Potential impact on cost-effectiveness estimates of using immature survival data: a case study based on transcatheter edge-to-edge repair (TEER) used for patients with severe mitral regurgitation at high surgical risk.

OBJECTIVE: To review the survival modelling used in cost-effectiveness studies evaluating an interventional procedure and to discuss implications for decision-makers. DESIGN: A case study of three economic evaluations that each used immature data from the EVEREST II High Surgical Risk (HSR) Study of transcatheter edge-to-edge repair (TEER) for patients with severe mitral regurgitation (MR) who were at high risk of surgery. SETTING: Estimation of patient survival in cost-effectiveness studies. PARTICIPANTS: The EVEREST II HSR Study included 78 patients who had TEER of the mitral valve using the MitraClip device and a retrospectively identified control group of 36 patients who received medical management and were followed up for 12 months. Observed survival (TEER arm only) was updated at 5 years. RESULTS: Two studies used 12-month observed mortality from EVEREST II HSR to model survival over lifetime horizons. Observed and modelled survival were associated with considerable uncertainty due to short follow-up and small numbers of participants. Modelling control patients' survival required an approximate 10-fold extrapolation based on 12-month observation of only 38 patients. Observed 5-year survival in the TEER group differed from that less mature follow-up suggesting that survival modelling based on shorter follow-up was unsatisfactory. No public domain data for the control group are available beyond 12-month follow-up so meaningful estimates using mature data for both arms are currently not possible. A third study developed survival models using incompletely reported transitions between MR grades in EVEREST II HSR and mortality rates observed for different MR grades derived from a study in an unrelated population. CONCLUSIONS: Modelling survival in such small samples followed up for only 12 months is associated with great uncertainty, and cost-effectiveness results based on these analyses should be viewed as premature and used cautiously in reimbursement decisions.

Percutaneous mitral valve repair in severe secondary mitral regurgitation: Analysis of index hospitalization and economic evaluation based on the MITRA-FR trial.

BACKGROUND: Percutaneous mitral valve repair (pMVR) is reimbursed in France for severe secondary mitral regurgitation (SMR), but French data regarding the hospitalization index stay are lacking. AIMS: Our objectives were to describe the index hospitalization stay and to evaluate the cost of hospital stay for pMVR used in SMR. METHODS: A secondary evaluation based on patients who were randomized to the intervention group of the MITRA-FR study was undertaken. The economic evaluation was conducted according to the French hospital perspective. Medical resource use was estimated using specific data collected from patients enrolled in the MITRA-FR study and non-specific data from national statistics. RESULTS: The population was represented by 144 patients who underwent pMVR at 33 French centres. There was a mean±standard deviation of 7.9±1.5 hospital staff during procedures. The mean procedure duration was 154±68 minutes and increased with the number of implanted clips. Median total length of stay was 8 days. The occurrence of a serious adverse event was not associated with an increased risk of admission to the critical care unit, but was associated with an increased length of stay. The mean total cost was 28,025±3424€, which includes 21,547€ for the cost of medical devices used during pMVR and 6478±3424€ for other costs. CONCLUSION: The cost of pMVR is substantial for patients with SMR, which advocates for further efforts to identify the patients with SMR who are likely to derive a clear clinical benefit from the procedure.

Drug interactions between emergency contraceptive drugs and cytochrome inducers: literature review and quantitative prediction.

The emergency contraceptive drugs (EC), levonorgestrel (LNG) and ulipristal acetate (UPA), are sensitive substrates of cytochrome P450 3A4 (CYP3A4). In 2016, the label of LNG was updated based on a drug-drug interaction (DDI) study showing a significant decrease in LNG exposure when co-administered with efavirenz, a known CYP3A4 inducer. DDI between UPA and CYP3A4 inducers are poorly characterized. The aims of this study were to review quantitative data from the literature on DDI with EC, to provide quantitative predictions of DDI between UPA and CYP3A4 inducers, and to identify moderate and severe DDI that may require a dose adjustment. A literature search was performed on pharmacokinetic DDI of LNG and UPA. Quantitative prediction of DDI with UPA was carried out by using the in vivo mechanistic static model (IMSM). Limited information was available on DDI with emergency contraception drugs. For LNG, data from eleven studies were retrieved, including five known CYP3A4 inducers that confirmed a risk of underexposure to LNG when co-administered with inducers. For UPA, only three studies were identified, including only one CYP3A4 inducer. The IMSM approach indicated that UPA is a sensitive substrate of CYP3A4, with an estimated contribution of 86% of CYP3A4 to oral clearance. Moderate to severe DDI were predicted in 17 cases with CYP3A4 inducers, and dosage adjustments were suggested. This study illustrates the ability of the IMSM approach to inform about the DDI profile of old and new drugs.