ (ng · h/mL) Salicylic acid

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Test name Cmax (ng/ml) AUC0-t (ng · h/mL) AUC∞ (ng · h/mL) From Polycap 5041.2 ± 1688.8 27,191.2 ± 571.8 28,304.8 ± 11,335.2 From aspirin 6204.0 ± 1344.1 27,773.0 ± 7404.0 28,840.4 ± 8442.2 Ramipril From Polycap 19.2 ± 9.1 14.8 ± 6.0 15.6 ± 6.2 From Altace 16.1 ± 8.0 13.3 ± 5.3 14.1 ± 5.4 Simvastatin From Polycap 7.8 ± 4.5 25.7 ± 14.7 27.9 ± 15.2 From Zocor 10.4 ± 6.9 32.6 ± 18.9 36.8 ± 20.5 Atenolol From Polycap 390.8 ± 156.8 3206.3 ± 1318.9 3332.7 ± 1334.3 From Ternomin 418.4 ± 201.1 3374.5 ± 1706.5 3519.5 ± 1715.6 Hydrochlorothiazide From Polycap 102.0 ± 53.2 626.0 ± 263.4 664.8 ± 265.4 From Microzide 97.3 ± 33.6 668.8 ± 261.3 711.5 ± 257.9 Clinical trial data assessing risk factor changes with Polycap formulation

The Indian Polycap Study (TIPS-1, 2007-2008) trial was the first clinical exposition of the beneficial effect of the use of a fixed dose combination pill (aspirin 100 mg + simvastatin 20 mg + atenolol 50 mg + hydrochlorothiazide 12.5 mg + ramipril 5 mg; trade name: Polycap) for CVD prevention against individual or grouped available drug therapies. (25) The study was performed in 2,053 participants without prior CVD but with at least one abnormal cardiovascular risk factor randomized to one of nine arms. Statistical comparisons were performed referent to groups administered singular or combinational drug therapy with no equivalent active agent. Statistically significant reductions in systolic blood pressure (-7.4 mmHg), low-density lipoprotein (LDL) cholesterol (-27 mg/dl), total cholesterol (-30.1 mg/dl) and heart rate (-7.0 bpm; p<0.001 for all) were found among Polycap participants in comparison to applicable groups without the effective drug. The short-term trial did not assess mortality.

The TIPS-1 trial was followed by TIPS-2 (2012) to evaluate the added effect of a

potassium supplement on a once daily Polycap prescription.(26) The TIPS-2 study additionally sought to determine efficacy and tolerability of a “full dose” (two Polycaps) prescription versus the “half dose” used during the TIPS-1 study. Five hundred and eighteen (518) participants from 27 centers in India with a history of vascular disease or diabetes mellitus were randomized to a treatment arm of “full dose” Polycap plus 30 mEq/L potassium supplement versus “half dose”. Analysis was performed between groups to assess the added effect of potassium. The “full dose” Polycap demonstrated statistically significant, incremental reductions in total (-7.2 mg/dl) and LDL (-6.6 mg/dl) cholesterol and systolic (-2.8 mmHg) and diastolic (-1.7 mmHg) blood pressure compared with the “half dose” Polycap with similar tolerability (6.9% vs. 7.8% discontinuation in the “half dose” and “full dose” arms, respectively). Clinical trial data assessing adherence improvement with Red Heart Pill formulations

The aforementioned formulations of aspirin 75 mg + simvastatin 40 mg + atenolol 50 mg + lisinopril 10 mg (trade name: Red Heart Pill 1c) and aspirin 75 mg +

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simvastatin 40 mg + hydrochlorothiazide 12.5 mg + lisinopril 10 mg (trade name: Red Heart Pill 2c) have been studied among 3,140 participants with prevalent or high-risk for atherothrombotic cardiovascular disease in the Kanyini GAP,(14) IMPACT(15), and UMPIRE (16) trials. These trials recruited participants from diverse primary and secondary care settings, including in the United Kingdom, Ireland, the Netherlands, India, New Zealand, and Australia. The mean age was 62 years, and the majority of participants were men (75%) with prevalent CVD (76%). Median (IQR) follow-up was 15 month (12 to 21).

These trials are also part of the Single Pill to Advert Cardiovascular Events

(SPACE) collaboration for individual participant data meta-analyses,(27) and they demonstrate a robust, consistent improvement in adherence with fixed-dose combination compared with usual care, even when drug costs are covered for both groups (Figure 1).(28) Individuals with low baseline adherence had the greatest improvements in adherence from 17% at baseline to 74% at trial end (RR = 4.46 [95% CI: 3.72 to 5.36]) compared with participants who were already adherent at baseline (86% to 90%; RR = 1.04 [1.01 to 1.07]). Fixed-dose combination therapy also led to a greater reduction in systolic blood pressure (-2.5 mmHg [95% CI: -4.5 to -0.4]) and LDL cholesterol (-3.5 mg/dl [95% CI: -6.96 to 0.00]) than control. There no difference in mortality between individual randomized to fixed-dose combination therapy compared with control (25/1569 (1.6%) vs. 29/1571 (1.8%); RR 0.86 [0.51 to 1.47]) or in the combined endpoint of fatal and non-fatal cardiovascular disease events (92/1569 (5.9%) vs. 75/1571 (4.8%); RR 1.23 [0.91 to 1.65]).

Figure 1. Adherence to individual CVD preventive treatments by visit (A, B and C) and adherence to combination therapy (defined as statin, anti-platelet and ≥2 BP lowering medications) by varying adherence at baseline (D, E and F).(28)

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When available adherence data are pooled (Table 5), individuals with either previous cardiovascular disease or high-risk for cardiovascular disease who were randomized to fixed-dose combination therapy had a 44% (95% CI: 26% to 65%) higher rate of adherence, though heterogeneity is present (I2 = 79%). Using the GRADE methodology, the quality of the overall evidence supporting fixed-dose combination therapy to improve adherence is strong based on the consistency and precision of effect, low risk of bias (including reporting bias) among the included studies, and indirectness of evidence. The level of recommendation would be strong based on the quality of evidence, the balance between desirable and undesirable effects, values and preferences, and cost. Table 5. Differences in adherence between the intervention and control groups in fixed-dose combination therapy trials that report adherence.

Fixed-dose combination therapy Comparator

Study Events Total Events Total Weight Relative Risk

(95% CI) FOCUS 2014(13) 169 350 133 345 21.3% 1.25 (1.05, 1,49) IMPACT 2014(14) 208 256 119 257 23.8% 1.75 (1.52, 2.03) Kanyini GAP 2014(15) 213 311 143 312 23.9% 1.49 (1.30, 1.72) UMPIRE 2013(16) 829 1002 621 1002 31.0% 1.33 (1.26, 1.41) Overall 1419 1919 1016 1916 100% 1.44 (1.26, 1.65)

11. Summary of comparative evidence on safety Safety

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Adverse effects: In the FOCUS trial, there was no evidence of differences in adverse events,

serious adverse events, or discontinuation between individuals randomized to fixed-dose combination therapy of aspirin + simvastatin + ramipril (32%, 6%, and 4%) compared with those randomized to its individual components (35%, 7%, and 4%).(13) Overall adverse events were modestly higher in the group randomized to the fixed-dose combination of aspirin + simvastatin + ramipril compared with the control group randomized to the individual components (35% vs. 33%), and these are outlined in Table 6.

Table 6. Adverse events reported in the FOCUS trial.(13)

Adverse Events FDC, N (%) Control, N (%) Any adverse event 124 (35.4) 112 (32.5) Any serious adverse event 21 (6.0) 23 (6.6) Interrupting treatment because of adverse event 14 (4.0) 13 (3.7) Death1 1 (0.3) 1 (0.3) Re-infarction 2 (0.6) 2 (0.6) Hospitalization 21 (6.0) 23 (6.7) Hematological adverse event 5 (1.4) 6 (1.7) Other cardiac adverse event 10 (2.8) 4 (1.1) Musculoskeletal adverse event 5 (1.4) 10 (3.8) Cough 5 (1.4) 6 (1.7) Dizziness 2 (0.6) 2 (0.6) Hypotension 0 (0.0) 7 (0.2)

1Control (cancer); Trinomia (road traffic accident); FDC=fixed-dose combination

Further, Table 7 demonstrates the rates of adverse events in the TIPS trial among the nine arms of the trial.(25) Table 7. Adverse events reported in the TIPS trial.(25) Treatment Group

Adverse Events P

(n = 412) As

(n=205) T

(n=205) T+R

(n=209) T+At (n=207)

R+At (n=205)

T+R+At (n=204)

T+R+At+As (n=204)

S (n=202)

Dizziness or hypotension 6.3% 4.9% 3.9% 1.9% 2.9% 5.4% 5.4% 5.4% 2.5% Cough 5.3% 1.5% 3.4% 7.2% 0.5% 3.9% 3.9% 5.9% 1.0% Gastritis/dyspepsia 1.2% 2.0% 2.0% 3.3% 1.0% 2.9% 2.5% 1.0% 2.5% Fatigue 1.7% 1.0% 2.0% 1.4% 1.9% 2.0% 3.4% 0.5% 2.0% Bradycardia 0.2% 0% 0% 0% 1.0% 0% 0.5% 0.5% 0% Creatinine increase by >50%

8.5% 9.3% 6.8% 7.7% 9.7% 7.3% 7.4% 10.3% 7.9%

Potassium >5.5 mmol/L 4.4% 5.9% 4.4% 5.3% 4.8% 5.9% 7.4% 6.9% 3.5% SGPT Doubled 2.9% 4.4% 3.4% 6.7% 4.8% 2.9% 0.5% 2.9% 5.0% A = Aspirin, T = Thiazide, R = Ramipril, At = Atenolol, S = Simvastatin, P = Polycap

Adverse event reporting in other secondary prevention trials have been similar to the FOCUS results. For example, there was no difference in serious adverse events in

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each of the Kanyini GAP,(14) IMPACT,(15) and UMPIRE(16) trials.(Table 8) Of note, none of these studies was designed nor powered to demonstrate a difference in CVD events of mortality. Table 8. Individual participant data summary of adverse events reported in the Kanyini GAP,(14) IMPACT,(15) and UMPIRE(16) trials.(28)

Serious Adverse Events FDC, N (%)

Usual care, N (%)

Any cause* 360 (23) 316 (20) Renal and urinary disorders 106 (6.8) 83 (5.3) Cardiac disorders 87 (5.5) 74 (4.7) Infections and infestations 75 (4.8) 62 (4.0) Gastrointestinal disorders 35 (2.2) 31 (2.0) Neoplasms benign, malignant and unspecified (incl cysts and polyps) 34 (2.2) 31 (2.0) Nervous system disorders 32 (2.0) 21 (1.3) Vascular disorders** 35 (2.2) 17 (1.0) Injury, poisoning and procedural complications 29 (1.9) 22 (1.4) Musculoskeletal and connective tissue disorders 26 (1.7) 25 (1.6) Investigations 20 (1.3) 17 (1.1) General disorders and administration site conditions 16 (1.0) 16 (1.0) Respiratory, thoracic and mediastinal disorders 15 (1.0) 14 (0.9) Metabolism and nutrition disorders 15 (1.0) 9 (0.6) Reproductive system and breast disorders** 6 (0.4) 17 (1.1) Hepatobiliary disorders 8 (0.5) 4 (0.3) Eye disorders 7 (0.5) 1 (0.1) Skin and subcutaneous tissue disorders 3 (0.2) 4 (0.3) Surgical and medical procedures 4 (0.3) 2 (0.1) Blood and lymphatic system disorders 5 (0.3) 0 (0.0) Psychiatric disorders 1 (0.1) 4 (0.3) Endocrine disorders 3 (0.2) 1 (0.1) Immune system disorders 1 (0.1) 1 (0.1) Congenital, familial and genetic disorders 0 (0.0) 1 (0.1) Ear and labyrinth disorders 1 (0.1) 0 (0.0) Social circumstances 0 (0.1) 1 (0.1)

*p=0.07; **p < 0.05; FDC=fixed-dose combination

Contraindications:

Contraindications of fixed-dose combination therapy are as for the individual components. 12. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group Cost effectiveness of multidrug therapy

A 2007 analysis by Lim and colleagues evaluated the use of a fixed dose combination therapy for individuals at high risk for CVD in 23 low- and middle-income countries. These authors estimated that use of multidrug therapy including aspirin, statin, and blood pressure lowering drugs would lead to the prevention of 17.9 million deaths from cardiovascular disease (95% uncertainty interval 7.4 million – 25.7 million) over 10 years, with more than half (56%) occurring in individuals less than 70 years.

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The cost would be US$4.7 billion per year ($3.3 billion – $6.1 billion) or $1.08 ($0.75 – $1.40) per person per year, ranging from $0.43 to $0.90 in low-income countries and from $0.54 to $2.93 in middle-income countries.(29) Cost effectiveness analyses by Gaziano et al. have estimated incremental cost effectiveness ratios (ICERs) for secondary CVD prevention of fixed dose combination therapy ranging from $306 per quality adjusted life year (QALY) to $388 per QALY gained.(30) Range of costs of the proposed formulations

The price of aspirin + simvastatin + ramipril and aspirin + atorvastatin + ramipril (trade name: Trinomia for both) has been and will continue to be implemented on a per country basis. The objective of Trinomia is to be cost-effective and therefore depending on the specific country environment, different prices would be adopted. Depending on the dose of ramipril and on the country where the product is already available, Trinomia retail market prices are at present in the range of 13 – 24€ per month (USD $16.24 – $29.98 per month, or USD $0.54 to $1 per day).(23)

In the present market conditions, in Guatemala, Nicaragua, Dominican Republic, Honduras, El Salvador, the market price of the fixed-dose combination of aspirin + simvastatin + ramipril (trade name: Trinomia) is below the sum of the three corresponding generics in those markets. Supplier and buyer cost estimates of individual components come from varying sources with high/low ratios that can exceed 50-fold, which can make it difficult to ascribe a single price to the various comparator components (Table 9). On the other hand, the cost-effectiveness model described below demonstrates that the increase of adherence provided by aspirin + atorvastatin + ramipril (trade name: Trinomia), in some cases even at higher prices that the sum of the generics depending on the market, provides reduction of CVD events with health system savings both in the long and middle terms. Table 9. Supplier and buyer costs (USD$) of the individual components reported by the 2013 International Drug Price Indicator Guide.(31)

Drug Dose

Supplier Median Price per Tablet1

High/Low Ratio

Buyer Median Price per Tablet1

High/Low Ratio

Aspirin 100 mg 0.0028 (5) 2.42 0.0049 (3) 3.06 Simvastatin 20 mg 0.0235 (2) 1.23 0.023 (5) 2.52 Simvastatin 40 mg Not reported -- 0.03 (1) -- Atorvastatin 20 mg 0.1612 (3) 6.48 0.0424 (5) 5.22 Atorvastatin 40 mg Not reported -- 0.1186 (3) 50.67 Atenolol 50 mg 0.0118 (10) 14.29 0.0066 (7) 17.98 Hydrochlorothiazide 12.5 mg Not reported -- 0.0105 (1) -- Ramipril Any dose Not reported -- Not reported -- Enalapril 10 mg 0.0269 (2) 1.75 0.0106 (5) 9.36 1Number of sources reporting data in parentheses.

As an alternative example to demonstrate that the pricing for Trinomia is not excessively low, the combination of aspirin + simvastatin + atenolol + hydrochlorothiazide + lisinopril (trade name: Polycap) is marketed at a retail cost of INR

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16 (USD $0.26) per day in India. Cadila Pharmaceutical, Ltd. has expressed a willingness to provide Polycap at half this cost to large purchasers (e.g., governments and insurance companies). A daily cost of USD $0.13 per day or USD $3.90 per month (wholesale price USD $7.80 per month) for Polycap is likely cost effective and will likely make fixed-dose combination affordable by a large segment of the population in low- and middle-income countries. Cost effectiveness analysis of fixed-dose combination of aspirin + atorvastatin + ramipril

A recent cost-effectiveness analysis from a UK payer perspective over a lifetime horizon (30 years) comparing the fixed-dose combination of aspirin 100 mg + atorvastatin 20 mg + ramipril 2.5 mg, 5 mg, or 10 mg (trade name: Trinomia) with its mono-components for secondary prevention in patients ≥40 years of age with a recent or non-recent (within the last 2 years) diagnosis of acute myocardial infarction was undertaken.(23)

A Markov model was developed to determine the public health outcomes presented as CV events prevented per 1,000 patients, and the costs and effectiveness in terms of life years (LYs) and quality adjusted life years (QALYs) gained with the fixed-dose combination of aspirin 100 mg + atorvastatin 20 mg + ramipril 2.5 mg, 5 mg, or 10 mg (trade name: Trinomia) compared with the same components in multiple monotherapy for secondary prevention.(23) Costs were expressed in British pounds for 2014. Different price scenarios for this fixed-dose combination over parity of its mono-components (total cost of £4.32 per month) were analyzed; +50%, +100% and +150%. The model was accounted for long-term adherence, with 86% of patients, being adherent to aspirin, statin, and ACE-inhibitor, while 14% were not adherent to any of the three drugs. This compared to 65% in the mono-components arm who were adherent to all three drugs while 35% were not adherent to any of the three drugs. A discount rate of 3.5% was applied to costs and benefits. One-way deterministic sensitivity analyses and probabilistic sensitivity analyses were conducted to identify the main drivers and uncertainty of the parameters.

It is predicted that in total 352 and 409 fatal and non-fatal CV events will occur per 1,000 patients in the fixed-dose combination of aspirin 100 mg + atorvastatin 20 mg + ramipril 2.5 mg, 5 mg, or 10 mg (trade name: Trinomia) versus the multiple mono-components arms, respectively, meaning a total of 57 additional fatal and non-fatal CV events can be prevented over a lifetime period by using fixed-dose combination of aspirin + atorvastatin + ramipril in place of its mono-components as multiple monotherapy (Table 10).

Table 10. Undiscounted public health outcomes of the fixed-dose combination of aspirin + atorvastatin + ramipril compared with its mono-components for a population size of 1,000 patients over a lifetime horizon.(23)

CV disease events Fixed-dose combination Mono-components Difference

ACS events 78 96 -18

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Revascularization (unplanned/unrelated to other CV events) 130 148 -18

Congestive heart failure with hospitalisation 41 43 -2 Stroke 30 37 -7 CV death 73 86 -13 Total fatal and non-fatal CV events 352 409 -57*

*Differences in total compared with sum is due to rounding; CV = cardiovascular; ACS = acute coronary syndrome.

Based on the model, over ten years it is estimated that for each 10% increase in adherence, additional 6.7% fatal and non-fatal CV events can be prevented. The potential of this result for the eligible UK population is striking: 3,260 CV events and 590 cardiovascular deaths could be prevented or postponed. These outcomes are based on a modified version of our model that assumes the prevalence of myocardial infarction survivors aged 25 years and older is 1.4%, inferred from data from the British Heart Foundation (32), an incidence of myocardial infarction of 0.112% (33) from a UK population of 45,271,000 in this age group (34), and that 10% of eligible patients switch from monotherapy to the fixed-dose combination will achieve a 20% improvement in adherence. If uptake of the fixed-dose combination is more than 10% in those eligible or patients at high risk of a first myocardial also receive the fixed-dose combination, the potential public health benefit may be even greater.

The total discounted lifetime incremental LYs gained in the fixed-dose combination of aspirin + atorvastatin + ramipril arm compared to mono-components arm was 57.30 per 1,000 patients whereas the total incremental QALYs gained were 53.77. The corresponding incremental cost effectiveness ratio of the fixed-dose combination of aspirin + atorvastatin + ramipril versus multiple monotherapy showed the fixed-dose combination of aspirin + atorvastatin + ramipril to be dominant at a cost of 50% over parity of its mono-components, £2,219 per QALY gained at 100% over parity, and £9,730 per QALY gained at 150% over parity. Table 11. Costs and effectiveness of fixed-dose combination of aspirin + atorvastatin + ramipril (trade name: Trinomia) versus its mono-components for a population size of 1,000 patients over a lifetime horizon for different price scenarios.(23) Trinomia price/month £6.47 £8.63 £12.95 (% over parity) (50%) (100%) (150%) Incremental LY 57.30 57.30 57.30 Incremental QALY 53.77 53.77 53.77 Incremental costs £82,602 £119,331 £523,198 Incremental cost per LY gained Dominant £2,082 £9,130 Incremental cost per QALY gained Dominant £2,219 £9,730 Abbreviations: LY = Life Years; QALY = Quality Adjusted Life Years.

However, these estimates reflect incremental cost effectiveness within a population that has high adherence rates at baseline and thus represents a potential substitution of individual components with fixed-dose combination, rather than a step-up to increase the number of components that individuals with prevalent CVD would be

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taking. Based on this latter scenario, the cost-effectiveness estimates by Lim(29) and Gaziano(30) may more applicable to individuals in low- and middle-income countries, where baseline adherence rates are very low and even to individuals in high-income countries where long-term adherence rates remain suboptimal.(9) Further, prices could be expected to reduce over time as additional fixed-dose combination formulations become available. 13. Summary of regulatory status of the medicine (in various countries)

A list of countries where each formulation has received regulatory approval and where each formulation is under review is included in Table 12.

Table 12. List of countries where each fixed-dose combination has received regulatory approval. Regulatory approval received

Aspirin + simvastatin + ramipril (Trinomia)

Guatemala, Nicaragua, Dominican Republic, Honduras, El Salvador, México, Argentina1

Aspirin + atorvastatin + ramipril (Trinomia)

Spain, Sweden, Romania, Greece and Portugal1

Austria, Belgium, Bulgaria, Czech Republic, Finland, France, Germany, Italy, Poland and

Ireland2 Aspirin + simvastatin + atenolol + hydrochlorothiazide + ramipril (Polycap) India, Zambia1 1Marketing Authorization Certificates available. 2Marketing Authorization Certificates pending to be issued. 14. Availability of pharmacopoeial standards Each of the drug substances has a monograph in both the European and United States Pharmacopeias. 15. Proposed (new) text that could be included in a revised WHO Model Formulary We recommend the following text: Uses: For patients who have indications for long-term treatment with aspirin, statin, and blood pressure lowering drugs. An alternative that is analogous to fixed-dose combinations for patients with HIV/AIDS would be, “Patients with atherothrombotic cardiovascular disease, such as previous myocardial infarction or ischemic stroke, as a complete regimen or in combination with other medicines.” NB we do not recommend a “substitution” indication here, in which patients are required to be already taking the same medicines separately, since a key target group for this medicine is those who are currently under- or untreated. Precautions: see under aspirin, simvastatin, bisoprolol, hydrochlorothiazide, and

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enalapril. Dose: We propose one or more of the following formulations: Aspirin 100 mg + simvastatin 40 mg + ramipril 2.5 mg, 5 mg, or 10 mg Aspirin 100 mg + atorvastatin 20 mg + ramipril 2.5 mg, 5 mg, or 10 mg Aspirin 100 mg + simvastatin 20 mg + ramipril 5 mg + atenolol 50 mg + hydrochlorothiazide 12.5 mg Adverse effects: see under aspirin, simvastatin, enalapril, bisoprolol, and hydrochlorothiazide.

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