An economic evaluation of a perindopril-based blood pressure lowering regimen for patients who have suffered a cerebrovascular event
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- Tavakoli, M., Pumford, N., Woodward, M. et al. Eur J Health Econ (2009) 10: 111. doi:10.1007/s10198-008-0108-3
Cerebrovascular disease (or stroke) is one of the main causes of long-term disability and the second leading cause of death worldwide. The economic impact of stroke is clearly seen, as it is the largest single cause of bed occupancy in hospitals in England and accounts for 6% of hospital costs. This analysis is the first to quantify the economic consequences of a blood pressure lowering regimen based on the PROGRESS study (perindopril-based regimen), for reducing future cardiovascular events.
A Markov decision analytical model was used to estimate the cost per quality adjusted life year (QALY) of blood pressure lowering in the treatment of patients presenting with a cerebrovascular event. The health states are based upon Barthel indices for which resource utilisation and health benefits have previously been estimated.
The participants for the economic analysis were obtained from the PROGRESS study database. 6,105 clinical study participants were recruited through both primary and secondary care centres.
The mean age was 64 years; 70% were male in the original study.
In the PROGRESS study, blood pressure lowering by a perindopril-based regimen was compared to standard care.
Main outcome measures
Cost per quality adjusted life year for the duration of the study (4 years) and for a time span of 20 years.
Using only direct hospital medical costs, the cost per QALY for a perindopril based regimen is £6,927 for the base study period and £10,133 for a 20-year time period. These results are sensitive to the cost of perindopril, the cost of the stroke unit, length of stay, and to a lesser extent, the cost of indapamide.
This analysis demonstrates a cost-effective treatment for patients suffering a cerebrovascular event with a blood pressure lowering regimen. The findings of this study are in line with current decisions and guidance by the national institute for health and clinical excellence (NICE) in England.
KeywordsBlood pressure loweringCerebrovascularMarkovCost-effectiveness
Cerebrovascular disease is the second leading cause of death worldwide [1, 2], and one of the main causes of long-term disability in developed countries [3, 4]. Worldwide, about 5 million people die per year from stroke  while a further 15 million will have non-fatal strokes, of whom a third will be disabled [1, 4]. The risk of further strokes remains high among stroke survivors; one in six can expect to have another stroke within a 5-year period .
Circulatory disorders, including cerebrovascular disease (stroke and transient ishaemic attack [TIA]), coronary heart disease (myocardial infarction [MI] and angina), congestive heart failure (including left ventricular dysfunction) and hypertension, account for 10% of gross NHS expenditure in the UK. They are, by far, the leading cause of morbidity and mortality [5, 6]. In the UK, stroke is the third most common cause of death. In Britain, over 123,000 people have a stroke each year [7, 8], with over 56,000 of these are fatal , and cerebrovascular disease is the single most important cause of severe disability . Financially, it is estimated that stroke accounts for over 4% of NHS expenditure and 6% of hospital costs [10, 11]. It is also estimated that 30% of patients die after a stroke within the first month and of those who survive for 1 year: 35% are significantly disabled, and about 5% will be admitted to long-term residential facilities , and at any one time there are 25–35 stroke patients in an average general hospital .
Stroke patients often suffer from coronary heart disease (CHD), and vice versa, reflecting the underlying atherosclerotic process so that the reduction in one is often accompanied by a reduction in the other . Furthermore, about one quarter of strokes are recurrent  and potentially preventable. Therefore, given the large impact of stroke associated with high prevalence, its link with CHD, hospitalisation rate, morbidity and mortality have resulted in a number of interventions in order to reduce the incidence of the disease [16–18].
It has been shown that blood pressure (BP) level is a strong predictor of both first and recurrent cerebrovascular events; lower BP is associated with a lower risk of stroke amongst both hypertensive and non-hypertensive patients [19–24]. The perindopril protection against recurrent stroke study (PROGRESS) was the first to demonstrate that BP lowering after a cerebrovascular event reduced future vascular events, regardless of initial BP level .
The primary objective was to assess the economic impact of the perindopril-based treatment used in PROGRESS, compared to standard care, when applied to patients in the UK who have recently experienced a cerebrovascular event. Two time periods were examined: (1) a 4-year period (that is, within the average duration of the study); (2) the lifetime of patients, assumed not to exceed 20 years. The criterion used was the incremental cost per quality adjusted life year (QALY) gained. Only direct UK NHS hospital costs were considered. Indirect costs, such as loss of productivity, were not included in this study as there were no suitable data available. As such, the analysis is conducted primarily from the tax-payers’ (UK NHS) point of view including mainly hospital (acute and rehabilitation) costs as other NHS costs such as GPs' fees were excluded due to lack of suitable data. Other ACE inhibitor comparators could not be included in the model because no comparable head-to-head patient data were available.
Methods and data
PROGRESS has been described in detail elsewhere . Briefly, 6,105 patients with a recent history of stroke or TIA from 172 centres in Asia, Australasia, and Europe were recruited and randomly assigned to active treatment (n = 3,051) or standard care (n = 3,054). Active treatment comprised a flexible regimen based on perindopril (4 mg daily), with the addition of the diuretic, indapamide (2.5 mg/d; 2 mg/d in Japan), at the discretion of physicians; 58% of patients were assigned combination therapy . Randomised treatment was administered “on top of” standard care, including the use of other blood pressure lowering agents, cholesterol lowering drugs and aspirin, at the discretion of the responsible physician. Follow-up lasted for an average of 4.1 years. The mean age of patients was 64 years and 70% were male. The primary outcome was total stroke (fatal and non-fatal); secondary outcomes included major vascular events, MI and heart failure. TIA was not included among the outcomes, although it was defined among the inclusion criteria.
Active treatment gave a relative risk reduction of 28% (95% CI 17–38%, p < 0.0001) for recurrent stroke versus standard care, with similar reductions in stroke rates among both hypertensive and non-hypertensive sub-groups . Benefit was also found for other cardiovascular outcomes [22, 25].
The economic model
Markov models are state transition models that evolve over time. Patients are assumed to be in only one state at any one time, and transitions between states were calculated over a specified period of time known as the Markov cycle, here taken to be a year that was dictated by the availability of the data. However, Markov models suffer from what is called ‘Markovian’ or memoryless assumption. That is, the movement between states is only dependent on the current state and not the previous history before entering that state and so it is assumed that patients in a given state can be treated as a homogeneous group. This problem can, however, be overcome to some extent by adding extra states to the model [26, 30]. Furthermore, while more than one event can occur in between measurements, the Barthel indices  were only recorded at the end each year (Markov cycle). This mirrored the data collection in the PROGRESS study which after the first year of follow-up patients were seen at annual visits. The Barthel index was used as surrogate for quality of life and mapped to utility values. The Barthel index captures ten activities of daily living and on each the patient is assessed as to their functional ability (e.g., feeding, walking, and bathing). Activities are rated as 0, 5, 10, 15 depending on the activity, 0 being worst functional state. The original scale has a maximum of 100. Whilst the Barthel index has critics, it is widely used in stroke trials, is disease sensitive, and in mapping to utilities had a correlation of 0.59, which appears reasonable. It also measures parameters important to the patient.
The Markov model is based on four health states defined by Barthel index scores. The literature review showed no consistency between authors and their research in the choice of cut off for Barthel indices, for example, one study might use categories of <80, 80–99, 100, and another 45–80, 81–100, etc. As no one set of categories had been widely accepted, we relied on the literature to give us an indication of meaningful changes and this was refined following discussions with clinical experts. It is reported and concluded  that a 20-point difference is highly likely to represent a genuine, clinically meaningful change. On the basis of this and other similar studies [32, 33], and after discussions with a team of consultants, a 20-point difference between Barthel indices were assumed to represent true differences in functionality and disease severity levels.
Figure 1a shows the process and the structure of the decision tree assumed. It shows the clinical pathway that a patient could potentially follow. All patients start with a stroke or TIA. This is represented by the square on the left hand side of the diagram. Based on the low frequency of more than two such events in PROGRESS, only the first two events were used to identify the cohorts. The patient cohorts were then allocated to four Health States based upon the Barthel index: <40, 41–60, 61–80, 81–100, and death. From year to year, individuals were allowed to move between these states, except death, which is obviously an absorbing state (Fig. 1b). While there were some differences in the strength (but not direction) of the effect of the perindopril-based BP reduction among participants with haemorrhagic and ischaemic strokes, including embolic strokes, in PROGRESS [22, 34], the numbers were too small for reliable analyses by stroke subtype in the present context.
The probability of moving from one state to another is called the transition probability. In practice, these are measured by the proportion of patients moving from one health state to another (or remaining in the same state) within each patient group and for each Markov cycle. Transition probabilities were obtained from PROGRESS yielding 840 observed probabilities for the 4 years of observation. Beyond this 4-year trial period, each transition probability, except those for transitions to death, was assumed to follow a beta distribution whose parameters were estimated from PROGRESS. When there were not enough observations to estimate the standard deviation of the beta distribution, triangular or uniform distributions were used instead .
Standardised mortality rates for different risk profiles after stroke, average age of 64 years
No further events
However, as with many other statistics, SMRs have to be interpreted with caution. They can vary from sample to sample and small sample sizes hence small number of deaths could make interpretation difficult. Another inherent problem with SMRs is that they cannot be used to compare different geographical areas, as each area’s population profile weights the age specific death rates differently. Finally, the cause of death reported in the case report may not reflect the underlying risk profile of patients and the SMRs used in this paper will go some way to address this problem.
Resource utilisation included cost of initial hospitalisation, number of bed days in hospital, type of unit, and prescribing (or pharmacotherapy) costs. No costs from outside the hospital were considered.
Resource utilisation and costs
Cost per procedure
Carotid duplex Dopplerb
ECG (1 for stroke and 2 for MI)a
Echocardiogram (needed in 30% in stroke and 80% in MI of cases)a
MRI scan (needed in 8% of cases)b
Blood tests on admission (biochem (£80) haematology (£30))a
Other direct costsa
AHP (Allied Health Professionals)a
X-ray and treadmill test (67% of MI)c
Prices were obtained from Scottish Health Service Costs , and the British National Formulary (2005) . The Dundee Stroke Unit Database also provided the number of days spent in the hospital for every health state based on the Barthel index, events experienced and the order of the events. Direct medical costs for each health state were based on hospitalisation according to the type of event (stroke/TIA or MI/angina) and length and place of stay (stroke unit, rehabilitation unit, geriatric unit (long-term stay) in hospital over a 10-year time period. Direct costs for each health state were then calculated using resource usages from Dundee Stroke Register (Stroke Unit Database), prices from the NHS official statistics, and Scottish Health Service Costs (2004). All costs are expressed in 2005 values. As far as the authors are aware, this is the first study that the length of stay has been measured over time as this allows measuring the costs more accurately (cost data are not reported here due to their large volume). These data and the information noted above from the Delphi panel were combined to estimate direct medical costs of each health state.
Costs per day in a stroke unit
Scottish health service costs, 2004
Geriatric unit (long-term stay)
The initial costs of hospitalisation (investigations and indirect staff) were estimated at £571 and £559 for stroke/TIA and MI/Angina patients, respectively (see Table 2). Costs of medication were obtained from the British National Formulary (2005): perindopril £10.95 and Indapamide £2.82 each for 30-tablet packs, respectively. It was assumed that indapamide would be allocated within the active treatment group to the same proportion of patients as in PROGRESS (58%). For the lifetime analysis, triangular distributions were assumed for costs in the extrapolations.
Utility values for each health state
Probabilistic sensitivity analysis is used to assess the uncertainty of the cost-effectiveness of the model and each parameter/variable/transition probability had to be assigned a probability distribution in order to conduct this analysis. Depending on the availability and the nature of each variable, different distributional assumptions were made. Triangular distributions were used for cost data as the data was generally skewed and only a small number of observations were available in some cases. Hence we could not use log normal or gamma distributions. For the utility parameters and transition probabilities beta distributions were used because they are bounded on the interval 0–1 . Finally, triangular distributions were used as proxies for beta distributions, if there were not enough observations [34, 48].
An annual discount rate of 3.5% has been used for both costs and benefits , as recommended by the UK Treasury and supported by the National Institute of Health and Clinical Excellence. Discounting is used to bring future costs and benefits into their equivalent present values for comparison purposes.
Disaggregated cost-effectiveness analysis
Incr cost (£)
Incr Eff (QALY)
Incr C/E (£)
Simple sensitivity analyses showed how this result depended upon cost assumptions. When the cost of perindopril was reduced by 10% (to £9.86), the incremental cost per QALY dropped to £3,485, and if the price of perindopril was reduced to £8.65 (a 21% reduction) the treatment became cost-saving. When the cost of care in the stroke unit was increased to £440, active treatment also became cost-saving (dominating). Finally, if the cost of indapamide is to increase by 30% to £3.67, the cost per QALY gained for perindopril-based treatment increases to £8,484.
Life time analysis
Our findings suggest that based on a 4-year period, the incremental cost per QALY for a perindopril based regimen versus standard care is £6,927. The life time incremental cost per QALY for BP lowering with a perindopril based regimen is £10,133 and this is well below notational boundaries accepted in recent appraisals by NICE.
The analysis was performed on active treatment versus standard care. It should be noted that many patients were already on anti-hypertensive medications and many more will have commenced these during the study. In the study, individual clinicians were allowed to decide whether one or two drugs were used in a patient. This was then matched with single or double placebo. The percentage on two agents and one agent was 58 and 42%, respectively.
The analysis was performed on the overall results for two reasons; firstly this is the randomised population (with the use of intention to treat data) and thus any internal bias is reduced and secondly the overall population captures real-life practice where a person with a lower blood pressure might be given only one agent and one with a higher starting BP given two agents. Hence the analysis should be valid for extrapolating to a population similar to that of the PROGRESS study.
Whilst the order of the events was felt to be important, it proved too complex to match the timing of the event, i.e., event 1 in year 1 and event 2 in year 4, to the resource utilisation. The timing of the event to some extent will be reflected in the Barthel index as this should be lower soon after a stroke and slowly improve. Thus the year in which the stroke took place would be associated with a lower Barthel index and greater resource utilisation.
Direct comparisons are problematic as different authors use different models, different assumptions, and different outcomes. However, the cost per QALY calculated for PROGRESS is similar to other health economic analyses of major cardiovascular intervention studies. For example, a health economic analysis put a value of £5,502 per life saved on lipid lowering strategies from Scandinavian Simvastatin Survival Study (4S) . In the UK it is estimated the cost to the NHS for every patient experiencing a stroke is £15,306 over 5 years, and when informal care costs are included this figure increases to £29,405 , thus suggesting that total costs are nearly twice the NHS hospital costs.
The original study was not designed to decide what agents should be used to lower blood pressure and therefore the question remains unanswered as to whether other anti hypertensive agents would deliver the same cost-effectiveness ratio. It does demonstrate the cost-effectiveness of blood pressure lowering in a population at risk of future events.
Whilst the analysis uses UK resource utilisation and costs, these results can be broadly generalised since the clinical benefits were obtained from a wide geographical population and the clinical benefits in PROGRESS were broadly consistent by age, sex, and geographic region, with no evidence of significant heterogeneity . However, the pattern of healthcare provision may vary from country to country, which may have differing impacts on resource utilization (e.g., number of days in hospital, investigations, etc) and thus could result in differing overall cost-effectiveness. Furthermore, the UK is usually a low user of health care resources in comparison to many countries. Other countries with greater resource use/ costs might find a lower cost-effectiveness value.
This work was funded from an unrestricted research grant from Servier Laboratories Ltd (UK) and a program grant from the Australian National Health and Medical Research Council. We thank Sam Colman for statistical support from The George Institute, University of Sydney, Australia.
Conflict of interest
Neil Pumford was until recently an employee of Servier Laboratories (the manufacturer of Coversyl/perindopril and Natrilix/indapamide), Manouchehr Tavakoli has received a grant in relation to the economic modeling from Servier. John Chalmers and Stephem MacMahon have received grants from Servier as Chief Investigators for PROGRESS and ADVANCE administered in Sydney. John Chalmers, Stephen MacMahon, and Mark Woodward have all received honoraria from Servier for presentations regarding the studies at scientific meetings. Alex Doney received some financial support from Servier to attend the European Stroke Conference 2006. Ronald MacWalter has received honoraria from Servier for presentations and reimbursement for attending International symposia.