Empagliflozin cost-effectiveness analysis in Japanese heart failure with mildly reduced and preserved ejection fraction.

AIMS: Empagliflozin, a sodium-glucose co-transporter 2 inhibitor, was shown to be effective in patients with heart failure with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved trial. The present study aims to evaluate the cost-effectiveness of empagliflozin among Japanese patients with HFpEF. METHODS AND RESULTS: A Markov cohort model was developed to evaluate the cost-effectiveness of empagliflozin added to standard of care (SoC) compared with SoC alone in patients with HFpEF from the perspective of the Japanese healthcare system and with a lifetime horizon. In addition to clinical events, the progression of disease severity was modelled based on the migration of Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores (KCCQ-CSS). Model inputs, including risk of clinical events, costs, and utilities/disutilities, were derived from EMPEROR-Preserved trial data, a claims database and published literature. The generalizability of model results was investigated by applying various subgroups including age, body mass index (BMI), and region Asia, based on the subgroup analysis of EMPEROR-Preserved data. In the base-case analysis, empagliflozin yielded additional quality-adjusted life years (QALYs; 0.11) with an incremental cost of $1408 per patient for Japanese patients with HFpEF. Incremental cost, mainly derived from drug acquisition cost ($1963 per patient), was largely offset by reduced cost in hospitalization for heart failure (HHF) and cardiovascular death (-$537 per patient and -$166 per patient, respectively). Treatment of empagliflozin provided incremental 0.11 QALYs and 0.08 life years compared with SoC alone. The incremental cost-effectiveness ratio (ICER) was $12 772 (¥1 662 689)/QALY, which was below the Japanese willingness-to-pay (WTP) threshold of $38 408 (¥5 000 000)/QALY. The results were consistent across all the subgroups considered, and empagliflozin was dominant over SoC alone in the region Asia and BMI < 25 kg/m2 subgroups. ICERs for the remaining subgroups ranged from $7520/QALY (¥978 972/QALY, patients with baseline age ≥ 75 years) to $31 049/QALY (¥4 041 896/QALY, patients with baseline New York Heart Association class III/IV). Deterministic sensitivity analysis result showed that the treatment effect on HHF is the biggest driver of the cost-effectiveness analysis, while the ICER will be still under the threshold even if no effect of empagliflozin on HHF was assumed. The probabilistic sensitivity analysis result showed that 64% of simulations were cost-effective based on the Japanese WTP threshold. CONCLUSIONS: Empagliflozin was demonstrated to be cost-effective for patients with HFpEF in Japan based on EMPEROR-Preserved trial data.

Cost-effectiveness analysis of empagliflozin in patients with heart failure with reduced ejection fraction in Japan based on the EMPEROR-Reduced trial.

BACKGROUND: Several studies have reported the cost-effectiveness of sodium-glucose co-transporter 2 inhibitors in heart failure patients; however, their economic implications have not been sufficiently elucidated in Japan. METHODS: A Markov cohort model was developed to evaluate the cost-effectiveness of empagliflozin plus standard of care (SoC) vs. SoC for patients with heart failure with reduced ejection fraction (HFrEF) in Japan. Model inputs, including risk of clinical events, costs, and utilities based on Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores were derived from EMPEROR-Reduced trial data, published literature, and a claims database. RESULTS: The model predicted lower lifetime hospitalizations for heart failure (HHFs) and additional quality-adjusted life-years (QALYs; 0.21) for empagliflozin plus SoC vs. SoC in the overall population. Increased costs of ¥100,495/patient ($772/patient), primarily driven by higher drug costs of ¥239,558/patient ($1,840/patient), were largely offset by reduced HHF management costs of -¥166,160/patient (-$1,276/patient), yielding an incremental cost-effectiveness ratio (ICER) of ¥469,672/QALY ($3,608/QALY). Results were consistent among subgroups and sensitivity analyses. In probabilistic sensitivity analysis, 82.5 % of runs were below the Japanese ICER reference value of ¥5,000,000/QALY ($38,408/QALY). CONCLUSIONS: Empagliflozin was demonstrated to be cost-effective for HFrEF patients in Japan based on the EMPEROR-Reduced trial data.

Optimization of pressure settings during adaptive servo-ventilation support using real-time heart rate variability assessment: initial case report.

BACKGROUND: Adaptive servo-ventilation (ASV) therapy is a recent non-invasive positive pressure ventilation therapy that was developed for patients with heart failure (HF) refractory to optimal medical therapy. However, it is likely that ASV therapy at relatively higher pressure setting worsens some of the patients' prognosis compared with optimal medical therapy. Therefore, identification of optimal pressure settings of ASV therapy is warranted. CASE PRESENTATION: We present the case of a 42-year-old male with HF, which was caused by dilated cardiomyopathy, who was admitted to our institution for evaluating his eligibility for heart transplantation. To identify the optimal pressure setting [peak end-expiratory pressure (PEEP) ramp test], we performed an ASV support test, during which the PEEP settings were set at levels ranging from 4 to 8 mmHg, and a heart rate variability (HRV) analysis using the MemCalc power spectral density method. Clinical parameters varied dramatically during the PEEP ramp test. Over incremental PEEP levels, pulmonary capillary wedge pressure, cardiac index and high-frequency level (reflecting parasympathetic activity) decreased; however, the low-frequency level increased along with increase in plasma noradrenaline concentrations. CONCLUSIONS: An inappropriately high PEEP setting may stimulate sympathetic nerve activity accompanied by decreased cardiac output. This was the first report on the PEEP ramp test during ASV therapy. Further research is warranted to determine whether use of optimal pressure settings using HRV analyses may improve the long-term prognosis of such patients.

Tolvaptan Reduces Long-Term Total Medical Expenses and Length of Stay in Aquaporin-Defined Responders.

The vasopressin type-2 antagonist tolvaptan (TLV) has clinical advantages including amelioration of congestion and normalization of hyponatremia in patients with decompensated heart failure (HF). However, there have been no studies on the cost-effectiveness of TLV therapy. We enrolled 60 consecutive hospitalized patients with stage D HF who received TLV [TLV (+) group], and 60 propensity score-matched HF patients without TLV treatment [TLV (-) group]. We excluded 54 patients who died or received cardiac replacement therapy within 1 year, and finally enrolled 32 patients who received TLV and 34 who did not, who were followed for > 1 year. Among 45 aquaporin-defined responders, whose urine aquaporin-2 relative to plasma arginine vasopressin level was > 1.4 × 10(3) L/g Cre, the TLV (+) group required significantly lower total medical expenses and shorter lengths of stay (LOS) compared with the TLV (-) group [11.2 (1.233.3) versus 31.2 (2.2-71.4) × 10(5) JPY/year, P < 0.001; 30 (0-304) versus 70 (20-221) days, P = 0.030]. In contrast, among the remaining 21 aquaporin-defined non-responders, medical expenses and LOS were comparable irrespective of TLV administration (P = 0.087 and P = 0.407). In conclusion, TLV therapy may reduce total medical expenses in aquaporin-defined responders with stage D HF.

Real-Time Assessment of Autonomic Nerve Activity During Adaptive Servo-Ventilation Support or Waon Therapy.

Adaptive servo-ventilation support and Waon therapy are recently developed non-pharmacological and noninvasive therapies for patients with heart failure refractory to guideline-directed medical therapy. These therapies decrease both preload and afterload, increase cardiac output, and appear to ameliorate autonomic nerve activity. However, the time course of autonomic nerve activity during these therapies remains unclear. We performed heart rate variability analysis using the MemCalc power spectral density method (MemCalc system; Suwa Trust Co, Tokyo) to assess autonomic nerve activity during adaptive servo-ventilation support and Waon therapy in two different cases and determined the time course of autonomic nerve activity during these therapies. During both therapies, we found a drastic increase in parasympathetic nerve activity and continuous suppression of sympathetic nerve activity. Heart rate variability analysis using the MemCalc method may be promising for the assessment of the efficacy of various treatments, including adaptive servo-ventilation support and Waon therapy, from the viewpoint of autonomic nerve activity.

How Should We Treat Early Post-Transplant Lymphoproliferative Disease After Heart Transplantation?

Although post-transplant lymphoproliferative disease (PTLD) is one of the major fatal complications encountered several years after heart transplant (HTx), little is known about early-PTLD emerging within the first year. We here describe the rare case of a 24-year-old female patient who suffered from early-PTLD (DLBCL: diffuse large B-cell lymphoma) associated with an Epstein-Barr virus (EBV) infection, that developed around the jejunum at 7 months after HTx. She suffered from acute abdominal peritonitis due to perforation of the jejunum soon after the first chemotherapy. She was treated successfully by emergent partial resection of the jejunum and colostomy after the discontinuation of everolimus (EVL) and successive low-dose chemotherapy under careful monitoring and adjustment of intravenous immunosuppressant including cyclosporine (CyA) and prednisolone to avoid a rejection reaction. Prophylactic strategies for early-PTLD in HTx recipients should be undertaken with caution.

Prophylactic Intra-Aortic Balloon Pump Before Ventricular Assist Device Implantation Reduces Perioperative Medical Expenses and Improves Postoperative Clinical Course in INTERMACS Profile 2 Patients.

BACKGROUND: Although intra-aortic balloon pump (IABP) is sometimes used before cardiac surgery to achieve better outcome in high-risk patients, the clinical impact of prophylactic IABP support before left ventricular assist device (LVAD) implantation in patients with worsening hemodynamics was unknown. METHODS AND RESULTS: We enrolled 22 patients with worsening hemodynamics who had received IABP support before LVAD (IABP group), and also enrolled 22 patients receiving neither IABP nor extracorporeal membrane oxygenation before LVAD, who were selected on propensity score matching (non-IABP group). Although both groups had similar preoperative background, the IABP group had shorter postoperative intensive care unit (ICU) stay, and more improved hemodynamics (P<0.05 for all). Serum total bilirubin and creatinine decreased significantly in the IABP group compared with the non-IABP group during 1 month after LVAD implantation (P<0.05 for both). Medical expenses during perioperative ICU stay were significantly lower in the IABP group compared with the non-IABP group, even including the cost of preoperative IABP support (P<0.05). CONCLUSIONS: Prophylactic IABP support in heart failure patients with worsening hemodynamics improves post-LVAD clinical course and reduces perioperative medical expenses.