Cost–Effectiveness of Angiotensin-converting Enzyme Inhibitors in Nondiabetic Advanced Renal Disease

Charles Christian Adarkwah; Afschin Gandjour


Expert Rev Pharmacoeconomics Outcomes Res. 2011;11(2):215-223. 

In This Article


This modeling study demonstrates that treating nondiabetic patients with advanced renal insufficiency with ACE inhibitors saves both money and lives. Despite the considerable costs of dialysis treatment, preventing ESRD does not necessarily lead to savings,[33] thus necessitating a detailed calculation of costs and benefits. As the benefit of ACE inhibitor therapy in patients with advanced chronic renal insufficiency has only recently been clearly demonstrated,[1] no other cost–effectiveness analysis is available for comparison. These results have important implications for the development of new treatment guidelines as current guidelines do not consistently recommend an ACE inhibitor in this patient group to delay the progression of renal disease.[34,35]

However, our model is far from perfect, but in modeling studies this is often the case owing to constraints of resources, time and information availability. Cost–effectiveness by treating nondiabetic advanced CKD with ACE inhibitors may be underestimated for several reasons. First, we did not model that ACE inhibitors reduce the risk of cardiovascular events,[36,37] which leads to additional savings. While our study does not consider savings from avoiding cardiovascular events, it does, however, consider that patients with CKD have a higher risk of cardiovascular death. This was captured by the mortality ratio for patients with CKD compared with the general population. Second, effectiveness (and thus savings) of benazepril may have been underestimated as ESRD treatment may have been initiated earlier than necessary in the ACE inhibitor arms of the RCTs by Hou et al.[1] and Ihle et al.[14] due to a drug-induced GFR decrease. Third, we did not consider, on the cost side, that some patients may discontinue ACE inhibitor therapy and thus incur no drug costs. The reason is that information on compliance was unavailable in the two RCTs.[1,14] Treatment discontinuation was only considered on the effect side, as the rate of compliance is implicitly incorporated in clinical trial results, that is, efficacy data refer both to adherers and nonadherers. For this reason, the Markov model includes patients who discontinue ACE inhibitor treatment in the ACE inhibitor arm. Fourth, we did not consider that the SHI is able to negotiate special drug discounts with pharmaceutical companies. And fifth, we were not able to consider healthcare costs that are unrelated to dialysis for patients who receive dialysis due to a lack of available data.

On the other hand, savings may be smaller than estimated by our model because some elderly patients may have a preference against replacement therapy and hence do not incur the associated costs. The bias seems small, however, given that the percentage of elderly patients requiring renal replacement therapy is small (e.g., less than 3% at the age of 80 years and above). Further limitations of the model relate to its data sources. First, the two trials considered as the source of our effectiveness data used, for ACE inhibition, enalapril and benazepril, respectively. Whether other types of ACE inhibitors can achieve the results reported in these studies is not clear. There are potentially important differences in the plasma protein binding, the affinity for ACE and the pharmacokinetics of different ACE inhibitors.[38] Still, there is no convincing evidence that generic long-acting ACE inhibitors (e.g., lisinopril and enalapril) are inferior to brand-name ACE inhibitors.[38,39] Second, our preference weights for patients with advanced renal disease were taken from a US study[38] as no similar data for German patients were available. Third, the model also uses some epidemiological data from developed countries other than Germany. One of the two studies we used as the source of our effectiveness data was conducted in China.[1] There is a debate on whether a significant difference between Caucasian and Asian populations exists due to ACE gene polymorphism, which might lead to a difference in the efficacy of ACE inhibitors. In fact, studies examining the association between differences in ACE gene polymorphism and the efficacy of ACE inhibitors have had contradictory results.[40] In a controlled trial performed among Japanese patients with nondiabetic CKD whose blood pressure was maintained at an average of 126/72 mmHg with ACE inhibitors, no significant correlation was observed between the type of ACE gene polymorphism (ACE gene insertion/deletion polymorphisms: deletion/deletion [DD], insertion/deletion [ID] or insertion/insertion [II]) and the efficacy of the intervention or renal outcome.[41] On the other hand, a controlled trial among 212 Caucasians demonstrated that ACE inhibitor therapy was protective against progression to ESRD only in patients with the DD genotype.[42] But even if this small trial is confirmed, treating white patients regardless of ACE genotype may not have a smaller impact than treating Asians. This is because whites with the DD genotype may have a stronger response than the average Asian patient. Furthermore, the study by Ihle et al.,[14] which was conducted in Australia, demonstrates a similar result to the study by Hou et al.[1] And third, longitudinal studies that have examined long-term outcomes of ACE inhibitor treatment in patients with advanced CKD are not available for model validation. This is a common limitation of models for the prevention of renal failure.


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