Comparative analysis of cost–effectiveness between isosorbide-5-mononitrate and isosorbide: a retrospective real-world evaluation

To our knowledge, our present study is one of a few studies to investigate the difference of clinical effectiveness and pharmacoeconomics between 5-ISMN and ISDN in the real-world setting. The principal finding of the present study is as follows: first, patients who received 5-ISMN treatment showed less frequency and dosage of sublingual nitroglycerin during the treatment of CHD, which indicated statistical significance. Second, in contrast to ISDN group, the 5-ISMN group saved total direct medical cost and shortened length of hospital stay. Fourth, the main factors relevant to direct medical cost included age, length of hospital stay and troponin level.

As a widely used nitrate, 5-ISMN has been used for treatment of CHD with a long time. By releasing nitric oxide, nitrates increase the level of cyclic guanosine monophosphate in smooth muscles and dilate coronary arteries and its collateral vessels [11]. Pharmacokinetic studies demonstrated that 5-ISMN might have an advantageous effect over ISDN, considering that it has no first-pass effect, low variation, greater bioavailability, slower clearance rate, and smaller volume of distribution at steady state, compared with its parental substance [10]. Wang compared the efficacy of both nitrates in Chinese chronic heart failure patients and found 5-ISMN improved the cardiac function more rapidly, alleviated chronic heart failure symptoms and signs more effectively than ISDN [12]. Our study obtained the similar result, it was observed that patients administered with intravenous 5-ISMN had a shorter average length of hospital stay compared with patients treated with ISDN.

Although it is well recognized that 5-ISMN is related with some adverse effects like hypotension and headache [13], the present real-world study demonstrated low and comparable incidence of adverse events in both the treatment groups. Kosoglou et al. evaluated the safety of 5-ISMN and ISDN in a randomized study, found that the incidence of treatment-related adverse events including headache, dizziness and nausea was lower among the patients receiving 5-ISMN than those ISDN [10]. In addition, because severity of adverse events is not so serious and did not need to be treated, we did not collect data about headache, vomiting and circulatory shock in this study. Furthermore, most adverse events could attribute to high initial dose or fast dripping speed, which could be avoided by tailored clinical practice in hospital. Since adverse events in the present study were collected based on final diagnosis in discharge, whether there were more adverse events that had occurred but had not been recorded was unclear. This therefore contributed to the difference in length of hospital stay and average hospitalization cost and need to be confirmed further.

It is worth mentioning that Derek et al. reported fixed-dose combination of isosorbide dinitrate and hydralazine therapy for blacks with heart failure reduced resource use and costs in African-American Heart Failure Trial (A-HeFT), long-term use of it displayed favorable cost–effectiveness [14]. In addition, one study focused on the cost comparison analysis between pentaerythrityl tetranitrate and ISDN prescribed to diabetic patients in Germany indicated that pentaerythrityl tetranitrate therapy tends to produce a saving in costs compared with ISDN therapy in diabetic patients when costs for co-medication are taken into account and after adjustment for age and co-morbidity [15]. The other cost–effectiveness study of nitrate therapy using a decision analysis demonstrated that despite a higher unit cost for ISMN, total anticipated treatment costs with this new long-acting nitrate are lower than those associated with ISDN and nitroglycerin patch therapy in patients with stable angina [16]. Moreover, a comparative study of isosorbide dinitrates and mononitrates in patients with ischemic heart disease and stable angina pectoris found that, although isosorbide dinitrate and mononitrates do not differ significantly in reduction of the anginal attacks and by an increase in exercise tolerance, but isosorbide dinitrate is more cost-effective. The results are similar with our findings, 5-ISMN could be a cost-effective treatment option for patients with CHD (either angina pectoris or myocardial infarction) comparing with ISDN. Sublingual nitroglycerin was used less frequently and with less dosage in the 5-ISMN group than that in ISDN group. Less usage of sublingual nitroglycerin may be less likely to induce the tolerance of it, which may result in a detrimental effect in the postischemic heart. Nitrate tolerance is the unavoidable outcome of continuous sublingual nitroglycerin use and remains a persistent therapeutic problem. Fan et al. [17] demonstrated that nitrate tolerance significantly exacerbated cardiac reperfusion injury as evidenced by increased cardiomyocyte apoptosis and necrosis, enlarged myocardial infarct size and decreased cardiac function recovery after reperfusion. The effect of smooth muscle relaxation induced by sublingual nitroglycerin might be mediated by changes in the activity of ALDH-2. Further studies confirmed this concept by demonstrating a marked attenuation of sublingual nitroglycerin-induced activation of the cyclic guanosine monophosphate-dependent cascade and vasodilatory potency after incubation with ALDH-2 inhibitors [18,19], so inactivation of the ALDH-2 play an important role in the sublingual nitroglycerin-induced tolerance. Conversely, ISMN and ISDN were unaffected by ALDH-2 inhibitors (or genetic ALDH-2 deletion) [19–21]. In addition, studies in clinical settings showed that chronic 5-ISMN treatment would not lead to NT. This was also proven by an experimental study which found that continuous infusion of 5-ISMN did not affect the blood pressure-lowering function of sublingual nitroglycerin [22]. By contrast, ISDN would rapidly induce nitrate tolerance at the early stage of treatment [13] and tolerance to its antianginal effects as well [23].

In brief, there are also limitations in our present study. First, this is an observational, retrospective, noninterventional, case-collection study, and the data are identified from patients’ electronic medical record database in a real-world setting, because of the limited information of the hospital information system, some of the principal clinical outcomes were not considered in this study. Second, the data included in this study came from different districts, since this is a bicentric study, the potential bias resulting from the different regions existed in this study. We used cost ratio between patients in the present study and the localized average patients to balance the bias. Third, our study focused only on direct medical costs and paid no attention to direct nonmedical and indirect costs, which may also be influential.

CHD patients using 5-ISMN were associated with fewer use of sublingual nitroglycerin, less hypotension incidence, shorter length of hospital stay and less hospitalization cost related to its comparator ISDN group. These findings suggested that the newer agent of 5-ISMN showed some advantages over traditional ISDN in relieving angina and myocardial ischemia. But a further study needs to be performed in the future, such as more consistent patients enrollment, and prospective study design used.

The authors thank L Li, Y Lin, X Ye and H Yao who performed the statistical analysis and database support work at Palan dataRx, and all the participants in the present study for their generous contributions.

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.