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Cost-Effectiveness in Italy of Preventive Treatment With Ramipril in Patients at High Risk of Cardiovascular Events

Posted on: Wednesday, 13 July 2005, 03:00 CDT

Key words: ACE inhibitor - Cardiovascular diseases - Cost- effectiveness analysis - Costs - Ramipril

ABSTRACT

Objectives: A cost-effectiveness analysis was conducted in Italy of preventive treatment with ramipril (an angiotensin converting enzyme [ACE] inhibitor) compared to no treatment in patients at high risk of cardiovascular death. The analysis was based on data extracted from the HOPE trial.

Methods: The current life table method was used in order to model a lifetime time horizon for outcomes and costs. The cohorts used were 1000 subjects on ramipril, and 1000 subjects on placebo enrolled in the HOPE trial. Kaplan-Meier curves at 5 years of the clinical study were fitted using an exponential model over a lifetime horizon, the outcome variables being myocardial infarction, stroke, revascularization and death. Total direct medical costs have been considered from a third-party payer's perspective - the Italian National Health Service. Resources involved in each event/ activity were estimated using the modified Delphi technique with a panel of six clinicians. Types of resources reported included drug therapies, laboratory and imaging tests, physician visits, outpatient and inpatient rehabilitation, as well as medical and surgical hospital admissions. The incremental cost per life year gained was the main measure of the analysis.

Results: ICER (incremental cost-effectiveness ratio) decreases with the length of the treatment period. After the first year the ICER is euro55 062 and subsequently decreases to about euro12 770 at 5 years, euro5945 at 10 years and euro3726 at 20 years. The two ways sensitivity analysis showed that at 5 years ICERs range from a saving of euro4059 to a cost of euro22 929 (at 20 years they are euro1814 and euro4434), mainly depending on the cost of drug and cost of events. Previous analyses in other countries based on the HOPE study obtained ICER values which are comparable with our results, when taking into account the different cost structure of the health care systems.

Conclusions: On the basis of these results, the use of ramipril is likely to represent an efficient use of public health expenditure in the Italian healthcare system.

Introduction

The Heart Outcomes Prevention Evaluation (HOPE)1 clinical trial has demonstrated that ramipril reduced the rate of death from cardiovascular causes, myocardial infarction and stroke. Most of this mortality burden is due to the clinical consequences of atherosclerosis, which is recognized as the most common cause of death and serious morbidity at least in the Western world, although the World Heart Organization (WHO)2 has predicted that in the near future it will also become the number one cause of mortality in the entire world. Indeed, the total number of people dying from coronary and cerebrovascular diseases is approximately 15 million a year (30% of all deaths worldwide), but only a fifth of all cardiovascular deaths occur in the Western world3. Together with mortality, the prevalence of cardiovascular diseases is a crude measure of its burden in the community. It is also possible to measure the severity of its social impact by calculating the disability-adjusted life years (DALYs) lost and, in the Western world, cardiovascular diseases account for about 20% of all DALYs lost due to disease. Beyond the obvious human and social consequences of atherosclerotic cardiovascular disease, this also has a very important counterpart in terms of the economic costs to the individual and the community. The economic burden of cardiovascular disease is steadily increasing and accounts for a large amount of the general health expenditure (the direct cost of cardiovascular diseases and stroke in the United States is estimated at $226.7 billion in 2004(4)).

Several factors contribute to this economic burden. The impact of the acute event (such as myocardial infarction and stroke) has to be considered first, in terms of emergency care, hospital stay in specialized units and use of medical, surgical and interventional approaches to reduce the sequelae of the ischaemic insult. After stabilization, the cost of life-long follow-up and secondary prevention should be taken into account. Moreover, the incidence of recurrent events and/or of chronic deterioration of myocardial and cerebral function adds a further socio-economic burden, due to the added costs of post-ischaemic heart failure and dementia. In an era of increasing cost containment, it is therefore very important to evaluate the cost-effectiveness of demonstrated preventive treatments in terms of their economic impact.

We conducted a cost-effectiveness analysis to compare the benefits of ramipril treatment compared to no treatment (placebo in HOPE study) and the use of medical resources in Italy. The results in terms of events averted (myocardial infarction, stroke, revascularization), life years gained and costs for the National Health Service were modelled from the first year of treatment throughout a patient's lifetime (30 years).

Methods

The model

As clearly shown by the HOPE study, treatment with ramipril has a major impact on costs and outcomes over a patient's lifetime, since it prevents the occurrence of cardiovascular events in high risk subjects. In this respect the preventive effect of this ACE inhibitor is above and beyond the expected therapeutic effect in patients affected by arterial hypertension and congestive heart failure (i.e. clinical conditions that are effectively managed by chronic ramipril administration). Therefore a lifetime horizon for costs and effectiveness was applied. The analysis was carried out for a 5-year ramipril treatment and projected for a 30-year ramipril treatment assuming continued and constant benefit from this drug, probably a conservative approach (see Discussion). The current life table method was used. The life table method involves construction of tables to calculate the mortality and the events/episodes experience of a given cohort of people. The cohorts used were 1000 subjects on ramipril and 1000 subjects on placebo, based on the HOPE trial. The mortality and event occurrence predicted on ramipril treatment was compared with those of the placebo group. The life years gained and the events avoided are the differences between the total life years and total events during each year of treatment and those observed in the placebo group. In a given year, deaths may occur at varying times, some early and some late. In the present study it was assumed that they occurred halfway through the year, on average, so that each death contributed half a year towards the total of life years lived.

To model the survival for placebo and ramipril treated patients, data from the HOPE trial were used. Briefly, the HOPE trial evaluated the effects of ramipril in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure. To this aim, 9297 patients (age ≥ 55 years) defined as at high cardiovascular risk, due to previous evidence of vascular disease or diabetes plus one other cardiovascular risk factor, were randomly assigned to receive ramipril (10mg/day) or placebo for a mean of 5 years. The primary outcomes were cardiovascular deaths, myocardial infarctions, strokes and deaths from any causes. In the present study the reference population was that studied in the HOPE trial (average age = 66 years, annual mortality rate = 3.0%). The annual probability of dying for any cause and for each age class for the Italian population was estimated using the data from national statistics5. The increment in the mortality rates with age was used to take into account the aging of the studied population over 30 years.

The HOPE trial reported the observed incidence at the end of the study for each event of interest (myocardial infarction, stroke, death from any cause, composite event made up by myocardial infarction, stroke or death from cardiovascular causes) and the survival Kaplan-Meier (KM) curves for the composite event (myocardial infarction, stroke or death from cardiovascular causes) for the placebo and the ramipril arm. These KM curves were fitted using an exponential model S(t) = exp(-λt), giving the annual composite event rates of λ^sub placebo^ = 4.54% and λ^sub ramipril^ = 3.47%. Using these values together with the observed incidence of the composite event at the end of the study, the effective follow-up time was estimated as being 4.3 years. By means of this value, the reported observed incidence of death from any cause and the exponential model, it was possible to estimate the annual mortality rate from any cause for the placebo (3.00%) and the ramipril group (2.54%) respectively, leading to a relative risk (hazard ratio) HR = 0.84, as reported by the HOPE study. This was assumed to remain constant for life.

The same procedure was used to estimate the cumulative probability of experiencing myocardial infarction, stroke and revascularizations, in order to assess savings gained from reduction in these events due to the ramipril treatment. In Table 1 all the event rates used for this analysis are reported.

Costs

In the present study total direct medical costs were considered. Data about direct non medical cost for transportation or social aids were not available and, \as for indirect costs (loss of productivity from morbidity and mortality), one should note that the study population is elderly and there would need to be a specific study on this Italian setting. At first, data were required to quantify the effect of the preventive therapy on the use of resources in terms of physical units (days in hospital, visits to a physician, drugs and laboratory tests), then valuing those effects in monetary terms using appropriate prices and unit costs.

Resources involved in each event/ activity were estimated using the modified Delphi technique which involves surveying staff and reaching a consensus in the estimated amount of time and materials required to perform specific tasks6. An expert panel of six clinicians (both cardiologists and neurologists) extrapolated from personal experience, taking into account routine medical practice in our country, the type and the amount of resources that are required by each specific episode. Each physician provided estimates of the healthcare resource utilisation for the management of myocardial infarction, revascularization and stroke (in the setting of the population subjected to ramipril preventive treatment), during the first year after the event and during the subsequent annual follow- up. A consensus was then reached giving the reference amount of resources for each event. Types of resources reported included drug therapies, laboratory and imaging tests, physician visits, outpatient and inpatient rehabilitation and hospital admissions (medical and surgical). The unit cost per resource has been derived from the following official sources: National Formulary for each drug7 (in Italy the price of drugs dispensed by the pharmacists in an outpatient setting is the same throughout the country), National Charges for Medical Visits and Laboratory Tests8 and, finally, DRG reimbursement rates for hospitalization and rehabilitation9. All costs were calculated in 2004 Euros. The estimated cost of the episodes (Table 2) is quite similar to results obtained with different methodology in a recent study10.

Table 1. Annual event rates (%) from the HOPE trial for the reference population

In order to consider the mortality rate of 30% during the first six months for stroke and myocardial infarction (MI), costs were reduced by the same amount in the first year of each event. The hospitalization for MI has been costed by applying the DRGs 121 and 122 (with and without complications) weighted by the case-mix of total stays which occurred in Italy in 2001 (34.9% DRG 121 and 65.1% DRG 122)11. In a similar way DRG 112 (percutaneous transluminal coronary angioplasty [PTCA]), DRG 106 (coronary artery bypass graft [CABG] with catheterization) and DRG 107 (CABG without catheterization) were used for revascularizations episodes. Since the majority of patients in the HOPE trial took ramipril 10mg/day, this dosage was used in the costing. Treatment cost was, therefore, the number of treatment years multiplied by the yearly cost of ramipril plus additional visits to physician and laboratory tests to monitoring the drug therapy. When an episode (MI, stroke or revascularization) occurred, no further ramipril treatment costs were included.

Even though patients on no ramipril treatment are probably patients who are normally treated with cardiovascular drugs, since they have experienced, for the vast majority, a cardiovascular event or a stroke (in the HOPE study, 81.4% of placebo patients had a history of coronary artery disease and 79.5% in those allocated ramipril), the cost of these treatments was ignored because data were unavailable. The assumption, (quite conservative, in order to fully assess the contribution of ramipril in economic terms), is that the patients not on preventive treatment are at zero cost until the experience of one of the events calculated in the study (MI, stroke, revascularisation). This obviously penalizes the economic benefit measurable with the ramipril treatment.

Table 2. Costs used in the model. Euros (2004 values)

Effectiveness

We estimated the effectiveness of ramipril treatment in reducing MI, stroke revascularization and mortality from the HOPE clinical trial, as compared with no preventive treatment (placebo in the HOPE trial). The relative risk reduction (showed in Table 1) was assumed to remain constant for life (30 years period in the model). The mortality rate of the general population for each age group was considered in the model, as well as the deaths from any cause (in the HOPE study the relative risk of death from any cause was 0.84 with a p value of 0.005). The number of MIs, strokes and revascularizations was calculated for each group of patients (1000 patients on treatment and 1000 patients on no treatment) for each year of the 30 years horizon of the model and as well the number of deaths. The outcome used has been the number of life years cumulated year by year in the two groups; the difference is the number of life years gained due to the treatment.

Cost-effectiveness

The cost per life year gained is the total cost of the group treated with ramipril treatment, minus the total cost of the no treatment cohort, divided by the difference in the total life years of the two groups. Therefore this incremental cost-effectiveness ratio (ICER) was obtained for each duration of treatment, from the first year until the thirtieth year.

The cost-effectiveness analysis was performed from a third-party payer's perspective, the Italian National Health Service, over a time horizon of a lifetime (30 years, giving the average age of patient at the first year of 65), but the values of ICERs were given for each relevant subperiod of treatment (at 5, 10, 20 and 30 years). All future costs and health outcomes were discounted at a rate of 3% per year. In the sensitivity analysis the results were calculated assuming different discounting rates, and also with no discounting.

Results

Baseline analysis

The difference in the number of cardiovascular events, strokes and revascularizations between ramipril treatment and no treatment is shown in Figure 1. The preventive treatment enables the avoidance of a sufficient number of events, particularly during the first 10 years, since a lot of patients are still alive (719 in the ramipril group and 675 in the placebo group). Afterwards the number of events averted is reduced, since the number of patients alive in the ramipril group is even larger (for example, at 20 years the ramipril group has an extra 20% of subjects still alive).

Years of life gained due to treatment with ramipril increase considerably between year 5 and year 20 (Figure 2).

The incremental cost-effectiveness ratio (ICER) decreases with the length of period of treatment. After the first year the ICER is euro55 062, about euro12 770 at 5 years, euro5945 at 10 years and euro3726 at 20 years (Figure 3).

The cost per life year gained seems to be reasonable, being much lower than the value suggested by NICE in the UK ('Below a most plausible ICER of 20 000/ QALY, judgments about the acceptability of a technology as an effective use of NHS resources are based primarily on the cost-effectiveness'12). This value of 20 000 is about euro29 515, almost double the ICER at 5 years (average exchange rate of period January-May 2004: 1.47578) and is related to QALYs; since in this study this value is related to years of life without any quality of life weight, it appears reasonable to expect a lower value when quality of life would be considered.

Figure 1. Myocardial infarctions, strokes and revascularizations averted (cumulated 1000 patients). - - Stroke averted. - MIs averted. --- Revascularizations averted

Figure 2. Life-years gained cumulated ( 1000 patients). - Life- years gained

Figure 3. Incremental cost-effectiveness ratio of ramipril versus no treatment. - Incremental cost-effectiveness ratio (ICER)

Sensitivity analysis

Since the individual patient data for the HOPE study were not available, we used the published average values and then projected them to the model. Therefore the distribution of cases was impossible to obtain, so our sensitivity analysis was a two ways analysis13,14, by systematically examining the impact of each cost variable by varying it across a plausible range of values, while similarly assessing the effectiveness of ramipril over the confidence intervals in the HOPE study around the hazard ratios of MI, stroke, death and revascularization, and counting the cost of ramipril.

Table 3. Incremental cost-effectiveness ratios in key sensitivity analyses (all values discounted 3%)

When the low efficacy is applied while maintaining the baseline costs, the ICERs obviously increase from euro12 770 to euro20 895 at 5 years, whereas the difference reduces at 10 years (euro8717 versus euro5945) until it becomes very low on prolonging the period (Table 3). The low efficacy, and an increase of 50% or a decrease of 50% in the cost of the events, results in a low variability of ICER values (respectively euro18 861 and euro22 929 at 5 years), whereas the cost of ramipril induces high variability, with an ICER at 5 years of euro30 775 following an increase of the price of 50%, and an ICER euro11 015 with a 50% price reduction.

In the baseline efficacy, increased costs reduce the ICER by half, and by contrast reduced costs result in an ICER of euro18 932. When the high effectiveness is considered, ICERs become lower in each sensitivity analysis, resulting in a saving of euro4059 and of euro4288 for each life year gained. Our results were not sensitive to changes in discounting: undiscounted values give an ICER at 5 years of euro12 499, and euro13 044 with a 6% discount rate. Even though the prevalent position about discounting in healthcare suggests discounting both costs and benefits15,16,17, we show in addition the ICER when only costs have been discounted, knowing that discounting of life years is contr\oversial among clinicians18. In this case the results are also well founded, since the ICER at 5 years is about euro11 775. In Figure 4 the best and the worse case for ramipril are compared to the baseline ICER results.

At 5 years ICERs range from -euro4059 to euro22 929 (at 20 years they are euro1814 and euro4434). In the long term, the real horizon for cardiovascular preventive therapy, the cost per life year gained has a quite stable value in our model.

Discussion

This analysis shows that the gain in life expectancy and in cardiovascular events avoided as a result of 5 years ramipril treatment is significant, and is obtained at a reasonable cost.

Previous analyses of the cost-effectiveness of ramipril based on the HOPE study obtained ICER values which are comparable with our results, particularly when taking into account the different cost structure of the health care systems where those studies have been performed. The seminal UK study of Malik et al.19 showed a cost of 13 600 per life year gained at 5 years (equivalent to euro21 685 in the year 2001); the result becomes rather similar to ours when calculated at 10 years (5300 equivalent to euro8450 in the year 2001, compared to our ICER of euro5945 of year 2004). At 20 years the ICER of the UK study is 1990 (equivalent to euro3029) versus euro3726 of the present study. The Swedish study20 performed in 2002 resulted in a cost added per life year gained at 5 years of euro16 600, while a model used in Spain21 on the same year showed an ICER of euro10 329. More recently, a study conducted in Germany obtained the ICER of ramipril after 4.5 years of treatment between euro1290 and euro9005 per life year gained22.

Figure 4. Sensitivity analysis: best and worse case of ramipril versus no treatment. --- High efficacy and +50% cost of events. - Low efficacy and -50% cost of events. - Base case

Long term outcomes and costs were modelled, even if the clinical evidence from HOPE was at 5 years, because the decisions about preventive therapy are easily assumed to be on the life time horizon. This is a usual and unavoidable feature of modelling in healthcare23. Only outcomes with statistical significance were considered from the HOPE trial. Therefore we excluded some relevant events like heart failure and worsening angina which would probably have improve the ICERs (Lamy et al.24 utilized in their study all outcomes and found that 90% of cases fall into a cost-neutral or cost-saving situation).

In 2003, more than 3 years after the publication of the HOPE study results, the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA)25 investigators showed the effects of another angiotensin converting enzyme inhibitor, i.e. perindopril (8mg/day), in a cohort of low- risk patients with stable coronary heart disease. Treatment was associated with a 20% reduction in the primary combined endpoint (cardiovascular death, myocardial infarction, or cardiac arrest) in 4.2 years. Although it might be tempting to speculate about the possibility of comparing the two trials, the differences in the two studied populations have to be taken into account. Moreover, only after a similar costeffectiveness analysis will it be possible to assess the relative impact of the two drugs in populations with a different cardiovascular risk profile.

The described model has several limitations.Given the HOPE data, benefit is unlikely to decrease on continued treatment, therefore we modelled for the hypothesis that there would be continued (or even added] benefit beyond 5 years treatment. This assumption would require verification in the future with long term observational studies. We derived the resource consumption related to the events from a panel of clinical experts, which might be somewhat unrepresentative of the real medical practice of the country. With the sensitivity analysis we have minimized this limitation. For simplicity, our model did not take into account the fact that some of the patients would develop other diseases, like tumours or neurological diseases, during the lifetime period of the simulation. Therefore the total direct medical costs could be slightly different, but not the mortality rate, because we had taken into account the general mortality of each age group. Moreover, it is usual in cost-effectiveness analyses to show the impact of a specific therapy on costs, assuming that the difference between the alternative therapies on other diseases is negligible.

A further limitation of the model is that it only considers years of life and not quality adjusted life years. However quality of life data were not available from the HOPE study. Also in this case, when it would possible to adjust the difference in survival between the treated patients and the non-treated patients by quality of life, the result would be very likely to improve the cost effectiveness of ramipril, as these patients experienced a lesser number of cardiovascular and stroke events.

Direct non medical costs, such as transportation and social aids for patients which could be quite relevant in the presence of cardiovascular events were not considered, as well as indirect costs (labour productivity lost). In particular the former costs have a significant magnitude in these pathologies: for instance, in the USA the indirect costs of cardiovascular diseases and stroke were estimated to be 38% of the total costs of these diseases in 2004(26)).

The direct medical costs of the patients in the no treatment group were underestimated, since we attributed to them a zero cost, unless an event occurred. Actually the patients in the HOPE study were already using a variety of cardiovascular drugs (e.g. aspirin or other antiplatelet agents, beta-blockers, lipid-lowering agents, diuretics, calcium channel blockers): 75.3% of placebo patients were taking antiplatelet agents.

In this model we did not use as an effectiveness measure the cost per stroke averted, as found in other studies27, since we reasoned that it is quite difficult to measure different levels of severity and the related costs; moreover, the cost per life year gained is useful to compare different alternatives in different clinical entities.

Finally, considering that effective preventive strategies usually result in an increase of medical costs, the costeffectiveness ratios of this study appear acceptable. On the basis of the results, the use of ramipril is likely to represent an efficient use of public health expenditure in the Italian healthcare system.

Acknowledgements

This study was supported by Gruppo sanofi-aventis. The authors would like to thank Dr. Maria Pia Sormani, biostatistician, for his special advice during the design phase of the study and the modelling. Any eventual errors contained in this study are the sole responsibility of the authors.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2985_4, Accepted for publication: 22 April 2005

Published Online: 12 May 2005

doi:10.1185/030079905X46331

Stefano Capri(a) and Stefano Perlini(b)

a CREMS Centre for Research on Health Economics and Management, Cattaneo University-LIUC, Castellanza, Italy

b Clinica Medica II, Dipartimento di Medicina Interna e Terapia Medica, IRCCS 'San Matteo', Universit di Pavia, Italy

Address for correspondence: Dr Stefano Capri, CREMS-Centre for Research on Health Economics and Management, Universit Cattaneo- LIUC, Corso Matteotti 22, 21053 Castellanza (VA), Italy. Tel.: +39- 0331-572472; email: scapri@liuc.it

Copyright Librapharm Jun 2005

Source: Current Medical Research and Opinion

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