Expensive Therapies Research Articles

Primary Aneurysmal Bone Cyst of Sacrum: A Case Report of a 12 years old boy from Pakistan

Aneurysmal bone cysts are locally invasive, benign lesions usually found in the spine or metaphysis of long bones. They can be primary (idiopathic) or secondary to other bone pathologies. Primary aneurysmal bone cyst usually occurs in the first two decades of life. We report a 12 years old male, a known case of Type-1 diabetes mellitus, with lower back pain radiating to the right lower limb for the past two months following a fall. There were no neurological deficits, although straight leg raises and Faber’s tests were positive. Neuroimaging suggested an enhancing 7 x 8 mm lesion involving the lamina of the first sacral vertebra with protrusion into the spinal canal. Bone scan ruled out metastatic pathology. Excision of the lesion with laminectomy and foraminotomy was done. Histopathology was suggestive of aneurysmal bone cyst. The patient is living a healthy life. Upfront surgical excision without preoperative embolization and expensive medical therapies can be an option in resource-limited settings. doi: https://doi.org/10.12669/pjms.40.12(PINS).10988 How to cite this: Qadri HM, Khawaja AA, Bashir R, Bashir A. Primary Aneurysmal Bone Cyst of Sacrum: A Case Report of a 12 years old boy from Pakistan. Pak J Med Sci. 2024;40(12):S95-S98. doi: https://doi.org/10.12669/pjms.40.12(PINS).10988 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Simultaneous or sequential kidney-liver transplantation in primary hyperoxaluria.

Primary hyperoxaluria type 1 is responsible for pediatric kidney failure in 1 to 2% of cases. Novel therapies based on RNA interference are changing the natural history of the disease. However, for those who do progress to kidney failure, and for patients living in countries that cannot afford these expensive therapies, liver-kidney transplantation may remain the only efficient therapy. The aim of the study was to evaluate the outcome of patients with primary hyperoxaluria type 1 who received simultaneous or sequential liver-kidney transplantation. We retrospectively evaluated 10 patients, five of whom received a simultaneous transplantation, and five underwent sequential transplantation, with a median postponement of the kidney transplantation of 8months (range 4-20). Among the patients, 5 were from medium-lowincome countries. Median follow up was 3.2years (range 1.6-11). Median estimated glomerular filtration rate at 6 and 12months was 81.2 (range: 45.7-108.8) and 79.3ml/min/1.73m2 (range 54.7-112.1) in patients who underwent simultaneous transplantation, and 45.7 (range 34.5-86.7) and 38.3ml/min/1.73m2 (range 29.9-77.5) in those with sequential transplantation (p:NS). Biopsies performed at 6 and 12months showed precipitation of calcium oxalate crystals in 7 patients, demonstrating the recurrence of deposition despite the delay between liver and kidney transplantation. No differences in kidney function or in post-transplant renal oxalate precipitation were observed between patients that underwent bilateral nephrectomy and those who did not. As of their most recent follow up, none of the patients has lost their kidney graft. Our study shows that by adapting the transplant strategy to individual cases, patients with primary hyperoxaluria type 1 can be successfully treated.

Sodium-glucose cotransporter 2 inhibitor therapy reduces the administration frequency of steroid injection in patients with diabetic macular edema: A cohort study using the Japanese health insurance claims database.

Severe diabetic macular edema (DME) is often resistant to anti-vascular endothelial growth factor therapy. Steroids are particularly effective at reducing edema by suppressing inflammation; they are also used as an alternative to expensive anti-vascular endothelial growth factor therapy in some patients. Therefore, the use of steroids in DME reflects an unmet need for anti-vascular endothelial growth factor therapy. Notably, triamcinolone acetonide (TA) injections are widely used in Japan. Here, we evaluated the frequency of TA as an indicator of the efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in DME treatment using a health insurance claims database. In this cohort study, we retrospectively analyzed the health insurance claims data of 11 million Japanese individuals from 2005 to 2019. The frequency and duration of TA injection after the initiation of SGLT2is or other antidiabetic drugs were analyzed. Among the 2,412 matched patients with DME, the incidence rate of TA injection was 63.8 times per 1,000 person-years in SGLT2i users and 94.9 times per 1,000 person-years in non-users. SGLT2is reduced the risk for the first (P = 0.0024, hazard ratio 0.66, 95% confidence interval 0.50-0.87), second (P = 0.0019, hazard ratio 0.53, 95% confidence interval 0.35-0.80) and third TA (P = 0.0053, hazard ratio 0.44, 95% confidence interval 0.25-0.80) injections. A subanalysis of each baseline characteristic of the patients showed that SGLT2is were effective regardless of the background factors. The use of SGLT2is reduced the frequency of TA injection in patients with DME. Therefore, SGLT2i therapy might be a novel, noninvasive and low-cost adjunctive therapy for DME.

Access to Expensive Therapies and Diagnostics for Kidney Care in Switzerland.

In Switzerland, nephrologists must frequently obtain pre-authorizations from health insurers for certain medications/tests for individual patients. These are time consuming and outcomes are inconsistent. Clinical experience suggest inequities in access to expensive medications, related to need for and processes involved with medication pre-authorization requests. An anonymous survey was conducted between November 2021 and March 2022 regarding experiences in applying for pre-authorizations for medications and genetic testing required for kidney care conducted among nephrologists in Switzerland. Ninety-four responses were received. The most common medications reported to require pre-approvals were rituximab, sodium glucose cotransporter-2 inhibitors (SGLT2i), mycophenolate mofetil (MMF) and eculizumab. Rebuttals were reported to be most frequently required for rituximab, eculizumab and SGLT2i, also the most frequently denied medications. Most frequent genetic testing requests were for complement and Alports spectrum disorders. Requests for genetic testing were reported to be most frequently denied for cystic renal diseases, congenital syndromes and nephrotic syndrome.Most nephrologists found requests for further information from the health insurers were seldom reasonable; 72% reported it was rarely/never possible to engage with the insurance physicians, 69% were concerned insurance physicians did not have relevant expertise. Respondents reported receiving different responses from different insurers for similar requests more frequently than from the same insurer (58% vs 8%). One in three nephrologists reported that the pre-authorizations process frequently resulted in a clinically relevant delay in treatment. Four of five respondents reported that the pre-authorization process frequently made them feel that they could not do their best for the patient. From the perspective of nephrologists, the pre-authorizations process in Switzerland is cumbersome, not transparent and inequitable, may result in denial or delays of important treatment for patients and contributes to moral distress.

Recent Advances in Gene Therapy for Hemophilia: Projecting the Perspectives.

One of the well-known X-linked genetic disorders is hemophilia, which could be hemophilia A as a result of a mutation in the F8 (factor VIII) gene or hemophilia B as a result of a mutation in the F9 (factor IX) gene, leading to insufficient levels of the proteins essential for blood coagulation cascade. In patients with severe hemophilia, factor VIII or factor IX activities in the blood plasma are considerably low, estimated to be less than 1%. This is responsible for spontaneous or post-traumatic bleeding episodes, or both, leading to disease complications and death. Current treatment of hemophilia relies on the prevention of bleeding, which consists of expensive lifelong replacement infusion therapy of blood plasma clotting factors, their recombinant versions, or therapy with recombinant monoclonal antibodies. Recently emerged gene therapy approaches may be a potential game changer that could reshape the therapeutic outcomes of hemophilia A or B using a one-off vector in vivo delivery and aim to achieve long-term endogenous expression of factor VIII or IX. This review examines both traditional approaches to the treatment of hemophilia and modern methods, primarily focusing on gene therapy, to update knowledge in this area. Recent technological advances and gene therapeutics in the pipeline are critically reviewed and summarized. We consider gene therapy to be the most promising method as it may overcome the problems associated with more traditional treatments, such as the need for constant and expensive infusions and the presence of an immune response to the antibody drugs used to treat hemophilia.

Fecal microbiota composition is a better predictor of recurrent Clostridioides difficile infection than clinical factors in a prospective, multicentre cohort study

IntroductionClostridioides difficile infection (CDI) is the most common cause of antibiotic-associated diarrhoea. Fidaxomicin and fecal microbiota transplantation (FMT) are effective, but expensive therapies to treat recurrent CDI (reCDI). Our objective was to develop a prediction model for reCDI based on the gut microbiota composition and clinical characteristics, to identify patients who could benefit from early treatment with fidaxomicin or FMT.MethodsMulticentre, prospective, observational study in adult patients diagnosed with a primary episode of CDI. Fecal samples and clinical data were collected prior to, and after 5 days of CDI treatment. Follow-up duration was 8 weeks. Microbiota composition was analysed by IS-pro, a bacterial profiling technique based on phylum- and species-specific differences in the 16–23 S interspace regions of ribosomal DNA. Bayesian additive regression trees (BART) and adaptive group-regularized logistic ridge regression (AGRR) were used to construct prediction models for reCDI.Results209 patients were included, of which 25% developed reCDI. Variables related to microbiota composition provided better prediction of reCDI and were preferentially selected over clinical factors in joint prediction models. Bacteroidetes abundance and diversity after start of CDI treatment, and the increase in Proteobacteria diversity relative to baseline, were the most robust predictors of reCDI. The sensitivity and specificity of a BART model including these factors were 95% and 78%, but these dropped to 67% and 62% in out-of-sample prediction.ConclusionEarly microbiota response to CDI treatment is a better predictor of reCDI than clinical prognostic factors, but not yet sufficient enough to predict reCDI in daily practice.

First-line serplulimab plus chemotherapy versus chemotherapy in PD-L1-positive esophageal squamous-cell carcinoma: a cost-effectiveness analysis

Patients with PD-L1-positive esophageal squamous-cell carcinoma (ESCC) were significantly more likely to survive when treated with serplulimab plus cisplatin plus 5-fluorouracil (serplulimab-CF). At this point, it is unknown whether this expensive therapy is cost-effective. From the Chinese healthcare system's perspective, we aimed to evaluate serplulimab-CF versus CF alone for cost-effectiveness. A partitioned survival model was constructed based on the ASTRUM-007 trial. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated. A further analysis of subgroups and scenarios was conducted. The willingness to pay (WTP) threshold of $38,258/QALY or $84,866/QALY is defined as three times the per capita gross domestic product value of the general region or affluent region. Compared with CF alone, in the overall (scenario 1), patients with PD-L1 expression level of 1 ≤ CPS < 10 (scenario 2), and patients with PD-L1 CPS ≥ 10 (scenario 3) populations, the ICERs were $69,025/QALY, $82,533/QALY, and $75,436/QALY for serplulimab-CF. Nevertheless, the probability of serplulimab-CF becoming cost-effective based on scenarios 1, 2, and 3 is only 2.71%, 0.94%, and 2.84%, respectively, at a WTP threshold of $38,258/QALY. When serplulimab costs < $4.84/mg, serplulimab-CF may be cost-effective at the WTP threshold of $38,258/QALY; otherwise, CF was preferred. Similar results were obtained from sensitivity analyses, suggesting the robustness of these findings. There was no cost-effectiveness in general regions of China for serplulimab-CF in PD-L1-positive ESCC compared to CF, although it is probably considered cost-effective in affluent regions. Serplulimab-CF may achieve favorable cost-effectiveness by lowering the price of serplulimab.

A randomized study evaluating tailoring of advanced/metastatic colorectal cancer (mCRC) therapy using circulating tumor DNA (ctDNA): TACT-D.

LBA3557 Background: Identifying non-responders to expensive salvage therapies with modest benefits and substantial treatment related adverse events (TRAEs) (e.g. regorafenib [Reg] or TAS102 [Tas] in mCRC) is key to precision care. Retrospective studies suggest that ctDNA changes at timepoints (4-10 weeks [wks] into therapy) before radiographic assessment may predict treatment outcomes. However, prospective studies assessing early ctDNA changes are lacking and clinical utility remains uncertain. Methods: TACT-D is a randomized study to validate early dynamic changes in ctDNA (ΔctDNA: change in either maximum variant allele frequency (maxVAF) or mean VAF in predicting treatment response/resistance. Patients (pts) with mCRC clinically eligible for Reg/Tas were randomly assigned 2:1 to either standard of care (SOC) or ctDNA arm. All pts had ctDNA sequencing by Guardant360 CDx assay on cycle 1 day 1 (C1D1) and C1D15. On SOC arm, pts were restaged at 8 wks. On ctDNA arm, ΔctDNA (C1D15 - C1D1) was run in real-time and increase in ctDNA (ΔctDNA &gt; 0) triggered early radiographic restaging. Therapy was continued for responders (RECISTv1.1 stable disease/response) and stopped for progression (non-responders). Co-primary endpoints were: 1) comparison of TRAEs among study arms and 2) association of ΔctDNA and objective response rate (RR). Key secondary endpoints were progression free (PFS) and overall (OS) survival. Study was powered (82%; 2-sided α = .05) to detect 30% decrease in toxicity. Results: Between 4/2019 and 8/2023, 100 pts were randomized; 80 evaluable had median age of 56 years, 46% were females, 44% and 56% received Tas and Reg, respectively. Baseline ctDNA levels (ρ 0.90) and ΔctDNA (ρ 0.68) using maxVAF (reported below) and mean VAF showed strong correlation (P &lt; .001). Median ΔctDNA for entire cohort was -47% with no significant difference by treatment arms (SOC -45% v Exp -58%, P = .79) and therapy (Tas -71 v Reg -44, P = .19). ΔctDNA increased in 18% pts. Grade 3/4 TRAEs (32% v 40%, P = .62) did not differ significantly between arms. No significant association was seen between ΔctDNA and RR (OR .88, P = 1.0), PFS (HR .99, P = .88) and OS (HR 1.00, P = .64). Notably, higher baseline maxVAF was strongly associated with response (median maxVAF: 21.8% in non-responders v 3.4% in responders), PFS (HR 1.02) and OS (HR 1.03) (all P &lt; .001). After adjusting for baseline maxVAF, ΔctDNA was found to be associated with both PFS (HR 1.87, P = .038) and OS (HR 3.55, P = .001). Conclusions: In the first prospective study of clinical utility of monitoring ctDNA in mCRC, baseline ctDNA was strongly prognostic for clinical benefit from salvage therapies in mCRC. Adjusted for this prognostic impact, ΔctDNA between C1D1 and C1D15 was predictive of clinical outcomes. Efforts are needed to establish novel signatures, optimal cutoffs/intervals for assessing ctDNA response in mCRC, tailored to pts and their therapy. Clinical trial information: NCT03844620 .

Real-world cost of disease progression (PD) after frontline (1L) R-CHOP in diffuse large B-cell lymphoma (DLBCL): An analysis of a large US claims database.

e19036 Background: Previous studies on the cost of PD in DLBCL do not reflect evolving standards of care and contain limited data on novel therapies in the relapsed/refractory setting. Here, we evaluated the cost of DLBCL PD after 1L therapy using recently available data from a US healthcare database of largely commercial health plan claims. Methods: Using previously published methods (Burke, et al. 2023), this retrospective cohort study analyzed data from IQVIA PharMetrics Plus. Patients (pts) with DLBCL receiving 1L therapy with R-CHOP between October 2016 and March 2021 were included. Index date was defined as a ≥60-day gap in treatment or initiation of new agents. Pts who received non-R-CHOP therapy after 1L were assigned to the ‘PD cohort’ and those not receiving second-line (2L) treatment for ≥2 years to the ‘no PD’ cohort. All pts had continuous enrollment in medical and pharmacy benefits from R-CHOP initiation to ≥2 years post index date, allowing time for post-1L relapse. Unadjusted all-cause healthcare costs per-patient-per-month (PPPM) and 3-year cumulative costs (2023 USD) were compared between cohorts. Generalized linear models were used to adjust for baseline characteristics including age, gender, US region, payer type, Charlson Comorbidity Index (CCI), index year, and healthcare costs 1 year before index date. Results: Overall, 824 pts were included (PD cohort, n=156; no PD cohort, n=668); mean follow-up was 41.6 months. In the overall cohort: 41% were female; and at index mean (SD) age was 58.6 (11.8) years and CCI (non-cancer comorbidity) was 2.5 (3.0). Baseline characteristics were generally similar between cohorts. In the PD cohort, 76 pts (48.7%) had multiple relapse events (3L+), 67 (42.9%) received stem-cell transplant, and 27 (17.3%) received chimeric antigen T-cell therapy (CAR-T). Adjusted mean PPPM cost was higher among the PD than no PD cohort ($11,432 vs $1,698, respectively; p&lt;0.001). A major cost driver was inpatient cost (40.1% and 21.6% of total cost for PD and no PD cohort, respectively). Treatments with CAR-T in the PD cohort were associated with an 18-fold increase in PPPM cost vs the no PD cohort ($29,794 vs $1,689, respectively; p&lt;0.001), and a 4-fold increase vs pts with PD who did not receive CAR-T ($7,829; p&lt;0.001). Adjusted 3-year cumulative costs were higher in the PD ($456,045) vs no PD ($60,519) cohort. Conclusions: Compared with a previous analysis on cost of PD after 1L R-CHOP in DLBCL (2010–2018; Burke, et al. 2023), this updated analysis indicates the cost is considerable, especially among pts receiving CAR-T in later lines, and is increasing, likely due to increasing utilization of novel, more expensive therapies. 1L treatments that prevent or delay relapse could thus reduce the economic burden of PD. Our findings are of use in determining the economic value of emerging 1L options that can successfully reduce the risk of relapse.

An international learning collaborative phase 2 trial for haploidentical bone marrow transplant in sickle cell disease

AbstractIn the setting of a learning collaborative, we conducted an international multicenter phase 2 clinical trial testing the hypothesis that nonmyeloablative–related haploidentical bone marrow transplant (BMT) with thiotepa and posttransplant cyclophosphamide (PTCy) will result in 2-year event-free survival (no graft failure or death) of at least 80%. A total of 70 participants were evaluable based on the conditioning protocol. Graft failure occurred in 8 of 70 (11.4%) and only in participants aged <18 years; all had autologous reconstitution. After a median follow-up of 2.4 years, the 2-year Kaplan-Meier–based probability of event-free survival was 82.6%. The 2-year overall survival was 94.1%, with no difference between children and adult participants. After excluding participants with graft failure (n = 8), participants with engraftment had median whole blood donor chimerism values at days +180 and +365 after transplant of 100% (n = 58), respectively, and 96.6% (57/59) were off immunosuppression 1 year after transplant. The 1-year grade 3 to 4 acute graft-versus-host disease (GVHD) rate was 10%, and the 2-year moderate–severe chronic GVHD rate was 10%. Five participants (7.1%) died from infectious complications. We demonstrate that nonmyeloablative haploidentical BMT with thiotepa and PTCy is a readily available curative therapy for most adults, even those with organ damage, compared to the more expensive myeloablative gene therapy and gene editing. Additional strategies are required for children to decrease graft failure rates. The trial was registered at www.clinicaltrials.gov as #NCT01850108.

Financial burden among metastatic breast cancer patients: a qualitative inquiry of costs, financial assistance, health insurance, and financial coping behaviors.

Metastatic breast cancer (MBC) patients often face substantial financial burden due to prolonged and expensive therapy. However, in-depth experiences of financial burden among MBC patients are not well understood. Qualitative interviews were conducted to describe the experiences of financial burden for MBC patients, focusing on the drivers of financial burden, their experience using their health insurance, accessing financial assistance, and any resulting cost-coping behaviors. Interviews were transcribed and qualitatively analyzed using a descriptive phenomenological approach to thematic analysis. A total of n = 11 MBC patients or caregiver representatives participated in the study. MBC patients were on average 50.2years of age (range: 28-65) and 72.7% non-Hispanic White. MBC patients were diagnosed as metastatic an average of 3.1years (range: 1-9) before participating in the study. Qualitative analysis resulted in four themes including (1) causes of financial burden, (2) financial assistance mechanisms, (3) health insurance and financial burden, and (4) cost-coping behaviors. Both medical and non-medical costs drove financial burden among participants. All participants reported challenges navigating their health insurance and applying for financial assistance. Regardless of gaining access to assistance, financial burden persisted for nearly all patients and resulted in cost-coping behaviors. Our findings suggest that current systems for health insurance and financial assistance are complex and difficult to meet patient needs. Even when MBC patients accessed assistance, excess financial burden persisted necessitating use of financial coping-behaviors such as altering medication use, maintaining employment, and taking on debt.

Accountable Care Organizations and Specialists: Opportunities for Neurologists.

More than 700,000 physicians and advanced practice clinicians participate in Medicare ACOs, which is responsible for the cost and quality of care for more than 13 million beneficiaries. Nearly 40 percent of neurologists who treat Medicare patients are already in an ACO. The Centers for Medicare and Medicaid services is now implementing a strategy for value-based specialty care that promotes active ACO management of specialty services while some ACOs are starting to direct referrals to preferred specialist networks. Neurologists can benefit from engaging with ACOs through enhanced patient data, an emphasis on team-based care, care coordination support for their patients, and financial rewards for performance. Neurologists can help ACOs as the population ages, including by helping ensure appropriate use of expensive new therapies for neurologic conditions.

Effect of Sildenafil in Neonates with Persistent Pulmonary Hypertension: An Interventional Study

Introduction: Persistent Pulmonary Hypertension of the Newborn (PPHN) reflects a disruption of the normal perinatal circulatory transition and is characterised by high pulmonary artery pressure. Inhaled Nitric Oxide (iNO) is considered the mainstay of treatment for PPHN. However, many developing and resource limited countries do not have access to such expensive therapy. Therefore, sildenafil, due to its easy availability and low cost, becomes the most commonly used drug in the management of PPHN in such settings. Aim: To study the treatment response and outcomes of neonates who received sildenafil for the management of PPHN. Materials and Methods: The present hospital-based prospective interventional study was conducted in the Neonatal Intensive Care Unit (NICU), BJ Medical College, Civil Hospital, Ahmedabad, Gujarat, between May 1, 2020, and April 30, 2021. Study was conducted on neonates with meconium aspiration syndrome and/or severe birth asphyxia admitted to the NICU. A total of 48 neonates with Two Dimensional (2D) echocardiography-proven PPHN were enrolled. Baseline clinical parameters including heart rate, respiratory rate, preductal and postductal Saturation of Peripheral Oxygen (SpO2), Oxygenation Index (OI), Saturation Oxygen Distending Pressure Index (SOPI), and Non Invasive Blood Pressure (NIBP) were monitored every six hours. Neonates who were on invasive/ non invasive ventilation had their Fraction of Inspired Oxygen (FiO2), Positive End Expiratory Pressure (PEEP), Peak Inspiratory Pressure (PIP), respiratory rate and flow rate monitored every six hours. Data were statistically analysed using Analysis of Variance (ANOVA) test. Results: During the study period, a total of 1080 neonates were admitted with meconium aspiration syndrome and/or severe birth asphyxia, out of which 48 neonates showed findings suggestive of PPHN on 2D echocardiography. A statistically significant improvement in oxygenation after sildenafil treatment was indicated by a significant reduction in OI from 35.3±8.6 to 13.2±2.1 (p-value&lt;0.001), a reduction in SOPI from 3.6±0.3 to 1.5±0.2 (p-value&lt;0.001), a reduction in FiO2 (%) from 94.6±8.19 to 24.2±4.5 (p-value&lt;0.001), an increase in Partial pressure of oxygen (PaO2) (mmHg) from 52±5.6 to 72±3.4 (p-value&lt;0.001), and an increase in SpO2 (%) from 83.5±8.6 to 93.5±5.1 (p-value&lt;0.001). Conclusion: The findings of the present study suggest that oral sildenafil can be successfully used to improve oxygenation in patients with PPHN, especially in a resource limited setting where facilities like Extracorporeal Membrane Oxygenation (ECMO) and iNO are not available, as demonstrated in the present study.

Are We Using Ezetimibe As Much As We Should?

Lipid-lowering therapies, particularly non-statin regimens, are underutilized as ~2/3 of patients with atherosclerotic cardiovascular (CV) disease (CVD) are not optimally managed, and do not attain target low-density lipoprotein cholesterol (LDL-C) concentrations, despite statin treatment. Statins have been the mainstay of hypolipidemic therapies; however, they are plagued by adverse effects, which have partly hindered their more widespread use. Ezetimibe is often the first added mode of treatment to attain LDL-C goals as it is efficacious and also allows the use of a smaller dose of statin, while the need for more expensive therapies is obviated. We herein provide a comprehensive review of the effects of ezetimibe in lipid lowering and reducing CV events and improving outcomes. Of the hypolipidemic therapies, oral ezetimibe, in contrast to newer agents, is the most convenient and/or affordable regimen to be utilized as mono- or combined therapy supported by data from CV outcomes studies attesting to its efficacy in reducing CVD risk and events. When combined with a statin, the statin dose could be lower, thus curtailing side-effects, while the hypolipidemic effect is enhanced (by ~20%) as the percentage of patients with target level LDL-C (<70 mg/dL) is higher with combined treatment versus a high-intensity statin. Ezetimibe could also serve as an alternative treatment in cases of statin intolerance. In conclusion, ezetimibe has an excellent safety/tolerability profile; it is the first added treatment to a statin that can attain LDL-C targets. In the combined therapy, the hypolipidemic effect is enhanced while the dose of statin could be lower, thus limiting the occurrence of side-effects. Ezetimibe could also serve as an alternative mode of treatment in cases of statin intolerance.

Mitigating the Burden of Medication Costs

This essay discusses medication cost−lowering strategies that clinicians can use in routine clinical and inpatient care to assist patients in affording and adhering to expensive therapy regimens.

Cost Savings and Waste Reduction Through Redispensing Unused Oral Anticancer Drugs

New strategies targeting waste are required to improve financial and ecologic sustainability of expensive therapies, such as oral anticancer drugs, that frequently remain unused by patients. Redispensing unused oral anticancer drugs seems to be a promising strategy when drug quality is guaranteed. To determine the waste reduction and net cost savings attained by redispensing oral anticancer drugs that go unused by patients compared with the standard practice of disposal. The ROAD study was a prospective single-group intervention conducted in the outpatient pharmacies of 4 hospitals in the Netherlands from February 1, 2021, to February 1, 2023, with 12-month follow-up of each patient. Patients with cancer and who had a prescription for an oral anticancer drug that could be stored at room temperature were included. Of 2426 eligible patients, 602 did not consent and 601 did not respond. Data analyses were performed from August 25, 2022, to April 19, 2023. Participants received oral anticancer drugs for use at home in special packaging (ie, sealed packaging with time-temperature indicator), to be returned to the pharmacy should these remain unused. The pharmacy ensured quality of returned drugs based on authenticity, appearance, remaining shelf life and adequate storage temperature. Drugs fulfilling quality requirements were redispensed to other patients. Total waste reduction and mean net annual cost savings per patient compared with the standard practice of disposal. Optimization of cost savings was explored by introducing variations in the quality assurance procedure and patient population. All analyses used the average exchange rate for 2021 €1 = US $1.18. Of 1223 patients with cancer who consented, 1071 participated (median [IQR] age, 70 [62-75] years; 622 [58.1%] were male). In all, 171 patients (16.0%; 95% CI, 13.8%-18.3%) returned 335 unused oral anticancer drug packages. Of the returned drugs, 228 packages were redispensed, which reduced waste by 68.1% (95% CI, 67.7%-68.5%) compared with the standard practice (disposal). Redispensing unused oral anticancer drugs comprised 2.4% (95% CI, 2.2%-2.5%) of total drug costs, providing mean net annual cost savings of US $680 (95% CI, $524-$837) up to $1591 (95% CI, $1226-$2002) per participant. The findings of this multicenter intervention study indicate that redispensing unused oral anticancer drugs is associated with waste reduction and cost savings, which in turn may improve the affordability and sustainability of cancer treatment. World Health Organization International Clinical Trials Registry Platform Identifier: NL9208.

Clomiphene Citrate in the Management of Infertility in Oligospermic Obese Men with Hypogonadism: Retrospective Pilot Study.

Background and Objectives: Obesity is a significant risk factor for hypogonadism and infertility that is further associated with reduced semen quality. The aim of this study is to evaluate the effect of clomiphene citrate (CC), prescribed for treating infertility, on serum testosterone and semen parameters, particularly in oligospermic obese hypogonadal men. Materials and Methods: A retrospective analysis of data related to men (n = 53) who underwent CC treatment for infertility and hypogonadism (testosterone < 300 ng/dL) was performed. Patients with obesity (BMI ≥ 30 kg/m2) and sperm concentration ≤ 15 × 106/mL were included for analysis. Results: The overall results showed that, in oligospermic obese men (n = 31), treatment with CC significantly improved baseline sperm concentration (4.5 ± 6.8 × 106/mL vs. 11.4 ± 15.5 × 106/mL, p < 0.05) and motility (31.5% ± 21.5% vs. 42.6% ± 14.7%, p < 0.05). Furthermore, subsequent examination of oligospermic hypogonadal obese men treated with CC (n = 13) revealed substantial improvements in baseline serum testosterone levels (193.8 ± 59.3 ng/dL vs. 332.7 ± 114.8 ng/dL, p < 0.05) along with an increase in sperm concentration, total motility, and normal morphology. Conclusions: The results of this retrospective study suggest that CC treatment not only improves chances of fertility outcomes by substantially improving semen parameters but also increases total serum testosterone levels in oligospermic obese men without any supplemental and expensive testosterone replacement therapy.

VOLY: The Monetary Value of a Life-Year at the End of Patients' Lives.

We explored the monetary value of the end-of-life (EoL) health gains, that is, the value of a life-year (VOLY) gained at the end of a patient's life in Croatia. We tested whether the nature of the illness under valuation (cancer and/or rare disease) is a factor in the valuation of EoL-VOLYs. The aim was for our results to contribute to the health and longevity valuation literature and more particularly to the debate on the appropriate cost-effectiveness threshold for EoL treatments as well as to provide input into the debate on the justifiability of a cancer and/or a rare disease premium when evaluating therapies. A contingent valuation was conducted in an online survey using a representative sample of the Croatian population (n = 1500) to calculate the willingness to pay for gains in the remaining life expectancy at the EoL, from the social-inclusive-individual perspective, using payment scales and an open-ended payment vehicle. Our approach mimics the actual decision-making problem of deciding whether to reimburse therapies targeting EoL conditions such as metastatic cancer whose main purpose is to extend life (and not add quality to life). Average EoL-VOLY across all scenarios was estimated at €67,000 (median €40,000). In scenarios that offered respondents 1 full year of life extension, EoL-VOLY was estimated at €33,000 (median €22,000). Our results show that the type of illness is irrelevant for EoL-VOLY evaluations. The pressure to reimburse expensive therapies targeting EoL conditions will continue to increase. Delivering "value for money" in healthcare, both in countries with relatively higher and lower budget restrictions, requires the valuation of different types of health gains, which should, in turn, affect our ability to evaluate their cost effectiveness.

A-249 Theranostic Algorithm: sensitivity and Specificity of a Composite Index Test for Guiding Treatment in Severe COVID-19

Abstract Background Since the outbreak of the pandemic, severely affected COVID-19 patients receive standard of care at intensive care unit (ICU), but clinical trials are still ongoing for new expensive treatments. There is a need for guiding therapeutic decisions to restrain the public healthcare costs and to target the most efficient therapy. Based on the pathophysiology of SARS-CoV-2 on its ACE2-receptor, the angiotensin pathway is activated and circulating biomarkers of interest can be measured. This diagnostic test accuracy study describes how to classify COVID-19 patients in severe vs mild cases with the intention of guiding treatment decisions, to prevent long term sequels like pulmonary fibrosis. A theranostic approach is proposed, which combines in vitro diagnostics and personalized therapeutics. Methods N = 17 severely affected COVID-19 with acute respiratory distress syndrome (ARDS) at ICU were included and compared to N = 7 mild or asymptomatic COVID-19 cases and to N = 10 healthy controls. Follow-up samples have been collected during pulmonology consultation at three time points during one year post-ICU (N = 39). Non-parametrical statistics were used; data are expressed as [median (IQR)] and P &amp;lt; 0.05 is considered to be statistically significant. The biological markers angiotensin-(1-7) (Ang-(1-7)), transforming growth factor beta (TGF-β), ferritin, C-reactive protein (CRP from Roche) and Krebs von den Lungen 6 (KL-6 from Fujirebio) were measured in plasma samples. Those biomarkers represent a disequilibrium in lung protection, fibrogenesis, inflammation and hyperplasia of alveolar epithelial cells type II. Cut-off for a composite index was obtained through receiver operating curve (ROC). Results COVID-19 patients show higher Ang-(1-7) concentrations than healthy controls (P &amp;lt; 0.05). Critical patients at ICU show Ang-(1-7) deficit [124 pg/mL (81–154)], compared to asymptomatic COVID-19 cases [147 pg/mL (138–201)] (P &amp;lt; 0.05). COVID-19 patients with insufficient Ang-(1-7) are eligible for substitution therapy and novel expensive therapies beside standard of care, while the subpopulation of high Ang-(1-7) is analyzed with a composite index test including TGF-β, ferritin and CRP. A composite index of &amp;lt;34 differentiates asymptomatic COVID-19 from severe COVID-19 at ICU having acute respiratory distress syndrome (sensitivity = 100%, specificity = 80%, AUC = 0.933, LR = 5). The patients without risk for pulmonary sequels are not eligible for expensive treatment.After 1 year, KL-6 (&amp;lt;275 U/mL) and TGF- β (&amp;lt;34 968 pg/mL) normalise in only 25%, respectively 33% of severe COVID-19 patients. Within the first year of FU post-ICU, the mean KL-6 value in the patient population does not significantly change at different measuring moments (P = 0.63), while TGF-β decreases gradually at 3, 6 and 12 months post-ICU (P &amp;lt; 0.0001). Conclusion This theranostic algorithm predicts whether a patient infected by SARS-CoV-2 is at risk of developing clinical complications and supports clinical decision making concerning therapy. A supported therapeutic choice, based on objective biomarker measurements, could diminish long-term sequelae like pulmonary fibrosis. Clinical trials using companion drugs (e.g. Ang-(1-7) substitution therapy, MAS-receptor agonist), anti-fibrotics, interferon therapy, or monoclonal antibodies, could also rely on those biomarkers. The measurement of Ang-(1-7) for example, could categorize patients in the targeted subpopulation before administrating Ang-(1-7) substitution therapy, aiming at obtaining better treatment efficacy.

Obesity: a gender-view.

There is a growing awareness of the importance of understanding gender differences in obesity. The aim of this short review was to revise the current evidence on anthropometric characteristics and nutritional and pharmacological aspects of obesity from a gender perspective. A literature search within PubMed was performed. Selected publications related to obesity and gender differences were reviewed. The prevalence of obesity among men is higher than in women, but women have a higher percentage of body fat content compared to men, and gender appears to be an important factor in the manifestation of central (android) or peripheral (gynoid) obesity. In addition, while in most clinical trials, women are still underrepresented, in clinical registration trials of anti-obesity drugs, women are commonly up-represented and gender-specific analysis is uncommon. Considering that adipose tissue is one of the factors affecting the volume of distribution of many drugs, mainly lipophilic drugs, gender differences might be expected in the pharmacokinetics and pharmacodynamics of anti-obesity drugs. Indeed, although Liraglutide 3mg, a long-acting glucagon-like peptide-1 receptor agonist, and naltrexone/bupropion display lipophilic properties, currently, a gender-dose adjustment for both these drugs administration is not recommended. In addition, despite that predicted responders to treatment offer substantial opportunities for efficient use, especially of expensive new therapies, such as anti-obesity drugs, data on gender differences to identify early responders to both these have not yet been investigated. Finally, bariatric surgery gender disparity reflects healthcare practices. Weight loss similar, but differing effects: women need more correction and face psychology challenges; men have worse physiology and fewer comorbidity improvements. Gender differences exist in obesity prevalence and phenotype, body fat distribution, drug efficacy, clinical trial representation, and different secondary effects of bariatric surgery. Gender is an important variable in obesity analysis.