CAUSAL INFERENCE DURING A PANDEMIC: EVIDENCE ON THE EFFECTIVENESS OF NEBULIZED IBUPROFEN AS AN UNPROVEN TREATMENT FOR COVID-19 IN ARGENTINA
Sebastian Calonico, Rafael Di, Tella Juan, Cruz Lopez, Del Valle, Vincent Pons, Amitabh Chandra, Matias Cattaneo, Asim Khwaja, Ariel Stern, Robert Lieli, Pedro Degiovanni, Rafael Di Tella, Juan Cruz, Lopez Del, Juan Cruz Lopez
Many medical decisions during the pandemic were made without the support of causal evidence obtained in clinical trials. We study the case of nebulized ibuprofen (NaIHS), a drug that was extensively used on COVID-19 patients in Argentina amidst wild claims about its effectiveness and without regulatory approval. We study data on 5,146 patients hospitalized in 11 health centers spread over 4 provinces, of which a total of 1,019 (19.8%) received the treatment. We find a large, negative and statistically significant correlation between NaIHS treatment and mortality using inverse probability weighting estimators. We consider several threats to identification, including the selection of "low" risks into NaIHS, spillovers affecting patients in the control group, and differences in the quality of care in centers that use NaIHS. While the negative correlation appears to be, broadly, robust, our results are best interpreted as emphasizing the benefits of running a randomized controlled trial and the challenges of incorporating information produced in other, less rigorous circumstances.
References
Abadie, Cattaneo, Econometric Methods for Program Evaluation, Annual Review of Economics
Abrevaya, Hsu, Lieli, Estimating conditional average treatment effects, Journal of Business & Economic Statistics
Austin, Jha, Romano, Singer, Vogus et al., National hospital ratings systems share few common scores and may generate confusion instead of clarity, Health Affairs
Azoulay, Graff Zivin, Li, Sampat, Public R&D investments and privatesector patenting: evidence from NIH funding rules, The Review of economic studies
Bang, Robins, Doubly robust estimation in missing data and causal inference models, Biometrics
Berger, Chandra, Garthwaite, Regulatory Approval and Expanded Market Size
Budish, Roin, Williams, Do firms underinvest in long-term research? Evidence from cancer clinical trials, American Economic Review
Busso, Dinardo, Mccrary, New evidence on the finite sample properties of propensity score reweighting and matching estimators, Review of Economics and Statistics
Calonico, Di Tella, Lopez Del Valle, Risk factors for in-hospital mortality in COVID-19 patients in Argentina: A competing risk survival analysis
Calonico, Di Tella, Lopez Del Valle, The Political Economy of a Miracle Cure: Learning about a Clinically Unproven Treatment for COVID-19 in Argentina
Cattaneo, Efficient semiparametric estimation of multi-valued treatment effects under ignorability, Journal of Econometrics
Chandra, Malenka, Skinner, The diffusion of new medical technology, Discoveries in the Economics of Aging
Chandra, Staiger, Identifying sources of inefficiency in healthcare, Quarterly Journal of Economics,
doi:10.1093/qje/qjz040Chernozhukov, Escanciano, Ichimura, Newey, Robins, Locally robust semiparametric estimation
Clemente, Freiberger, Ravetti, Beltramo, Garro, An in silico analysis of Ibuprofen enantiomers in high concentrations of sodium chloride with SARS-CoV-2 main protease, J Biomol Struct Dyn. Jan,
doi:10.1080/07391102.2021.1872420Concato, Corrigan-Curay, Coronavirus en Argentina: investigadores cordobeses prueban con éxito un tratamiento con ibuprofeno
Cutler, Skinner, Stern, Wennberg, Physician Beliefs and Patient Preferences: A New Look at Regional Variation in Health Care Spending, American Economic Journal: Economic Policy
Day, Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists, BMJ
Doyle, Graves, Gruber, Evaluating measures of hospital quality: Evidence from ambulance referral patterns, Review of Economics and Statistics
Doyle, Graves, Gruber, Kleiner, Measuring returns to hospital care: Evidence from ambulance referral patterns, Journal of Political Economy
Drake, Fairfield, Pius, Non-steroidal anti-inflammatory drug use and outcomes of COVID-19 in the ISARIC Clinical Characterisation Protocol UK cohort: a matched, prospective cohort study, Lancet Rheumatol,
doi:10.1016/S2665-9913(21)00104-1El, Farmacéuticos ofrecen Ibuprofeno Inhalado Gratis
Finkelstein, Gentzkow, Hull, Williams, Adjusting risk adjustment-accounting for variation in diagnostic intensity, The New England journal of medicine
Finkelstein, Gentzkow, Williams, Sources of Geographic Variation in Health Care: Evidence From Patient Migration, Quarterly Journal of Economics,
doi:10.1093/qje/qjw023García, Daniela, Porta, Alasino, Muñoz et al., Ibuprofen, a traditional drug that may impact the course of COVID-19 new effective formulation in nebulizable solution, Medical Hypotheses, Med Hypotheses,
doi:10.1016/j.mehy.2020.110079García, Doreski, Salva, Giler, Quinodoz et al., Ibuprofeno Inhalado para tratar COVID-19, Revista Argentina de Terapia Intensiva. A
Huespe, Bisso, Di Stefano, Terrasa, Gemelli et al., COVID-19 Severity Index: a predictive score for hospitalized patients, Medicina intensiva
Hull, Estimating hospital quality with quasi-experimental data
Kalil, Treating COVID-19-Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics, JAMA,
doi:10.1001/jama..4742Kragholm, Torp Pedersen, Fsobol, Non-steroidal anti-inflammatory drug use in COVID-19, The Lancet Rheumatology
Libster, Pérez Marc, Wappner, Coviello, Bianchi et al., Early high-titer plasma therapy to prevent severe Covid-19 in older adults, New England Journal of Medicine
Mcclellan, Staiger, Comparing hospital quality at for-profit and not-for-profit hospitals. The changing hospital industry: Comparing not-for-profit and for-profit institutions
Muñoz, Alasino, Garro, Heredia, García et al., High concentrations of sodium chloride improve microbicidal activity of ibuprofen against common Cystic Fibrosis pathogens, Pharmaceuticals (Basel),
doi:10.3390/ph11020047Polack, Thomas, Kitchin, Absalon, Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine, New England Journal of Medicine
Robertson, Houtz, When Desperate Patients Go to Court for Unproven Treatments-The Battle for Hospital Independence, New England Journal of Medicine
Rubin, Causal inference using potential outcomes: Design, modeling, decisions, Journal of the American Statistical Association
Salva, Doreski, Giler, Quinodoz, Guzmán et al., Reversal of SARS-CoV2-Induced Hypoxia by Nebulized Sodium Ibuprofenate in a Compassionate Use Program, Infect Dis Ther,
doi:10.1007/s40121-021-00527-2Santos, Zanardi, Alo, Rodriguez, Magdaleno et al., Pulmonary Edema in COVID-19 Treated with Furosemide and Negative Fluid Balance (NEGBAL): A Different and Promising Approach,
doi:10.3390/jcm10235599Singanayagam, Patel, Charlett, Bernal, Saliba et al., Duration of infectiousness and correlation with RT-PCR cycle threshold values in cases of COVID-19, England, January to, Eurosurveillance
Skinner, Causes and consequences of regional variations in health care, Handbook of Health Economics
Skinner, Staiger, Technology diffusion and productivity growth in health care, Review of Economics and Statistics
Słoczyński, Wooldridge, A general double robustness result for estimating average treatment effects, Econometric Theory
Van Der Laan, Laan, Robins, Unified methods for censored longitudinal data and causality
Zhang, Gunther, Franco, Klassen, Impact of hypertonic saline on hospitalization rate in infants with acute bronchiolitis: A meta-analysis, Pediatr Pulmonol,
doi:10.1002/ppul.24066Zuckerman, Barlavie, Niv, Accessing unproven interventions in the COVID-19 pandemic: discussion on the ethics of 'compassionate therapies' in times of catastrophic pandemics, Journal of Medical Ethics Published Online First,
doi:10.1136/medethics-2020-106783Zurita-Lizza, Doreski, Potential reversal of pulmonary vasoplegia by inhaled ibuprofenate in COVID-19 pneumonia, Clinical and Translational Discovery
