Proceedings of the Fourth Genoa Meeting on Hypertension, Diabetes, and Renal Diseases
Economic Evaluation of Angiotensin Receptor Blockers in Type 2 Diabetes, Hypertension, and Nephropathy
Maura Ravera,
Michela Re and
Simone Vettoretti
Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine, University of Genoa, Department of Cardio-Nephrology, Azienda Ospedaliera Universitaria San Martino Genoa, Genoa, Italy
Address correspondence to: Dr. Maura Ravera, Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, 16123 Genoa, Italy. Phone: +39-10-353-8959; Fax: +39-10-353-8959; E-mail: mauraravera{at}unige.it
There is a rising incidence and prevalence of ESRD as a resultof diabetes, with poor outcome and growing costs. Recently,two large trials, the Irbesartan Diabetic Nephropathy Trial(IDNT) and Reduction of Endpoints in NIDDM with the AngiotensinII Antagonist Losartan (RENAAL), showed that angiotensin receptorblockers (ARB) are more effective than traditional antihypertensivetherapies at reducing progression toward ESRD in hypertensivepatients with type 2 diabetes and overt nephropathy, regardlessof changes in BP. The results of these two trials were usedto compare the costs of ARB with those of renal replacementtherapy (dialysis and renal transplantation) in an effort toestablish whether ARB are cost-saving because they delay ESRD.Two different pharmacoeconomic approaches were used. With regardto the RENAAL trial, the number of ESRD days on losartan therapyas compared with the number of ESRD days on standard antihypertensivetherapy was calculated, and the difference between the two wascombined with the costs of ESRD. In the IDNT trial, Markov modelswere applied to assess the economic impact of irbesartan andto extrapolate future clinical and cost outcomes. Several economicanalyses were performed in the United States and in Europeancountries. Applying pharmacoeconomic models showed that treatmentwith ARB was associated with a greater improvement in life expectancyand lower total costs compared with amlodipine and standardantihypertensive therapy. Therefore, treating patients withtype 2 diabetes, nephropathy, and hypertension with ARB is life-and cost-saving compared with traditional antihypertensive therapy.
The prevalence and incidence of ESRD that is treated by dialysisand renal transplantation are rising worldwide (1–3).Although 90% of treated patients with ESRD come from more developedcountries that can still afford the cost of renal replacementtherapy, the expenditures are dramatically rising, thus representingan economic problem even for industrialized countries (4). By2001, the costs of the ESRD program had reached almost $23 billionin the United States—nearly three times higher than 10yr before—with continuously increasing Medicare and non-Medicareexpenditures (1). In Europe, dialysis alone takes up approximately2% of the total health care budget, even though <0.1% ofthe population needs renal replacement treatment (4). Dialysisis a very expensive treatment modality, costing >$50,000per patient per year in the United States (1). In Europe, themean annual cost ranges from a minimum expense of 30,000 euroin the United Kingdom to a maximum of 60,000 euro in France.Renal transplantation provides ESRD care at a lower cost. Althoughthe first-year renal transplantation costs are elevated becauseof surgery and hospitalization expenditures, as of the secondyear, costs become markedly lower than dialysis-related expenditures(5–12). However, because of the ongoing shortage of kidneysthat are available for transplantation, dialysis treatment continuesto be the most prevalent modality of treatment for most patients.
Diabetic nephropathy is one of the most frequent causes of ESRD.In the past few years, the number of patients who have diabetesand have begun renal replacement therapy has not increased inthe United States alone, where they represent >40% of allnew cases of ESRD, but also in Japan, Australia, and New Zealand,as well as in European countries. Most of these patients (>90%)have type 2 diabetes (13). The economic burden of ESRD secondaryto diabetes is obviously overwhelming.
Pharmacoeconomic Analysis of Angiotensin Receptor Blockers in Type 2 Diabetes and Nephropathy
Two large trials evaluated the renoprotective role of angiotensinreceptor blockers (ARB) in patients with type 2 diabetes andovert nephropathy (14,15). The Irbesartan Diabetic NephropathyTrial (IDNT) trial showed that treatment with irbesartan wasassociated with a reduction of the risk for serum creatininedoubling (DSC), ESRD, and death compared with amlodipine orstandard antihypertensive therapy (24% versus amlodipine and19% versus control group, respectively). The risk for ESRD inthe irbesartan group was 23% lower than in the conventionaltherapy and amlodipine groups analyzed together. In the Reductionof Endpoints in NIDDM with the Angiotensin II Antagonist Losartan(RENAAL) trial, treatment with losartan resulted in a 15% reductionof the risk for the same primary composite end point that wasconsidered in the IDNT trial, whereas the risk for ESRD was25% lower in the losartan group than in the conventional treatmentgroup. It is interesting that the benefit of ARB went beyondBP control in both studies. The results of these two trialswere used to compare the costs of ARB with those of ESRD (dialysisor renal transplantation) in an effort to establish whetherARB are cost-saving because they are able to delay ESRD.
A simple method was used in the RENAAL study and was based onthe number of days that the patients experienced ESRD multipliedby the daily cost of ESRD. The number of days on ESRD was estimatedby subtracting the area under the Kaplan-Meier survival curvefor time to the minimum of ESRD or all-cause death from thearea under the Kaplan-Meier survival curve for all-cause death.Losartan reduced the number of ESRD days in patients with type2 diabetes and overt nephropathy by an average of 5.7 d overa 2-yr period. This difference was calculated between ESRD daysin the losartan and the control groups. It increased duringfollow-up, became significant from the third year on, and becamelonger than 40 d over a 4-yr period. This difference then wasmultiplied by the mean daily cost of ESRD (weighed mean costbetween dialysis and renal transplant) in each country. Thecost of losartan then was subtracted, and the net cost savingswere obtained. Results of this analysis in North America andin Europe are shown in Figure 1. All costs are reported in euro(exchange rate at December 31, 2004). During a 4-yr period,treatment with losartan was associated with a net cost savingthat ranged from 3,500 euro in Canada to nearly 6,000 euro inFrance (6,7,16,17).
Figure 1. Mean ESRD-related costs and net cost saving per patient at 4 yr in North America and Europe (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan study) (6,7,16,17). , net cost saving; /pt, euros per patient (exchange rate at December 31, 2004).
However, this method uses data only from the RENAAL study anddid not take into consideration either the probability of receivinga renal transplant or the different mortality rates observedin the various countries. Therefore, extrapolation to all patientswith type 2 diabetes is not possible. Furthermore, this methoddoes not allow for assessment of long-term clinical outcomesand costs. Markov models were used to overcome this limitation(18). Markov models are a standard method that simulates thecourse of long-term, progressive disease and have been usedin chronic diseases such as diabetes. These models assume thata patient is always in one of a finite number of discrete healthstates called Markov states. All events are represented as transitionsfrom one state to another.
A Markov model was created in the IDNT to simulate the long-termtreatment of hypertensive patients with type 2 diabetes andovert nephropathy and to extrapolate future clinical and costoutcomes. The model included three treatment strategies andfive primary health states: Overt nephropathy, DSC, ESRD treatedby dialysis, ESRD treated by renal transplant, and death. Allpatients started in the "overt nephropathy" state. The modelwas run over 3-, 10-, and 25-yr time horizons using 1-yr cycles.Patients transitioned to new states or remained within the samestate in each cycle. For example, patients in the overt nephropathystate could either remain in the same state or reach DSC, thusmoving to the DSC state, or they could reach ESRD and then moveto dialysis or renal transplant or die. Transition probabilitiesfor patients in the overt nephropathy and DSC states were calculatedusing the frequencies of events that were observed during thefirst 3 yr of the IDNT. Mean probability for the first 3 yrwas used to calculate transition probabilities for the fourthyear and beyond. Once a patient developed ESRD, the probabilitiesof death or of transition from dialysis to renal transplantand vice versa were assumed to be independent of the treatmentarm. Because no studies have compared the effects of irbesartan,amlodipine, and standard therapy in ESRD patients, these probabilitieswere derived from country-specific ESRD management and outcomedata (8–12,19,20).
Mean ESRD-free time was approximately 8.1 yr in the irbesartancohort with a 1.41-yr gain as compared with amlodipine and a1.35-yr gain as compared with conventional treatment. Moreover,simulated long-term treatment with irbesartan was associatedwith a lower incidence of ESRD as compared with amlodipine orcontrol. At 10 yr, the cumulative incidence of ESRD was 36%in the irbesartan arm, 45% in the control arm, and 49% in theamlodipine arm. At 25 yr, it was 47, 55, and 59%, respectively.Combined with country-specific data, these figures providedlife expectancy results. At 10 yr, simulated treatment withirbesartan was associated with a 6.40-yr life expectancy inthe United States, with a gain of nearly 2 mo compared withamlodipine and 4 mo versus standard therapy. At 25 yr, higherlife expectancy was observed for Europe than for the UnitedStates, regardless of treatment. Moreover, irbesartan was associatedwith higher life expectancy compared with amlodipine and standardtherapy in all of the countries where the analysis was performed,with gains ranging from 7 to 10 mo (8–11,19,20).
These clinical results have important financial implications.The costs of both medication and ESRD were assessed in all threetreatment arms. Costs were taken from each country-specific,third-party payer perspective (Medicare system in the UnitedStates, Ontario Health Insurance Schedule of Benefits and Feesin Canada, National Health Service in the United Kingdom, SocialSecurity in France, Institut National d’Assurance de Maladieet Invaliditè in Belgium, GKV in Germany, Sistema Nacionalde Salud in Spain, and Sistema Sanitario Nazionale in Italy).The costs for patients with overt nephropathy and DSC includedstudy drugs and concomitant antihypertensive agents, as reportedin IDNT. Because the aim of the study was to evaluate the incrementalcosts among the treatment arms alone, all costs that were consideredsimilar in the three treatment arms (e.g., visits to the generalpractitioner, expenditures as a result of cardiovascular events,urinary albumin determination) were excluded from the analysis.Study drug costs were calculated by dividing the number of daysof exposure to each dose by the number of patients, multipliedby the mean duration of follow-up, multiplied by the cost ofeach daily dose (daily dose costs were taken from Average WholesalePrice in the United States, Ontario Drug Formulary in Canada,British National Formulary in the United Kingdom, VIDAL in France,INAMI in Belgium, Rote List in Germany, Catalogo de EspecialidadesFarmaceuticas in Spain, and Informatore Farmaceutico in Italy).The cost of drugs was assumed to remain constant for the entiresimulation period. The price of the most often prescribed drugswas used for each class of concomitant antihypertensive therapy.
Figure 2 shows total costs and cost savings at 10 yr simulationfor North America and Europe. In the United States, treatmentwith irbesartan is associated with lower costs, thus leadingto cost savings of nearly 24% compared with expenditures foramlodipine and 17% compared with controls. Similar data areobserved for Canada, whereas some variations among the variouscountries are evident in Europe. In the United Kingdom, forexample, the net cost saving is nearly 18% compared with amlodipineand 12% compared with controls, whereas total costs are twiceas low as in the United States. Total costs and cost savingsat 25 yr are available for the United States, Belgium, and France.Net cost savings range from 20,000 to 27,000 euro versus amlodipineand 11,000 and 16,000 euro versus control (8–11,19,20).Therefore, irbesartan therapy is associated with net cost savings(nearly 25% of the expenditure for patients with type 2 diabetesand hypertension and nephropathy) in all countries, althoughtotal costs were different among countries.
Figure 2. Total costs and cost savings at 10 yr for hypertensive patients who have type 2 diabetes and nephropathy and are treated with irbesartan, compared with amlodipine and conventional therapy in North America and Europe (9–11,19,20).
A similar analysis was also performed in Italy (12) and showedthat annual costs per patient for dialysis treatment are similarto costs in other European countries. First-year transplantationcosts in Italy are as high as in North America or Germany, whereasannual costs as of the second year are similar to mean Europeanexpenditures. In Italy, simulated treatment with irbesartanwas associated with a life expectancy of >10 yr at 25 yr,with a gain of 7 and 10 mo compared with amlodipine and standardtherapy, respectively, consistent with what was reported inother European countries (8–11). Economic analysis showedthat treatment with irbesartan was associated with lower totalcosts compared with both amlodipine and control. In Italy, netcost saving was nearly 13,550 euro versus amlodipine and 8,000euro versus control. These cost savings were similar to thosereported in other countries. Cost savings became evident after3 yr of treatment with irbesartan and increased over time. Abreakdown of the total cost over a 10-yr simulation period showedthat the costs of ESRD represent the main expenditure (89 to95%), whereas the cost of amlodipine, irbesartan, and concomitantantihypertensive therapy make up only 8 to 10% of the 10-yrexpenditure. One-way sensitivity analysis was performed on lifeexpectancy and total costs by varying each probability and costby ±10% at a time while holding other parameters constant,so as to rank their impact order. In all of these analyses,it was assumed that the probabilities would return to thoseof the control group after the 3-yr trial period in all treatmentarms. Only the within-trial effects of irbesartan and amlodipinewere taken into consideration. Further sensitivity analyseswere performed on the annual costs of ESRD, the annual costsof irbesartan, and the time horizon of the analysis. Accordingto one-way sensitivity analysis of 10-yr life expectancy, theparameter with the greatest impact was the transition from overtnephropathy to death, followed by the transition from dialysisto death. One-way sensitivity analysis of 10-yr costs showedthat the parameter with the greatest impact was the annual costof dialysis, with costs for irbesartan only resulting in eighthplace. We conclude that treatment with irbesartan is life andcost saving even in Italy (12).
To understand how much can be saved, we must keep in mind thatexpenditure for the entire population with type 2 diabetes inItaly is nearly 5 billion euro, corresponding to 6.65% of theoverall national health expenditure. Mean annual costs rangefrom 1,500 euro for a patient who has type 2 diabetes withoutcomplications to >5,000 euro for a patient with both micro-and macrovascular complications (21–23). Treating patientswho have diabetes and overt nephropathy with ARB might leadto annual cost savings of 150 million euro, corresponding toa 3% decrease in the overall costs for type 2 diabetes and an0.2% decrease in the overall national health expenditure.
One of the main limitations, however, must be acknowledged inthe pharmacoeconomic approach of both the RENAAL trial and IDNT.Indeed, the key recommendation of all of the international guidelinesfor economic studies is that the pharmacoeconomic profile ofa drug be determined by comparing it with the current best alternativeor current standard care. None of the existing economic analysesof losartan or irbesartan in type 2 diabetes with nephropathyhas evaluated the potential benefits that are derived from alternativerenin-angiotensin-aldosterone system blocking agents, i.e.,angiotensin-converting enzyme (ACE) inhibitors, other ARB, orthe association of both. Because no clinical data that havecompared directly the efficacy of losartan or irbesartan withACE inhibitors or other ARB in type 2 diabetes and overt nephropathyare available, a valuable cost-effectiveness comparison analysisof these different therapies is not possible. This comparisoncan be made only indirectly. Cost-effectiveness analysis thatwas performed in type 1 diabetic and in nondiabetic nephropathiesshowed that chronic treatment with ACE inhibitors is cost-effectiveas well (24,25). Cost-effectiveness analysis of dual blockadetherapies probably would be even more effective. Preliminaryresults, indeed, suggest that association therapy is more renoprotectivethan ARB or ACE inhibitors alone, both in diabetic and nondiabeticnephropathies (26,27).
Optimization of available resources to maximize health willbe the key challenge to health care systems, both public andprivate, such as managed care organizations, in the next decade.Several countries recently introduced guidelines or legislationto mandate cost-effectiveness assessment of at least some aspectsof health care, particularly for the reimbursement of pharmaceuticals,and it is expected that thresholds for cost-effectiveness maybe established for the acceptance of reimbursement or formularylisting. When we consider the most important reno- and cardioprotectivestrategies that are recommended by the international guidelinesin type 2 diabetes, intensive BP reduction is the most cost-effectivetherapy as compared with intensive glycemic control and serumcholesterol level reduction (28). Last, treating patients whohave type 2 diabetes with hypertension and overt nephropathywith ARB is renoprotective and cost saving and prolongs life.
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Abstract
Introduction
, net cost saving; 
/pt, euros per patient (exchange rate at December 31, 2004).