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national agendas on universal prevention and treatment the availability and affordability of these drugs. It is See Articles page e1346 and
e1359
packages and financial protection.1,2 Universal coverage a shining example of international coordination and
of prevention and treatment of chronic diseases is a collaboration. Addition to the list enables more than
relevant topic in view of rising non-communicable 1 billion people with high blood pressure worldwide to
disease epidemics in the world’s ageing populations.3–8 regularly take medication that can prevent strokes and
In addition, there is increasing recognition of the late myocardial infarctions, and thereby reduce the risk of
chronic consequences of major infections, exemplified disability in middle age and premature death.15
by post-tuberculosis lung damage, metabolic conse Inevitably, the economic study by Lung and colleagues9
quences in HIV, neuropathologies from meningitis is based on limited empirical observations as patients
and malaria, and chronic morbidity from neglected were followed up for only 2 years and the differences in
tropical diseases such as lymphatic filariasis. These blood pressure between the triple-pill and usual care
trends demand a shift towards the development and groups showed a plateau after 6 weeks in the TRIUMPH
stepped-up provision of new and integrated models of trial. The TRIUMPH trial cannot be considered as a pure
care for chronic conditions, especially in low-income efficacy trial. In real-life settings, one can expect short-
and middle-income settings.7 Positive evidence for term compliance and Hawthorne effects, whereas in the
fixed-dose combinations is accumulating, along with long-term economic evaluation changes in long-term
affordable strategies to improve access to, and use of, behaviour and compliance are important.9 In addition,
effective medical prevention and treatment, especially in non-linearity of the risk functions, depending on absolute
chronic conditions.4–6,9–13 Fixed-dose combinations have blood pressure levels, age, and selective survival effects
important advantages for patients and health systems, might result in huge differences in outcomes between
including simpler dose schedules, decreased pill burden, subpopulations.
reduced stockouts, and easier task sharing, training, Lin and colleagues10 take fixed-dose combinations
and supervision compared with single-pill strategies, one step further and show the potential health effects
resulting in promotion of large-scale access, acceptance, and cost reductions of the large-scale introduction of
and production, such as recommended by Thomas fixed-dose combinations including aspirin, lisinopril,
Lung and colleagues9 and John Lin and colleagues10 in atenolol, and simvastatin to address multiple risk
The Lancet Global Health. factors. Their careful and well documented model-
Lung and colleagues9 report both health and based economic analyses attempt to assess the options
economic benefits of a fixed-dose combination for secondary cardiovascular disease risk prevention
triple pill, comprising amlodipine, telmisartan, and in large country populations across the world. They
chlorthalidone, in the treatment of high blood pressure recommend a large-scale introduction of this polypill
in an economic analysis of the Triple Pill versus Usual for secondary prevention as the study shows that
Care Management for Patients with Mild-to-Moderate among adults aged 30–84 years with established
Hypertension (TRIUMPH) trial.14 This triple-pill strategy atherosclerotic cardiovascular disease, compared
has been proven to improve patients’ adherence to with current care, it would avert 40–54 major adverse
medication regimens and blood pressure control rates cardiovascular events for every 1000 patients treated
compared with usual care in Sri Lanka, and Lung and for 5 years, with an incremental cost-effectiveness ratio
colleagues show that this strategy reduced health-care compared with current care on the basis of public sector
costs and improved outcomes in terms of life-years prices over a lifetime analytical horizon of Int$168
gained and disability prevented. (95% uncertainty interval 55 to 337) per disability-
Consequently, in an unusually rapid reaction, WHO, adjusted life-year averted in China, $154 (57 to 289) in
with the support of relevant societal and professional India, $88 (15 to 193) in Mexico, $364 (147 to 692) in
Nigeria, and $64 (cost-saving to 203) in South Africa cost-offsets from preventing secondary events will
(0·4–6·2% of the per capita gross domestic product be low in many resource-limited settings. Hopefully,
in these countries). These estimates are three to four in the near future, monitoring the implementation
times higher in case of retail market prices. of up-scaling efforts will teach us about the real-life
There is one caveat: aspirin in primary cardiovascular effectiveness of these fixed-dose combinations.
disease prevention was recently shown to be Findings from economic evaluations—cost-
ineffective.16 Secondary prevention in polypill trials effectiveness estimates—often stimulate debates on
showed improvements in proxy outcomes, but what cost-effectiveness threshold is economically
not in mortality outcomes, possibly because of an attractive. The WHO-CHOICE programme has modified
insufficient sample size or follow-up duration. Primary its position substantially after the Second Panel on Cost-
and secondary cardiovascular disease prevention had Effectiveness.17 The Panel concluded that there is no
been assessed as early as 2003, including the potential absolute cost-effectiveness threshold and that individual
benefits of polypill combinations.8 countries should define their own approach.18 The UK,
Other treatment combinations are already in use in through the threshold of £20 000–30 000 per healthy-
the treatment of chronic conditions, including lung year gained set by the UK National Institute for Health
health,3,4,6 diabetes,5 HIV, and tuberculosis.7,11 In lung and Care Excellence, is the only country that applies
health, there is the question of whether a simple strategy an absolute standard in decision making on package
of using a combined corticosteroid–rapid-onset long- formulations. The best approach globally is to respect
acting β2 agonist inhaler as required or, if clinically national governmental decision making that can take
indicated, both as required, and regularly, reduces into account country standards, the overall situation in
asthma exacerbations in children and adults in low- the country, and the particulars of the health system.17–20
income and middle-income settings, with a possible However, one would like to see an earlier involvement of
potential role in the management of post-tuberculosis funding bodies, both internationally and nationally.
chronic lung disease.4,6 Real-life policy making in low-income settings is
Rigorous epidemiological and economic evaluation of complex and will increase in complexity as more options
fixed-dose combinations is complex: monotherapeutic become available to deal with the health burden of
strategies, in many cases, are the norm and widely chronic conditions. Although cost-effective, the overall
accepted in health guidelines and in clinical practice. national budget impacts, especially in the larger countries,
Both insufficient effectiveness information and ethical of most new intervention packages can nevertheless be
boundaries in the identification of control groups make huge, as the number of people with chronic conditions
the use of mathematical modelling unavoidable.17,18 is ever increasing. Assuming concurrent retail market
In a state-of-the-art approach, Lin and colleagues10 pharmaceutical prices, these budgets might be at 10% of
used estimates from the Prospective Urban Rural the per capita gross domestic product. Would ministries
Epidemiology (PURE) study, including compliance, as a of health and finance or national cabinets prefer to use
control. They used the proxy outcomes of a single trial this money in a different way in health or otherwise?
in a low-income and middle-income country and the Inevitably, the ongoing equity debates in allocation of
aggregated compliance data from two trials in high- country resources have been part of national decision
income countries, calibrated against recent burden making for decades, especially in the case of low-income
of disease estimates. They optimistically include the and middle-income countries. It is striking that the UN
health effects of the four individual drugs on secondary Sustainable Development Goals’ leading themes are the
event prevention among post-first-event patients. inequalities between population subgroups, including
These combined, multiplicative, indeed proxy effects gender, the poor, the disabled, and minorities but also
of their polypill are simulated in scenarios to estimate the huge inequalities between countries. These equity
the potential population benefits. It is realistic to weigh questions have not been clearly addressed in the two
the benefits against both the health-care cost based studies, or in most other recent evaluations. Certainly,
on international generic pricing versus existing local from now on, progressive realisation—ie, the promotion
commercial pricing. However, the assumed potential of equity in universal access and coverage—will be higher
on the agenda, given proven effectiveness and efficiency 6 Beasley R, Fingleton J, Weatherall M. Restriction of LABA use to combination
ICS/LABA inhaler therapy in asthma. Thorax 2013; 68: 119–20.
of new interventions and strategies.1,2,19–21 7 Garrib A, Birungi J, Lesikari S, et al. Integrated care for human
To promote acceptance, funding, and access, existing immunodeficiency virus, diabetes and hypertension in Africa.
Trans R Soc Trop Med Hyg 2018; published online Sept 28. DOI:10.1093/
recommendations in relation to the upcoming high- trstmh/try098.
level UN meeting should be kept in mind: they focus on 8 Niessen LW, Mohan D, Akuoku JK, et al. Tackling socioeconomic inequalities
and non-communicable diseases in low-income and middle-income
political leadership beyond health, to exclude no one, countries under the Sustainable Development agenda. Lancet 2018;
391: 2036–46.
to regulate and legislate, internationally and nationally 9 Lung T, Jan S, de Silva HA, et al. Fixed-combination, low-dose, triple-pill
the upcoming universal health coverage efforts, antihypertensive medication versus usual care in patients with
mild-to-moderate hypertension in Sri Lanka: a within-trial and modelled
while upholding quality of care.1 Universal coverage economic evaluation of the TRIUMPH trial. Lancet Glob Health 2019; published
online Aug 30. http://dx.doi.org/10.1016/S2214-109X(19)30343-2.
of prevention and treatment of chronic conditions
10 Lin JK, Moran AE, Bibbins-Domingo K, et al. Cost-effectiveness of a
will have to be a substantial part of this international fixed-dose combination pill for secondary prevention of cardiovascular
disease in China, India, Mexico, Nigeria, and South Africa: a modelling
collaborative process, to reduce inequalities in financing study. Lancet Glob Health 2019; published online Aug 30.
of, access to, and use of treatments, between countries http://dx.doi.org/10.1016/S2214-109X(19)30339-0.
11 Hwang TJ, Keshavjee S. Global financing and long-term technical assistance
and within countries.19–21 for multidrug-resistant tuberculosis: scaling up access to treatment.
PLoS Med 2014; 11: e1001738.
12 Murray CJ, Lauer JA, Hutubessy RC, et al. Effectiveness and costs of
*Louis W Niessen, S Bertel Squire interventions to lower systolic blood pressure and cholesterol: a global and
Faculty of International Public Health and Clinical Sciences, regional analysis on reduction of cardiovascular-disease risk. Lancet 2003;
361: 717–25.
Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK (LWN,
13 Gallardo CR, Rigau Comas D, Valderrama Rodríguez A, et al. Fixed-dose
SBS); Department of International Health, Johns Hopkins combinations of drugs versus single-drug formulations for treating
Bloomberg School of Public Health, Baltimore, MD, USA (LWN) pulmonary tuberculosis. Cochrane Database Syst Rev 2016; 5: CD009913.
louis.niessen@lstmed.ac.uk 14 Webster R, Salam A, de Silva HA, et al. Fixed low-dose triple combination
antihypertensive medication vs usual care for blood pressure control in
We declare no competing interests. We are supported by the UK National patients with mild to moderate hypertension in Sri Lanka: a randomized
Institute for Health Research (NIHR) Foundation project grant 16/136/35 for clinical trial. JAMA 2018; 320: 566–79.
NIHR Global Health Research Unit ‘IMPALA’ (LWN, SBS) and grant 16/137/87 on 15 WHO. Fixed-dose combination antihypertensives. https://www.who.int/
HIV- NCDs (LWN), using Official Development Assistance funding. The views selection_medicines/committees/expert/22/fixed-dose_combination_
expressed are not necessarily those of the UK National Health Service, the NIHR, antihypertensives/en/ (accessed Aug 18, 2019).
or the UK Department of Health. 16 McNeil JJ, Woods RL, Nelson MR, et al. Effect of aspirin on disability-free
survival in the healthy elderly. N Engl J Med 2018; 379: 1499–508.
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open 17 Bertram MY, Lauer JA, De Joncheere K, et al. Cost-effectiveness thresholds:
Access article under the CC BY 4.0 license. pros and cons. Bull World Health Organ 2016; 94: 925–30.
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