V-scheiner.brunel.ac.uk

Economic Evaluation of ASCOT-BPLA:
Antihypertensive treatment with an
amlodipine-based regimen is cost-effective
compared to an atenolol-based regimen
Peter Lindgren, Martin Buxton, Thomas Kahan, et al.
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Economic Evaluation of ASCOT-BPLA: Antihypertensive
treatment with an amlodipine-based regimen is cost-effective
compared to an atenolol-based regimen

Peter Lindgren1,2, Martin Buxton3, Thomas Kahan4, Neil R Poulter5, Björn Dahlöf6, Peter
S Sever5, Hans Wedel7, Bengt Jönsson8 on behalf of the ASCOT trial investigators
1i3innovus, Stockholm, Sweden
2Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
3Brunel University, Uxbridge, UK
4Department of Clinical Science, Danderyd Hospital, Karolinska Institutet, Stockholm,
Sweden
5Imperial College, London, UK
6Sahlgrenska University Hospital/Östra, Göteborg, Sweden
7Nordic School of Public Health, Göteborg, Sweden
8Centre for Health Economics, Stockholm School of Economics, Stockholm, Sweden
Keywords
Hypertension, primary prevention, amlodipine, atenolol, cost-effectiveness
Address for correspondence:
Peter Lindgren
i3innovus
Vasagatan 38
11120 Stockholm
Sweden
Fax: +46854528549
peter.lindgren@healtheconomics.se
The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all
authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the
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Abstract

Objective
To assess the cost-effectiveness of an amlodipine-based strategy compared to an atenolol-
based strategy in the treatment of hypertension in the UK and Sweden.

Design
A prospective, randomized trial complemented with a Markov model to assess long-term
costs and health effects.

Setting
Primary care.

Patients
Patients with moderate hypertension and three or more additional risk factors.

Interventions
Amlodipine 5–10 mg with perindopril 4–8 mg added as needed or atenolol 50–100 mg
adding bendroflumethiazide 1.25–2.5 mg and potassium as needed

Main outcome measures
Cost per cardiovascular event and procedure avoided, and cost per quality-adjusted life
year gained.

Results
In the UK, the cost to avoid one cardiovascular event or procedure would be 18 965 €,
and the cost to gain one quality-adjusted life year would be 21 875 €. The corresponding
figures for Sweden were 13 210 € and 16 856 €.

Conclusions
Compared to the thresholds applied by NICE and in the Swedish National Board of
Health and Welfare’s Guidelines for Cardiac Care, an amlodipine-based regimen is cost-
effective for the treatment of hypertension, compared to an atenolol-based regimen in the
population studied.
Introduction
Optimal first line therapy and subsequent sequencing of antihypertensive drugs has been
controversial for decades. This is reflected in different recommendations made in recent
guidelines worldwide. [1-4] Before 1995, almost all randomized trial evidence on
hypertension management related to diuretics and to a lesser extent beta-blockers. [5]
However newer drug classes were increasingly being used and have consequently been
evaluated in major trials. Enthusiasm for any potential advantages of the newer agents (at
least on surrogate end points) has been tempered in some situations by concerns over
their increased cost. Despite the reality that the majority of hypertensive patients need at
least two agents to reach currently-recommended targets, until recently no trial data were
available to compare the benefits of newer combinations of drugs with the standard most
commonly used regimen of a beta-blocker with a diuretic.
The Blood-Pressure-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial
(ASCOT-BPLA) randomized 19 257 patients to receive either amlodipine 5-10 mg
adding perindopril 4 – 8 mg as needed to reach BP targets, or atenolol 50 – 100 mg
adding bendroflumethiazide 1.25 – 2.5 mg and potassium as needed.
Patients included in the trial were men and women aged between 40 and 79 years, with
either untreated hypertension (a systolic blood pressure ≥160 mm Hg or a diastolic blood
pressure ≥100 mm Hg) or treated hypertension with a systolic blood pressure ≥140 mm
Hg or a diastolic blood pressure ≥90 mm Hg. Patients were also required to have at least
three of the following risk-factors: male sex, age above 55 years, smoking, left
ventricular hypertrophy, other abnormalities on electrocardiogram, type 2 diabetes,
peripheral arterial disease, previous stroke or transient ischemic attack, microalbuminuria
or proteinuria, a ratio of plasma total cholesterol to HDL-cholesterol of 6 or higher, or a
family history of early CHD. The trial was stopped prematurely after a median of 5.5
years due to a significant beneficial effect of the amlodipine-based regimen on all-cause
mortality (HR 0.89, 95% CI:0.81-0.99). The hazard ratio (HR) for the primary endpoint
(myocardial infarction (MI) including silent events and fatal CHD) was 0.90 (95 %
confidence interval, CI: 0.79 – 1.02) in favour of the amlodipine-based regimen. There
were also significant reductions in the number of fatal and non-fatal strokes (HR 0.77, 95
% CI: 0.66 – 0.89), total cardiovascular events and procedures (HR 0.84, 95% CI: 0.78 –
0.90) and in the incidence of new-onset diabetes in the amlodipine-based group (HR 0.70,
95% CI: 0.63 – 0.78). [6]
Looking only at the cost of medication, newer treatments (such as amlodipine and
perindopril) are typically more expensive than their older comparators (such as atenolol
and thiazides) but in ASCOT they induced superior preventive effects on all major CV
outcomes. In order to make a rational decision when allocating resources in health care,
it is necessary to take potential savings due to decreased morbidity and mortality into
consideration. If the net costs still indicate that the newer strategy adds costs, a formal
estimation of the cost-effectiveness of the treatment is necessary. The scope of this study
was to conduct an economic evaluation of ASCOT-BPLA. This prospective economic
evaluation was a prespecified analysis of the trial. Analyses were conducted for the UK
and Sweden, the two largest contributors in terms of numbers of patients in the trial.
Material and methods
Two approaches were taken in the analysis of the cost-effectiveness of the amlodipine-
based regimen: A within-trial analysis estimating the costs and events avoided during the
trial period; and a modelling approach extrapolating costs and the potential benefits of
avoiding events on long-term survival and quality-adjusted survival over the life-time of
the patients.
In the within-trial analysis, resources used during the trial period (and being recorded on
the case report forms) were multiplied by their unit cost, and an average cost per patient
was estimated. Resources used included use of study drug, end-point related
hospitalizations, non-endpoint related hospitalizations and concomitant medications using
standard published sources for unit costs. [7-11] Prices are expressed in Euros (€), using
the average exchange rates during 2006 to convert for British Pounds and Swedish
Kronor to the € (1 € = 0,68 GBP, 9,25 SEK). [12] For a more in-depth description of the
costing approach, please refer to our previously reported study of the lipid-lowering arm
of ASCOT. [13] In the within-trial analysis, we used the average total number of events
per patient during the trial as the measure of effectiveness.
To estimate long-term cost and effects, a Markov model [14] consisting of six states was
constructed: Event free, diabetes, MI, coronary revascularization, stroke, and death. The
four event states (MI, diabetes, stroke and revascularization) are implemented as tunnel
states to allow for differentiation of costs and lost utility over time. Patients in the event
free state stand a risk of suffering any of the four events, which in the case of strokes and
MI:s may or may not be fatal. Patients in the event states either die or remain within their
current state for the rest of the simulation. This means that only first events are explicitly
incorporated in the model. Patients developing diabetes (or having diabetes at baseline),
have a subsequent risk of developing MI, stroke or undergoing revascularization.
The transition probabilities used in the model are derived from the clinical trial through
survival modelling, with the exception of the risk of an event being fatal which was
estimated through logistic regression. These data are available online. Mortality
following an event was estimated based on the entire trial sample (i.e. not estimated
separately by treatment arm). This means that we are assuming no difference in mortality
after an event for the two treatments. Any potential survival benefit is thus only caused
by a difference in the risk of events. To avoid an underestimation of the mortality in
higher age groups which were not represented in the trial, the model is programmed so
that mortality does not fall below that of the general population (stratified by age and
gender). [15]
The cost of the study drug is based on the mean number of days each dose was prescribed
during the trial period and the daily cost of the drug (see table 1). Because perindopril is
not available on the Swedish market it was assumed to have the same relative price
compared to the other study drugs as in the UK (0.81 € per 4 mg). We also conducted
analyses where it was assumed to have the same price as the two most commonly used
ACE-inhibitors in Sweden (ramipril 10 mg and enalapril 20 mg, 0.18 € and 0.05 €
respectively).

Table 1. Drug costs (€) used in the analysis
UK
Source: Swedish Drug Tariff (FASS) and Monthly Index of Medical Specialities [10, 11] Costs for events were estimated by comparing the resource consumption during the year prior to the event to that one and two years following it (data available online). Health economic guidelines in Sweden and the UK differ in their view of costs caused by lost production (indirect costs) [16, 17] which Swedish guidelines recommend including, whereas the UK guidelines do not. Therefore only Swedish analyses incorporate indirect costs. This was based on a study of indirect costs and quality-of-life in Swedish ASCOT-patients. [18] Two measures of health outcomes were included in the model: life-years gained (LYG) based on the predicted survival in the two treatment groups and quality-adjusted life years (QALY) gained. In the latter case each life-year is weighted according to the health status of the patients. The weights used (called utility weights) are normally between 1 and 0 where 1 represents a health state equal to perfect health and 0 to a health state equivalent to death. Event-free patients are assumed to have the same utility weights as individuals in the general population (adjusted for age and gender). [19, 20] To account for the effect of events, data from the above mentioned survey of Swedish patients was used. [18] This study indicated that patients with MI had moved back to their original utility level after one year, while no such improvement was seen in stroke patients. No data were collected for patients undergoing coronary revascularization. We therefore assume that they had a slightly smaller decrease in utility than the average patients with MI, based on results from another Swedish survey. [21] Uncertainty was incorporated into the model through probabilistic analysis using 2nd order Monte Carlo simulation. 1000 simulations where performed. In each of the simulations, each parameter was sampled from its underlying distribution. The distributions were estimated by performing non-parametric bootstrapping of each parameter. [22] Uncertainty was reported in the form of cost-effectiveness acceptability curves. [23] In the base-case, a cohort similar to that of the clinical trial was analysed (63 years of age, 19 % female, 27 % diabetic). Patients were assumed to be treated for 6 years, and followed for the remainder of their life. In the long-term model, costs and effects were discounted at 3.5 % per annum in the UK and 3 % per annum in Sweden in accordance with guidelines in the two countries.
Results
Table 2 shows the results from the within-trial analysis. As expected in the amlodipine-
based group, the cost of the study drugs was higher compared to the atenolol-based
strategy, but there were lower costs for all other resource categories, thus offsetting 38 –
50% of the drug costs during the 5.5-year trial period.
Table 2. Mean costs, number of events and incremental cost-effectiveness during the trial
period.

UK Sweden
Amlodipine-
Atenolol-based Amlodipine-
Atenolol-based
Mean cost (€) per
patient
Study drug
2440 (2425 ; 2455) 2525 (2509 ; 2543) 2240 (2227 ; 2254) 2318 (2303 ; 2334) 2167 (2127 ; 2207) 2418 (2375 ; 2459) 2396 (2353 ; 2438) 2649 (2604 ; 2693) 3352 (3148 ; 3557) 3447 (3221 ; 3673) 2523 (2369 ; 2678) 2595 (2425 ; 2765) Events per
patient
Primary endpoint1
effectiveness*
Cost to avoid one
1Silent and non-silent MI and fatal CHD. Mean values and 95% confidence intervals. DRG = Diagnosis Related Group (potentially end-point related hospitalizations) * Compared with atenolol-based therapy Table 3 shows modelled lifelong predictions of costs, outcomes, and cost-effectiveness. The chief explanatory factor for the difference in survival and quality adjusted survival is the difference in discounting recommended in the UK and Swedish guidelines (3.5 and 3% per year). This also affects the total predicted costs. The inclusion of indirect costs in the Swedish analysis is of minor importance due to the mean age of the population (63 years) when included in the trial. Table 3. Predicted per patient life-time costs (€), health outcomes and incremental cost-
effectiveness.
UK1 Sweden2
Amlodipine-
Atenolol-based Amlodipine-
Atenolol-based
Costs
Drug
Health outcomes
Incremental cost-
effectiveness3
Cost per LYG
1Costs and effects discounted at 3.5% per annum
2Costs and effects discounted at 3% per annum
3Relative to atenolol-based regimen
LYG = Life Years Gained; QALY = Quality Adjusted Life years
The cost-effectiveness acceptability curve shown in figure 1 shows the probability, given
our data that the amlodipine-based strategy is cost-effective for different levels of
willingness-to-pay to gain one QALY. The difference between the UK and Sweden is
once again mainly due to the difference in discount rates, where the higher rate used in
the UK leads to a lower valuation of future cost offsets and health gains compared to
Sweden, and thus a lower probability of the strategy being considered cost-effective.
<Figure 1 – CEAC >
The assumptions in the model were tested in one-way sensitivity analyses. These
indicated that the most sensitive variable is the proportion of females in the population,
followed by the discounting factor used (data available online). In an all-female
population, the incremental cost-effectiveness ratio (ICER) was 32 000 € per QALY in
the UK and 24178 € per QALY in Sweden. Factors such as the average age, changes in
the costs caused by events and the utility reduction caused had very limited impact on the
results, as had extrapolating the duration of the intervention beyond the trial period.
Using the price of enalapril or ramipril as proxies for the price of perindopril in Sweden
lead to lower cost-effectiveness ratios (5 964 € and 3 606 € per QALY gained), due to the
low prices of these drugs (generic enalapril is the cheapest antihypertensive drug on the
Swedish market). The introduction of generic amlodipine also have a large impact of the
results. At a price of 0.10 € per day in Sweden and 0.15 € per day in the UK the cost to
gain one QALY becomes 7 257 € and 8 372 € in the respective countries.
Discussion
In the UK, our study indicates a cost of 18 695 € to prevent one cardiovascular event or
procedure, or 21 875 € to gain one QALY during with six years of treatment with the
amlodipine-based, compared with the atenolol-based regimen. This falls well below the
threshold value of 20 000 GBP (29 000 €) per QALY included in the most recent NICE
guidelines to indicate cost-effectiveness. [17] The corresponding figures were 13 210
and 16 856 € in Sweden, where the National Board of Health and Welfare has published
guidance for prioritizations in cardiovascular medicine. [24] In this guidance an ICER
below 100 000 SEK/QALY (11 000 €) was classified as low, and a ratio below 500 000
SEK/QALY (55 000 €) as moderate. Using these criteria, the cost-effectiveness ratio in
our Swedish analyses fall just above the ‘low’ threshold.
There is reason to believe that the cost-effectiveness ratios reported here are somewhat
overestimated. Although the model incorporates new-onset diabetes as an end-point, the
costs associated with the microvascular complications due to diabetes are not included
since they are likely to occur after the end of the trial. Diabetes is also associated with
excess non-cardiovascular mortality, which is not incorporated here. Indeed, excluding
the additional cost for diabetes has a very limited impact on the results of our model,
leading to an increase in the ICER of about 100 €. Using the cost reported in patients with
no or microvascular complications only (assuming macrovascular complications are
captured in the events costs of our model) that was reported in the CODE-2 in Sweden
(1762 €) gives an ICER of 16 450 €. This may still be an underestimation, as the largest
cost increase in CODE-2 was observed for patients with both micro- and macrovascular
complications. [25] Costs included were based on the data collected in the trial which has
the advantage of giving very high internal validity. Some potentially important costs were
not collected, and are thus omitted from the event costs. This includes costs for
rehabilitation following a stroke and costs for admittance to nursing home facilities.
Furthermore, with the expiration of the patent on amlodipine, drug prices have fallen.
This will of course lead to even more beneficial cost-effectiveness ratios. For example, in
our model, a reduction in the price of amlodipine by 30% would give a cost-effectiveness
ratio of 17 000 €/QALY in the UK and 13 500 €/QALY in Sweden. Indeed, with the
current price of 0.10 € per day for amlodipine in Sweden and 0.15 € in the UK the cost
effectiveness ratio would be 7 257 €/QALY in Sweden and 8 372 €7QALY in the UK.
Some authors have argued for the inclusion of costs associated with increased survival
(consumption minus production) to properly analyze the cost-effectiveness from a
societal perspective. [26, 27] Such data are available for Sweden. [28] Including them in
the analysis increases the cost-effectiveness ratio somewhat: 15 900 € per QALY gained.
Conclusion
Based on the threshold values for cost-effectiveness employed by the authorities in
Sweden and the UK, an amlodipine-based treatment regimen appears to be cost-effective
compared to an atenolol-based regimen in patients with moderate hypertension and
additional risk factors.

Acknowledgements
The study was supported by the principal funding source, Pfizer, New York, USA. A full
list of the ASCOT investigators may be found elsewhwere. [29]
Conflict of interest statement
PL, MB, TK, NP, BD, PS, HW and BJ have served as consultants to and received travel
expenses, payment for speaking at meetings or funding for research from pharmaceutical
companies marketing anti-hypertensive drugs, including AstraZeneca, Sanofi-Aventis,
Bayer, Bristol-Myers Squibb Co, Merck, Sharpe and Dohme, Novartis, Pfizer, , Schering,
and Servier. PL, MB, TK, NP, BD, PS, HW and BJ received financial support from
Pfizer to cover administrative and staffing costs of ASCOT, and travel , accommodation
expenses or both incurred by attending relevant meetings.
Figure legends
Figure 1. Cost-effectiveness acceptability curve indicating the probability that the
amlodipine-based strategy is cost-effective compared to the atenolol-based strategy at
different willingness-to-pay thresholds to gain one quality adjusted life-year.

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Tables for online publication only
Table A1. Costs (€) associated with the events in the model.
UK
Difference 1st year after event
to 1 year prior to the event
Non-fatal MI
Difference 2nd year after event
to 1 year prior to the event
Non-fatal MI
Mean values and 95% confidence intrevals. MI = Myocardial infarction
Table A2. Sensitivity analysis.
UK
Variable
Low value
High value
High ICER
High ICER
Reduction of utility (coronary revascularisation) Costs in €. ICER = Incremental cost-effectiveness ratio

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