Magnitude and time-course of excess mortality during COVID-19 outbreak: population-based empirical evidence from highly impacted provinces in northern Italy

Background: The real impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on overall mortality remains uncertain as surveillance reports have attributed a limited number of deaths to novel coronavirus disease 2019 (COVID-19) during the outbreak. The aim of this study was to assess the excess mortality during the COVID-19 outbreak in highly impacted areas of northern Italy. Methods: We analysed data on deaths that occurred in the first 4 months of 2020 provided by the health protection agencies (HPAs) of Bergamo and Brescia (Lombardy), building a time-series of daily number of deaths and predicting the daily standardised mortality ratio (SMR) and cumulative number of excess deaths through a Poisson generalised additive model of the observed counts in 2020, using 2019 data as a reference. Results: We estimated that there were 5740 (95% credible set (CS) 5552–5936) excess deaths in the HPA of Bergamo and 3703 (95% CS 3535–3877) in Brescia, corresponding to a 2.55-fold (95% CS 2.50–2.61) and 1.93 (95% CS 1.89–1.98) increase in the number of deaths. The excess death wave started a few days later in Brescia, but the daily estimated SMR peaked at the end of March in both HPAs, roughly 2 weeks after the introduction of lockdown measures, with significantly higher estimates in Bergamo (9.4, 95% CI 9.1–9.7). Conclusion: Excess mortality was significantly higher than that officially attributed to COVID-19, disclosing its hidden burden likely due to indirect effects on the health system. Time-series analyses highlighted the impact of lockdown restrictions, with a lower excess mortality in the HPA where there was a smaller delay between the epidemic outbreak and their enforcement

Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study

Background: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally. Methods: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005. Findings: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12·0 years (IQR 5·5–27·0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14·7 mmol/L (IQR 11·6–18·4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3·93 mmol/L, IQR 2·6–5·8) versus non-high-income countries (9·3 mmol/L, 6·7–12·7), with greater use of three or more lipid-lowering therapies (LLT; high-income 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24·5 years (IQR 17·0–34·5) versus 37·0 years (29·0–49·0) in high-income countries (adjusted hazard ratio 1·64, 95% CI 1·13–2·38). Interpretation: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH

Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study

Homozygous Familial Hypercholesterolaemia International Clinical Collaborators: Tycho R Tromp, Merel L Hartgers, G Kees Hovingh, Antonio J Vallejo-Vaz, Kausik K Ray, Handrean Soran, Tomas Freiberger, Stefano A Bertolini, Mariko Harada-Shiba, Jing Pang, Gerald F Watts, Susanne Greber-Platzer, Martin Mäser, Thomas M Stulnig, Christoph F Ebenbichler, Khalid Bin Thani, David Cassiman, Olivier S Descamps, Daisy Rymen, Peter Witters, Raul D Santos, Liam R Brunham, Gordon A Francis, Jacques Genest, Robert A Hegele, Brooke A Kennedy, Isabelle Ruel, Mark H Sherman, Long Jiang, Luya Wang, Željko Reiner, Vladimir Blaha, Richard Ceska, Jana Dvorakova, Lubomir Dlouhy, Pavel Horak, Vladimir Soska, Lukas Tichy, Robin Urbanek, Helena Vaverkova, Michal Vrablik, Stanislav Zemek, Lukas Zlatohlavek, Sameh Emil, Tarek Naguib, Ashraf Reda, Sophie Béliard, Eric Bruckert, Antonio Gallo, Moses S Elisaf, Genovefa Kolovou, Hofit Cohen, Ronen Durst, Eldad J Dann, Avishay Elis, Osama Hussein, Eran Leitersdorf, Daniel Schurr, Nitika Setia, Ishwar C Verma, Mohammed D Alareedh, Mutaz Al-Khnifsawi, Ali F Abdalsahib Al-Zamili, Sabah H Rhadi, Foaad K Shaghee, Marcello Arca, Maurizio Averna, Andrea Bartuli, Marco Bucci, Paola S Buonuomo, Paolo Calabrò, Sebastiano Calandra, Manuela Casula, Alberico L Catapano, Angelo B Cefalù, Arrigo F G Cicero, Sergio D'Addato, Laura D'Erasmo, Alessia Di Costanzo, Tommaso Fasano, Marta Gazzotti, Antonina Giammanco, Gabriella Iannuzzo, Anastasia Ibba, Emanuele A Negri, Andrea Pasta, Chiara Pavanello, Livia Pisciotta, Claudio Rabacchi, Carlo Ripoli, Tiziana Sampietro, Francesco Sbrana, Fulvio Sileo, Patrizia Suppressa, Patrizia Tarugi, Chiara Trenti, Maria G Zenti, Mika Hori, Mahmoud H Ayesh, Sami T Azar, Fadi F Bitar, Akl C Fahed, Elie M Moubarak, Georges Nemer, Hapizah M Nawawi, Ramón Madriz, Roopa Mehta, Arjen J Cupido, Joep C Defesche, M Doortje Reijman, Jeanine E Roeters-van Lennep, Erik S G Stroes, Albert Wiegman, Linda Zuurbier, Khalid Al-Waili, Fouzia Sadiq, Krzysztof Chlebus, Mafalda Bourbon, Isabel M Gaspar, Katarina S Lalic, Marat V Ezhov, Andrey V Susekov, Urh Groselj, Min-Ji Charng, Weerapan Khovidhunkit, Melih Aktan, Bulent B Altunkeser, Sinan Demircioglu, Melis Kose, Cumali Gokce, Osman Ilhan, Meral Kayikcioglu, Leyla G Kaynar, Irfan Kuku, Erdal Kurtoglu, Harika Okutan, Osman I Ozcebe, Zafer Pekkolay, Saim Sag, Osman Z Salcioglu, Ahmet Temizhan, Mustafa Yenercag, Mehmet Yilmaz, Hamiyet Yilmaz Yasar, Olena Mitchenko, Alexander R M Lyons, Christophe A T Stevens, Julie A Brothers, Lisa C Hudgins, Christina Nguyen, Rano Alieva, Aleksandr Shek, Doan-Loi Do, Ngoc-Thanh Kim, Hong-An Le, Thanh-Tung Le, Mai-Ngoc T Nguyen, Thanh-Huong Truong, Dirk J Blom, Frederick J Raal, Marina Cuchel.Background: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally. Methods: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005. Findings: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12·0 years (IQR 5·5-27·0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14·7 mmol/L (IQR 11·6-18·4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3·93 mmol/L, IQR 2·6-5·8) versus non-high-income countries (9·3 mmol/L, 6·7-12·7), with greater use of three or more lipid-lowering therapies (LLT; high-income 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24·5 years (IQR 17·0-34·5) versus 37·0 years (29·0-49·0) in high-income countries (adjusted hazard ratio 1·64, 95% CI 1·13-2·38). Interpretation: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH.Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society.info:eu-repo/semantics/publishedVersio

Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study

Background Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally. Methods The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005. Findings Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12·0 years (IQR 5·5–27·0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14·7 mmol/L (IQR 11·6–18·4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3·93 mmol/L, IQR 2·6–5·8) versus non-high-income countries (9·3 mmol/L, 6·7–12·7), with greater use of three or more lipid-lowering therapies (LLT; high-income 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24·5 years (IQR 17·0–34·5) versus 37·0 years (29·0–49·0) in high-income countries (adjusted hazard ratio 1·64, 95% CI 1·13–2·38). Interpretation Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH. Funding Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Societ