Expert Review of Pharmacoeconomics & Outcomes

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Cost-effectiveness analysis of antihypertensive

triple combination therapy among patients
enrolled in a Medicare advantage plan

Xin Wang , Hua Chen , Essien EJ , Jun Wu , Omar Serna , Rutugandha

Paranjpe & Susan Abughosh

To cite this article: Xin Wang , Hua Chen , Essien EJ , Jun Wu , Omar Serna , Rutugandha
Paranjpe & Susan Abughosh (2020): Cost-effectiveness analysis of antihypertensive triple
combination therapy among patients enrolled in a Medicare advantage plan, Expert Review of
Pharmacoeconomics & Outcomes Research, DOI: 10.1080/14737167.2020.1800457

To link to this article: https://doi.org/10.1080/14737167.2020.1800457

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EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH
https://doi.org/10.1080/14737167.2020.1800457

ORIGINAL RESEARCH

Cost-effectiveness analysis of antihypertensive triple combination therapy among

patients enrolled in a Medicare advantage plan
Xin Wanga, Hua Chena, Essien EJa, Jun Wub, Omar Sernac, Rutugandha Paranjpea and Susan Abughosha
a
Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, Houston, TX, USA; bDepartment of
Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, Clinton, SC, USA; cCareAllies, Houston, TX, USA

ABSTRACT ARTICLE HISTORY

Objective: To assess the cost-effectiveness of single pill fixed dose triple combination therapy vs. free Received 18 February 2020
triple combination therapy for the prevention of cardiovascular events among patients with Accepted 21 July 2020
hypertension. KEYWORDS
Methods: A Markov model with a five year cycle was constructed. Two decision models incorporating Combination
strict and more relaxed adherence definitions estimated quality adjusted life years (QALYs) and health- antihypertensive; single pill;
care costs for single pill fixed triple combination therapy vs. free-drug combination therapy. free drug; adherence;
Results: When the strict adherence measurement criteria were applied, the total QALYs loss and cost/ cost-effectiveness
patient were 6.38 QALYs, $486,026.20 for the single pill triple combination therapy and 8.64 QALYs,
$406,405.26 for the free combination therapy. ICER for single pill combination therapy compared to free
combination therapy was 33,826.46/QALY. When the relaxed adherence measurement criteria were
applied, the total QALYs loss and cost/patient were 8.09 QALYs, $493,404.26 for the single pill triple
combination therapy and 8.76 QALYs, $436,415.14 for the free combination therapy. ICER for single pill
combination compared with free combination therapy was 84,932.26.
Conclusion: This study suggested that single pill triple combination therapy was cost-effective in
comparison with free combination therapy under a willingness to pay threshold of 50,000 when the
strict adherence measurement criteria was applied.

1. Introduction Three single pill triple-combination, FDA approved thera­

pies available in the market for treatment of hypertension
Hypertension is a medical condition in which the blood
include: Exforge HCT®, Tribenzor®, and Amturnide®.
pressure is persistently elevated in the arteries [1].
A comparison of single-pill, fixed-dose combination (FDC)
Guidelines from the American College of Cardiology/
dual therapies versus free-drug therapies revealed enhanced
American Heart Association (ACC/AHA) suggest combination
adherence, improved clinical outcomes, and lowered total
antihypertensive drug therapy as first-line treatment for
medical costs associated with FDC [9,10].
patients with stage 2 hypertension [2,3] as well as for
Medication adherence, a real-world problem defined as
patients with comorbidities such as diabetes, heart failure,
‘whether patients have taken the medication as prescribed’
and chronic kidney disease [4]. Studies have reported
has become a major concern for various health-care stake­
improved blood pressure and tolerability with the use of
holders [11]. Non-adherence to anti-hypertensives is quite
combination therapy in the treatment of hypertension [5].
common ranging from 3%-65% [12–14]. A prior study compar­
For example, combination of an angiotensin-converting
ing adherence among single pill triple combination therapy
enzyme [ACE] inhibitor and thiazide diuretic allowed syner­
users, free triple combination therapy users, and fixed dose
gistic lowering of blood pressure [5]. Single pill fixed dose
dual combination therapy plus a third agent revealed that
combination of perindopril and indapamide was associated
different adherence definitions resulted in variations in adher­
with a reduced risk of major macrovascular or microvascular
ence measures among each treatment group [15].
events and cardiovascular mortality [6]. Additional benefits of
Although many antihypertensive regimens are available as
combination therapy include lower dosage, reduced side
generic formulations in the US market, most of the fixed dose
effects, and improved adherence [5,7]. Current data (includ­
combination regimens (FDC) are only available as brand-name
ing data from the Antihypertensive and Lipid-Lowering
drugs. For example, only one of the single pill triple combina­
Treatment to Prevent Heart Attack Trial [ALLHAT]) revealed
tion therapy (Exforge HCT) is available as a generic since 2014.
that at least 25% of patients with hypertension require
Combinations that are only available as brand names and not
a triple-combination therapy combining antihypertensive
as generic are often more expensive and may potentially lead
drugs from three different classes to reach currently recom­
to higher copays which may further have a negative effect on
mended blood pressure levels [8].
medication adherence [16,17]. Observational studies have

CONTACT Susan Abughosh smabughosh@uh.edu Department of Pharmaceutical, Health Outcomes and Policy, University of Houston, College of
Pharmacy, Houston, TX 77204-5047, USA
© 2020 Informa UK Limited, trading as Taylor & Francis Group
2 X. WANG ET AL.

demonstrated an increase in pharmacy costs on switching to

a fixed dose combination therapy [18–20].
Mixed results were reported in assessing drug costs
between fixed-dose and free-drug combination antihyperten­
sive regimens, potentially due to heterogeneity in study
designs, patient populations, and drugs being evaluated
[18,21]. For example, previous studies have reported lower
drug costs for single pill fixed-dose combination therapy com­
pared to free-drug combination therapy [9,22–24]. However,
other studies have reported significantly higher costs for sin­
gle pill fixed dose combination therapy compared to free-drug
combination therapy [10,19].
With respect to the economic evaluation of anti-
hypertensive combination therapy, previous literature has
reported that loose dose dual combination therapy was
more cost-effective than monotherapy [25] while single pill
triple combination therapy was more cost-effective than dual Figure 1. Decision analytical model.
therapy [26]. However, the comparison of single pill triple
combination therapy versus free triple combination therapy
is still lacking [26]. as detailed in a previous study [15]. For the strict definition,
Most of the economic evaluations to assess cost- adherence was measured as the total number of days when all
effectiveness are based on efficacy studies. However, the three drug classes were available divided by the total number
results may vary when real-world effectiveness incorporating of days during the follow up period (Model 1) and for the
medication adherence is considered, further resulting in dif­ relaxed definition, adherence was measured as the total num­
ferent decisions on resource allocation [27]. Assessing the ber of days when at least one drug class was available divided
potential economic impact of anti-hypertensive combination by the total number of days during the follow up period
therapies by incorporating adherence is of vital importance to (Model 2) [30,31]. The Markov model of disease progression
payers, policy makers and clinicians. Thus, the objective of the is illustrated in Figure 2 and the economic analysis was con­
current study was to assess the cost-effectiveness of single pill ducted using Microsoft Excel 2013.
fixed dose triple combination therapy vs. free triple combina­
tion therapy for the prevention of cardiovascular events
2.2. Costs calculation
among hypertensive patients incorporating medication adher­
ence into the decision analytical model. This study was conducted from the payer’s perspective by
using the amounts paid by insurance plans to estimate direct

2. Methods
2.1. Study design
This study was a cost-effectiveness analysis (CEA) with
a lifetime horizon which compared single pill fixed dose triple
combination therapy vs. free triple combination therapy for
the prevention of cardiovascular events among hypertensive
patients. Components of free triple combination therapy are
given elsewhere [28]. The study population comprised of
elderly hypertensive patients aged65 or more enrolled in
a Texas Medicare Advantage Plan between January 2014 and
December 2016. The descriptive characteristics of the patients
are given elsewhere [15]. Two decision analytic models with
a Markov structure of five years cycle were constructed that
simulated the progression from hypertension to related cardi­
ovascular events until death by incorporating medication
adherence in each treatment arm using two different adher­
ence definitions (Figure 1). The 5-year cycle was selected
under the assumption that cardiovascular events might not
develop immediately but may develop within 5 years. The
model included transition probabilities between different dis­
ease states and this structure has been validated in a prior
study [29]. Medication adherence to each treatment strategy
was measured using a strict definition and a relaxed definition Figure 2. Markov model structure.
 EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH 3

health-care costs, including drug costs, hospitalization related analysis using two different definitions [15]. The probability
costs, and out-patient visits costs. The direct medical costs of developing hypertension-related cardiovascular events was
were obtained from published literature and various websites obtained by using the Framingham risk equations which incor­
[32–34]. The costs for each combination therapy treatment porate post-treatment blood pressure and other parameters to
and cardiovascular related hospitalizations are presented in calculate the risk of developing cardiovascular disease [39].
Table 1. Further, for single pill triple combination therapy a blood
pressure reduction to 120 mm Hg and for free triple pill
combination therapy a blood pressure reduction to 160 mm
2.3. Health utilities Hg was used to calculate hypertension-related cardiovascular
Health utility scores are used to measure health-related quality of event probabilities [26]. The transition probabilities are listed
life, with optimal health assigned a value of 1.0 and worst health in Table 3. Since medication adherence affects treatment out­
(death) assigned a value of 0.0. In economic analyses, the quality comes and risk of complications, adherence-adjusted risk of
adjustment weight for each health state is multiplied by the time in cardiovascular events was modeled by assuming that adher­
the state and then summed to calculate the number of Quality ent patients will achieve full treatment benefit, while non-
Adjusted Life Years (QALYs) [35]. Health utility values for each adherent patients will achieve partial treatment benefit, and
disease state were obtained from cost-effectiveness registry data­ thus lead to a higher risk of complications. Due to lack of
base [36]. The utility values are presented in Table 2. empirical data, the risk of developing cardiovascular events for
adherent patients was assumed to be 60% of non-adherent
patients. The adherence-adjusted risk of developing cardiovas­
2.4. Base-case analysis cular events was then incorporated in the model [40–44].
Cardiovascular complications related to hypertension
In the base-case analysis, the simulation model was used to assess included coronary heart disease (CHD), myocardial infarction
disease progression, costs, QALYs, and the incremental cost- (MI), stroke, and other CVDs. The model comprised of six
effectiveness ratio (ICER) per quality-adjusted life-year (QALY) health states: ‘Healthy’ with hypertension, CHD, MI, stroke,
gained for the simulated cohorts. In the base-case analysis, the other CVD, and death from cardiovascular or other causes
model examined two different treatment strategies which (Figure 2). Cost and quality of life (QL) value were assigned
included single pill triple combination therapy and free drug triple to each health state. In general, patients entered the model in
combination therapy. Patients on each treatment strategy were the ‘healthy with hypertension and without other comorbid­
classified into an adherent or non-adherent group depending on ities’ state and could experience any one of the above events
their adherence level using 80% as a cut off. Expected lifetime costs during each cycle.
and QALYs loss for each treatment group were assessed and the
incremental costs and incremental QALYs were calculated. Cost-
effectiveness ratios were calculated by dividing incremental costs
by incremental QALYs. Costs and QALYs were both discounted at 2.6. Assumptions
3% per year [37,38]. Finally, costs were expressed in 2017 This study included the following assumptions: (1) In order to
U.S. dollars. estimate the medication cost, patients were assumed to
remain on the same dose throughout the duration of the cost-
effectiveness model. (2) For the cost estimation, drug costs of
2.5. Probability concomitant medications used for treating diseases other than
The probability of being adherent and non-adherent for each hypertension were assumed to be similar among the two
treatment group was based on the adherence rates adjusted triple combination therapy regimens, thereby not including
for potential confounders from a previous retrospective them in the drug costs calculation. (3) The medication adher­
ence rate for each combination therapy was obtained from
a previous retrospective analysis which measured the adher­
Table 1. Direct medical costs of different treatments and comorbidities.
ence rate of each treatment arm over a one-year period. The
Costs (2017 US dollars)
adherence rate was assumed to vary ± 0.3% over time among
Single pill therapy 2421.22
Dual combination plus a third agent 1227.17
Free combination 435.87 Table 3. Transition probabilities in Markov model [39,45–47].
Myocardial infarction 33331.28
CHD 53920.79 Probability
Stroke 50019.78 Probability parameters for parameters for free
Other CVD 8213.21 single pill fixed dose triple triple combination
Diseases combination therapy therapy
HTN 1 1
MI 0.0952 0.1525
Table 2. Health utility values.
Other CHD 0.2484 0.3319
Disease Utility Utility loss Stroke 0.0235 0.0686
HTN 0.98 0.02 Other CVD 0.1323 0.3400
MI 0.865 0.135 MI death 0.046 0.052
CHD 0.91 0.09 Other CHD death 0.0259 0.0546
Stroke 0.39 0.61 Stroke death 0.05 0.05
Other CVD 0.682 0.318 Other CVD death 0.047 0.047
4 X. WANG ET AL.
those who developed comorbidities and those without comor­
bidities [48]. (4) Lastly the risk of developing cardiovascular
events among adherent patients was assumed to be 60% of
non-adherent patients in the base-case analysis.
2.7. Sensitivity analyses
Due to variations in the input parameters, one-way and prob­
abilistic sensitivity analysis were conducted to account for
uncertainty.
One-way sensitivity analysis was conducted by varying the
following data: (1) discount rate at 0%, 3%, and at 5%, (2) drug
prices (±25%), (3) the costs and the use of other health
resources (±25%), (4) health utility weights for each health
state (±25%), (5) risk of developing each cardiovascular disease
and CVD mortality.
In addition, probabilistic sensitivity analysis was conducted
by varying the probability distributions of model parameters
simultaneously, based on published 95% CI, normal or uniform
distributions [49]. A total of 10,000 estimates of costs, LYs,
QALYs, and incremental cost per QALY saved and per LYG
(life year gained) were obtained by using Monte Carlo simula­
tion [50]. The results are presented in the cost-effectiveness
acceptability curve, which illustrates the cost-effectiveness of
treatment strategies at different levels of willingness to
pay [51].
3. Results
3.1. Cost-effectiveness
When the strict adherence measurement criteria were applied,
significant differences between adherence rates of single pill
triple combination therapy and free combination therapy were
not observed in the multivariate model from the prior study
[15]. Thus, adherence rates were not included in the economic
model (Model 1). In this scenario, the total expected QALYs
loss and cost/patient were 6.38 QALYs, and 486,026.20 USD for
the single pill triple combination group and the total expected
QALYs loss and cost/patient were 8.64 QALYs, and 406,405.26
USD for free combination group. The incremental cost for the
single pill therapy group compared to free combination ther­
apy group was 79,620.94. USD The incremental QALYs for the
single pill group compared to free combination group were
2.26. ICER for single pill combination compared with free
combination group was 33,862.46. Overall, the single pill
Table 4. Results of CEA models.
CEA model using the strict adherence measurement definition
Total costs
Treatment group (discounted)
Single pill fixed dose triple combination $486,026.20
therapy
Free triple combination therapy $406,405.26
CEA model using the relax adherence measurement definition
Single pill fixed dose triple combination $493,404.26
therapy
Free triple combination therapy $436,415.14
QALY: Quality Adjusted Life Year; CEA: Cost-Effectiveness Analysis.
combination therapy group was more cost-effective compared
to the free triple combination group.
When the relaxed adherence measurement criteria were
applied, significant differences between the adherence rates
of single pill triple combination therapy and free combination
therapy were observed in the multivariate model from the
prior study [15]. Thus, adherence was included in the eco­
nomic model (Model 2). In this scenario, the total expected
QALYs loss and cost/patient were 8.09 QALYs, and 493,404.26
$ for the single pill triple combination group and the total
expected QALYs loss and cost/patient were 8.76 QALYs, and
436,415.14 USD for free triple combination group. The incre­
mental cost for the single pill group compared to free combi­
nation group was 56,989.12 USD. The incremental QALYs for
the single pill group compared to free combination group
were 0.67. ICER for single pill combination compared to free
combination group was 84,932.26. Using a willingness to pay
threshold of 50,000, USD the single pill combination therapy
group was not cost-effective as compared to the free triple
combination group. The results are presented in Table 4.
3.2. Sensitivity analysis
The one-way sensitivity analysis using adherence measured by
the strict criteria demonstrated that the results were robust for
parameters evaluated in the one-way sensitivity analyses. In
most cases, the single pill triple combination therapy was
proven to be cost-effective, the ICERs were lower than
50,000 USD/QALY. Although the single-pill triple combination
therapy remained more costly (due to drug costs) compared
to free combination therapy, it was still more cost-effective.
The one-way sensitivity analysis using adherence measured by
the relax criteria demonstrated that the results were also
robust for the parameters evaluated in the one-way sensitivity
analyses. The results for both the models are illustrated in
a tornado diagram in Figure 3. Adherence and costs were
the main factors driving the results of the economic model.
3.3. Probabilistic sensitivity analysis
The cost-effectiveness acceptability curve for the first eco­
nomic model is plotted in Figure 4. The probabilistic analysis
revealed that there was more than 81.90% probability for the
single pill triple combination therapy to be cost-effective
compared to the free triple combination therapy at
a willingness-to-pay threshold of 50,000 USD/QALY.
Total QALY Loss Incremental Incremental Incremental costs/QALY
(discounted) costs QALYs gained
6.38 $79,620.94 2.26 33,862.46
8.64 Reference Reference
8.09 $56,989.12 0.67 84,932.26
8.76 Reference Reference
 EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH
Figure 3. One-way sensitivity analysis results of comparison of the cost-effectiveness of single pill triple combination therapy vs. fixed dose dual combination
therapy.
The second economic model demonstrated that there was
a 33.58% probability for the single pill triple combination
therapy to be cost-effective compared with the free triple
combination therapy at a willingness-to-pay threshold of
50,000 USD/QALY (Figure 4). Lastly, it also demonstrated that
there was a 79.85% probability for the single pill triple combi­
nation therapy to be cost-effective compared to the free triple
combination therapy at a willingness-to-pay threshold of
100,000 USD/QALY.
4. Discussion
This study was the first to assess the cost-effectiveness of
single pill triple combination therapy vs free combination
therapy by incorporating medication adherence. It found
that the ICER for the single pill triple combination therapy in
comparison to the free combination therapy using the strict
adherence measurement was less than 50,000, which is the
5
most commonly used willingness to pay threshold in US
[52,53]. This suggested that single pill triple combination ther­
apy was more cost-effective in comparison to free combina­
tion therapy. This finding was validated by a previous study
which estimated the cost-effectiveness of a single-pill triple
antihypertensive combination therapy compared to its dual
components from the Greek payer’s perspective. The study
reported that even though the single pill triple combination
therapy was more expensive in Greece, it was still cost-
effective as compared to the dual therapy for hypertensive
patients with uncontrolled blood pressure [26].
The results of the cost-effectiveness analysis of the first
economic model using the strict adherence measurement
criteria were driven by treatment efficacy in reducing blood
pressure since adherence was not included. In the second
model using the relaxed adherence measurement criteria,
adherence was included in the cost-effectiveness model and
the single pill triple combination therapy was not cost
6 X. WANG ET AL.
Figure 4. Cost-effectiveness acceptability curve (single pill triple combination vs. free triple combination therapy).
effective as compared to the free combination therapy using
50,000 as the willingness to pay threshold. However, it was still
considered cost-effective when 100,000 was used as the will­
ingness to pay threshold. In summary, the cost-effectiveness
of the single pill triple combination therapy compared to the
free combination therapy varied when different adherence
measurement criteria were applied.
The major finding of the current economic study incorpor­
ating adherence measured using the strict criteria was consis­
tent with previous finding from a Korean study that compared
the cost-effectiveness of a single-pill fixed dose dual combina­
tion (amlodipine/atorvastatin) with that of loose dose dual
combination therapy in preventing cardiovascular disease.
The study utilized the strict adherence measurement criteria
in the decision analytical model and reported a similar con­
clusion that the single-pill fixed dose dual combination was
more cost-effective as compared to the loose dose combina­
tion therapy [54].
A previous review study which assessed factors causing
variation in cost-effectiveness of first-line antihypertensive
therapy for uncomplicated hypertension reported that cost-
effectiveness results were strongly driven by relative costs of
drug classes [55]. In the current study, the sensitivity analysis
results demonstrated that the finding of the main analysis
remained stable in spite of varying the drug price by ±25%.
Costs however continued to largely influence results of the
cost-effectiveness analysis model.
This study has several limitations. Adherence rates of each
combination therapy incorporated in the decision analytical
model were derived from patients aged more than 65 years
old enrolled in a Texas-based Medicare advantage drug plan.
Thus, these results can be generalized to only patients with
 EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH
similar demographics, health states, and risk factors. In the
US. Also, the decision analytical model was built based on
various assumptions, for instance, in order to estimate the
medication, cost it was assumed that patients remained on
the same dose throughout the duration of the cost-
effectiveness model. However, this dose may vary which
could potentially influence the cost-effectiveness results.
Any violation in assumptions would alter the results. The
model structure did not include non-CVD mortality which
might affect the results of the study. The utility values used
in the study were obtained from different studies published
in various countries, whose patient population may differ
slightly from the US population thereby slightly affecting
the outcomes in the model. Lastly, the results of sensitivity
analysis demonstrate that the cost of CHD largely impacts
ICER and should be further evaluated in future studies.
5. Conclusion
This study reported that the single pill triple combination
therapy was more cost-effective in comparison with the
free combination therapy when adherence was measured
using a strict measurement criteria at a willingness to pay
threshold of 50,000. However, the results varied when
a relaxed adherence measurement criterion was used,
which indicated that different adherence measurement cri­
teria affected results of the economic model. To date, there
is no gold standard for measuring adherence for multiple
regimens. Further research needs to validate different
approaches of modeling adherence in economic studies
to estimate the impact of adherence on health economic
outcomes. Cost-effectiveness analysis from a societal per­
spective (including indirect costs) also needs to be further
investigated.
Author contributions
All authors agree to be accountable for all aspects of the work.
XW and SA were involved in the conception, design, analysis, inter­
pretation of the data, drafting of the paper and revising it critically for
intellectual content, and approval of the version to be published.
HC, EE, JW, OS, and RP were involved in the conception, design,
interpretation of the data, drafting of the paper and revising it critically
for intellectual content, and approval of the version to be published.
Funding
There was no funding obtained for this study.
Declaration of interest
Xin Wang, Hua Chen, Essien EJ, Jun Wu, Omar Serna, Rutugandha
Paranjpe, and Susan Abughosh declare that they have no relevant affilia­
tions or financial involvement with any organization or entity with
a financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript. This includes employment, consul­
tancies, honoraria, stock ownership or options, expert testimony, grants or
patents received or pending, or royalties.
7
Reviewers disclosure
Peer reviewers on this manuscript have no relevant financial relationships
or otherwise to disclose.
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