Ricardo Román

Background and objectives. Hereditary transthyretin amyloidosis with polyneuropathy (hATTR-NP) is a rare, progressive, life-threatening disease for which inotersen, an antisense oligonucleotide, is the only disease-modifying therapy with marketing authorization in Peru. Using inotersen as an illustrative case, we examined whether the conventional cost-per-QALY (quality-adjusted life-year) framework is an adequate sole basis for coverage decisions in rare diseases, and we estimated the cost-effectiveness of inotersen versus best supportive care (BSC) under the two Peruvian public-payer perspectives — the Ministry of Health/Integral Health Insurance (MINSA/SIS) and the Social Health Insurance (EsSalud).Methods. We built a four-state Markov model (mild, moderate, severe polyneuropathy, and death) with annual cycles over a 40-year horizon and a 5% discount rate, reported per CHEERS 2022. Because longitudinal data are scarce, two alternative transition-probability matrices were used — one derived from the NEURO-TTR trial (Benson 2018) and one from the Institute for Clinical and Economic Review (ICER) 2020 evidence report — yielding nine analytical scenarios (eight deterministic plus an integrated probabilistic model, 10,000 iterations). Stage-specific utilities and direct medical costs (Peruvian soles, 2024) were obtained through top-down macro-costing. A budget impact analysis and a price-threshold analysis were performed; results were interpreted against the official Peruvian threshold (RM N° 267-2025/MINSA) and international benchmarks.Results. Annual direct medical costs rose from S/13,297 (mild) to S/68,306 (severe) under MINSA/SIS and from S/29,202 to S/139,576 under EsSalud. With Benson-2018 transitions, inotersen produced an incremental 4.44 QALYs (EsSalud) / 4.21 (MINSA) at an incremental cost of ≈ S/11.4 million, giving an incremental cost-effectiveness ratio (ICER) of S/2,563,550 (EsSalud) and S/2,735,944 (MINSA) per QALY; with ICER-2020 transitions the gain fell to 1.29 QALYs and the ICER rose to ≈ S/6.1 million per QALY. The integrated probabilistic model gave a mean ICER of S/2,512,302 per QALY. Across all scenarios the ICER was roughly 100–250 times the official Peruvian AVAC threshold (S/25,007) and ≈80–195 times GDP per capita, exceeding even the Highly Specialised Technologies (HST) ceiling of the UK National Institute for Health and Care Excellence (NICE). The eligible national population is small (≈10–30 patients), yet the 5-year budget impact reached ≈ S/51 million (range S/17–170 million).Conclusions. Under a decision rule based on the cost-utility ratio alone, inotersen would fall far outside every existing threshold — Peruvian and international ultra-orphan. Precisely for that reason, the cost-per-QALY framework, taken in isolation, cannot capture severity, rarity, unmet need and equity and — compounded by structural local-data scarcity and by the sensitivity of the point estimate to defensible structural choices — is an insufficient sole basis for coverage decisions in rare diseases. A complementary multi-criteria decision framework, aligned with Peru’s HTA network (RENETSA), is warranted.

Background and objectives. Hereditary transthyretin amyloidosis (ATTRv) is a rare, progressive disease caused by deposition of transthyretin-derived amyloid fibrils. Inotersen, an antisense oligonucleotide that inhibits hepatic transthyretin production, is approved by the FDA and EMA but is not fully implemented in low- and middle-income countries (LMICs). We systematically reviewed the evidence on the efficacy, safety and economic impact of inotersen in adults with ATTRv, jointly synthesizing clinical and economic evidence with particular attention to its transferability to LMICs, where treatment access remains limited.Methods. We searched MEDLINE (PubMed), Embase, CENTRAL and SciELO for efficacy and safety evidence, and EconLit, NHS-EED and the CEA Registry (in addition to the clinical databases) for economic evidence (July–August 2025), without language or date restrictions. We followed PRISMA guidelines for reporting our findings. We included randomized controlled trials and economic evaluations with or without economic modelling. Two reviewers screened and extracted data independently, with a senior reviewer for solving discrepancies. Risk of bias was assessed with RoB 2.0 (randomized evidence), ROBINS-I for open-label studies and the Philips and Drummond checklists for economic studies. We synthesised the information retrieved without a meta-analysis.Results. One pivotal trial (NEURO-TTR), reported across five publications including a 170-week open-label extension, and six economic evaluations were included. Inotersen improved neuropathy and quality-of-life outcomes (e.g., mNIS+7 difference −19.7; 95% CI −26.4 to −13.0; Norfolk QoL-DN −11.7; 95% CI −18.3 to −5.1), but serious adverse events — including grade 3–4 thrombocytopenia — were more frequent with inotersen. All economic evaluations adopted a payer perspective; cost-effectiveness ratios were well above conventional thresholds (e.g., ICUR CA$1,322,377/QALY [CADTH reanalysis]; £150,636/QALY [NICE]; €382,984/QALY [NCPE]). Only one study came from a middle-income country (a Mexican budget-impact analysis; US$2.3 million/year, 0.036% of the national health budget) and reported no cost-effectiveness estimate. Risk of bias was moderate for the NEURO-TTR trial and critical for the open-label extension.Conclusions. The evidence favoured inotersen for efficacy and safety in the short term, although long-term evidence is uncertain. Economic studies indicate that inotersen is not cost-effective at current market prices. Evaluation frameworks for rare and orphan diseases are needed to inform the introduction of these therapies where no treatment is currently available, particularly in LMICs.

Background/Objectives: In patients with severe aortic stenosis (AS), extra valvular cardiac damage is associated with outcomes following intervention. We aimed to analyze differences in AS-related cardiac damage between surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) patients in a contemporary cohort of patients with severe AS. Methods: Patients who underwent SAVR or TAVR in a tertiary care center from 2017 to 2022 were included in this retrospective analysis. Clinical and echocardiographic parameters before surgery were compared, and patients were classified according to two available cardiac damage staging systems. Additionally, all-cause mortality 1-year post-intervention was assessed according to these stages. Results: Eight hundred and seventy-four patients were included (524 underwent TAVR and 350 underwent SAVR). TAVR patients were significantly older (81.9 ± 6.1 vs. 69.5 ± 9.5 years; p < 0.001), more commonly female (52.4% vs. 37.7%; p < 0.001), and had higher surgical risk (EuroSCORE II 6.2 ± 7.0 vs. 2.7 ±3.3; p < 0.001). Compared with SAVR, patients treated with TAVR had significantly more advanced (right-sided) cardiac damage, both with Généreux (37.8% vs. 23.1%; p < 0.001) and Gutiérrez-Ortiz (16.5% vs. 9.0%; p = 0.007) staging systems. Moreover, regardless of the type of intervention or the staging system used, mortality was significantly higher in patients with right-sided damage. Conclusions: In a contemporary cohort of severe symptomatic AS patients, those treated with TAVR had significantly more extensive cardiac damage compared with those who underwent SAVR. This finding raises the question of when to intervene in patients chosen for TAVR. Earlier intervention, before advanced cardiac damage ensues, might help to improve outcomes.

Background: Several cardiac damage staging systems for aortic stenosis (AS) have been proposed, but their usefulness in patients undergoing surgical aortic valve replacement (SAVR) remains unknown. Objectives: We aim to externally validate two staging systems in patients who underwent SAVR. Methods: Single-centre prospective cohort of patients treated with SAVR (2017–2022). Based on baseline echocardiographic parameters, patients were classified into the different stages of two published staging systems (Généreux et al. and Gutiérrez et al.), and the discriminatory yield of these systems for 1-year mortality was evaluated. Results: In total, 350 patients were analysed (mean age 69 (9.4) years, 37.8% were female). The median EuroSCORE II was 1.7 (1.1–3.1), and 1-year mortality occurred in 17 (4.8%) patients. The staging system developed by Gutiérrez et al. had an area under the ROC curve (AUC) of 0.687 (95% CI: 0.571–0.803) and was superior to Généreux et al.’s system (AUC of 0.554; 95% CI: 0.439–0.669; p = 0.008). Applying Gutiérrez et al.’s system, 1-year mortality rates progressively increased with higher damage staging: 1.9% (2/103) for Stage 0; 5.1% (5/175) for Stage 1; 12.5% (5/40) for Stage 2; and 15.6% (5/32) for Stage 3 (which represents right-sided damage measured by right ventricular–arterial coupling (RVAc); p= 0.038). No significant differences in outcomes between stages were found when using the staging proposed by Généreux et al. (p = 0.218). Conclusions: In a surgical cohort of patients with AS, a cardiac staging system that included RVAc showed greater discriminatory power for 1-year mortality. Assessing the interrelation between right ventricular function and afterload could help in better risk stratification in this context.

Background: Isolated left ventricular apical hypoplasia (ILVAH) is a rare, probably congenital, cardiac condition recently reported in the last two decades. Although most cases are asymptomatic or mildly symptomatic, some severe and fatal cases have been reported, leading to more efforts for appropriate diagnosis and treatment. We describe the first, and severe, case of this pathology in Peru and Latin America.Case summary: A 24-year-old male with a history of long-standing alcohol and illicit drug use presented with symptoms of heart failure (HF) and atrial fibrillation (AF). Transthoracic echocardiography showed biventricular dysfunction along with spherical left ventricle, abnormal papillary muscles’ origin from the left ventricular apex, and an elongated right ventricle wrapping around the deficient left ventricular apex. Cardiac magnetic resonance confirmed these findings and revealed subepicardial fatty replacement at the left ventricular apex. The diagnosis of ILVAH was made. He was discharged from hospital with carvedilol, enalapril, digoxin, and warfarin. Eighteen months later he remains mildly symptomatic at New York Heart Association functional class II without worsening HF nor thrombo-embolism.Discussion: This case highlights the usefulness of multimodality non-invasive cardiovascular imaging for accurate diagnosis of ILVAH as well as the importance of close follow-up and treatment of established complications (HF and AF).

Durante los últimos años, se ha observado la asociación del supradesnivel de ST en la derivación aVR con el compromiso de la arteria descendente anterior (DA), tronco coronario izquierdo (TCI) y coronaria derecha (CD), en el contexto de un infarto de miocardio agudo con segmento ST elevado (IMA-STE). Por medio del electrocardiograma se puede predecir con una probabilidad del 80% el compromiso de TCI frente a DA, cuando la relación aVR sobre V1 es mayor a la unidad. Asimismo, la presencia de un supradesnivel en aVR se asocia a mayor mortalidad a los 30 días en IMA-STE de cara anterior e inferior. Por lo expuesto previamente, se recalca la importancia del análisis de la elevación del ST en aVR en un IMA-STE de cara anterior puesto que predice compromiso de gran territorio vascular y empeora el pronóstico del paciente.