Lessons of the Hydroxychloroquine Debacle: Solid COVID-19 Research Matters

The public and scientists alike are starting to grasp at almost any report which may show hope in stemming the tide of deaths and disability from COVID-19. However, we must remember patient safety first and interpret patient risks based upon this. One usually would not recommend therapy unless the benefit reaches statistical certainty in two prospective randomized controlled studies. However, we do not have years to wait for these studies, we are forced to act on best evidence, but in some cases the evidence is less than actionable.

Much of the early treatment initiatives were based upon anecdotal reports. This is what happened with the hydroxychloroquine (HCQ) debacle which was touted by President Trump from reports he had heard from Chinese officials. This was supported by a small study out of France,¹ which reported an improvement in fatalities. However, a number of other recent reports have found otherwise. 

·      A study from Brazil evaluated low and high dosage of chloroquine and discontinued the study early because 18.9% of the patients in the high dose group developed QTc interval abnormalities compared to 11.1% in the low dosage group. The lethality in the high dose group was more than twice that of the low dose control.²

·      A study from France did not support the use of HCQ for hospitalized COVID-19 patients who required oxygen. They studied 181 patients and found a rate of ICU Transfer of 20.2% in the group taking HCQ and 22.1% in the control group.³And 9.5% of patients taking HCQ required discontinuation because of EKG events.³

·      A retrospective study of 368 patients from the United States Veterans Administration found rates of death in the HCQ group to be over twice that of the control group (27.8% vs. 11.4% P = 0.03).⁴

·      A memo from Evercore ISI analyst, Umer Raffat, revealed that a small Chinese trial (ClinicalTrials.gov Identifier: NCT04261517) involving HCQ did not perform better than placebo, with 13 (86.7%) of the experimental group versus 14 (93.3%) of the control group clearing the virus in 7 days.⁵ The next day, an article by Ruojing (Angus) Liu, who trained at the same Chinese University whose journal published the article, questioned the validity of the negative conclusion.⁶

·      The much-awaited prospective study out of New York was submitted to the FDA on April 20, 2020. As of the date of our article, the FDA has not released this data. However, on April 23, 2020 on CNN, Gov. Andrew Cuomo of New York was asked about the results and stated he has seen them and it was in his opinion not a positive study.

Finally, the original French report has been discredited by an April 3, 2020 warning from the International Society of Antimicrobial Chemotherapy, the society whose journal published the paper.⁷

The National Institutes of Health (NIH) does not recommend the use of HCQ7 and on April 24, 2020, the “FDA caution(ed) against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems”.⁸

Similar concerns may also be true regarding the benefits of angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). In this case, there is concern of both benefit and potential harm. There are conflicting stances with limited clinical data to back either position.

Regarding the possible adverse effects of ACEi and ARBs Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID) has stated, “If you look at the mechanistic rationale for concern, it's there and it's-and it's firm….”¹⁰

In addition, there is also an argument that they may be helpful.¹¹ This argument appears to be supported by a Chinese laboratory studies which we have previously expressed concerns. The laboratory research in mice used losartan (angiotensin II receptor antagonist) with an acute exposure not specified, and may not have had adequate time for upregulation of ACE-2 receptor.¹² In a prior publication, only a 30 minute pre-treatment of the inhibitor was used and the effect on ACE-2 receptor expression is unknown and therefore long-term viral effect on the lung cannot be determined.¹³

A recent article from New York City studied 2411 patients, 334 of which were receiving ARBs or ACEi. They observed that “mortality rates for patients with hypertension not taking an ACEi or ARB, taking an ACEi, and taking an ARB were 26.7%, 32.7%, and 30.6%, respectively.” This increase appeared to be clinically meaningful and our calculations indicate it has P <0.0005. The authors failed to make recommendations since the study did not adjust for known confounders.¹⁴

An article from China reported fantastic results regarding favorable outcomes in patients taking ACEi and ARBs, a 2.6 times better survival.¹⁵  “Unadjusted mortality rate was lower in the ACEI/ARB group versus the non-ACEI/ARB group (3.7% vs. 9.8%; P = 0.01).” This seems at odds with the article from Richardson, et al., which observed an increase in mortality taking these drugs.

Another study from Wuhan China studied 1178 patients, 115 who were on ACEi or ARBs. They found: no differences between the two groups in survival (9.1% vs. 9.8%; P = .85), ARBs (19.5% vs. 23.9%; P = .42).¹⁶

Thus, further investigation into ACEi and ARB research needs to be critically conducted; as the reported research data does not appear to be adding up. Enacting a therapeutic regime with the expectations that you will see a greater than 60% decrease in mortality but instead you might see a 22% increase would be a disaster. Similar to the HCQ debacle, these results may be too good to be true.

In the new reality of making decisions with limited and incomplete data, it is important that decision makers and scientists are free from biases.¹⁷ Biases can be financial and even geopolitical pressure created by the huge trade war and divisive rhetoric between the United States and China.

In a time of great national fear and stress, we must be careful in both reporting and interpreting messaging, including the results of unconfirmed research. Let’s not repeat the mistakes of HCQ for unproven benefits, since these are powerful drugs which may also cause harm.

References:

(1)     Gautret P, Lagier JC, Parola P., et al.  Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial.  International Journal of Antimicrobial Agents.  March 20, 2020.   https://www.sciencedirect.com/science/article/pii/S0924857920300996  

(2)    Borba MGS, Val FFA, Sampaio VS, et al. Effect of High vs LowDoses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection A Randomized Clinical Trial  Jama Network Open.  April 24, 2020. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2765270  

(3)    Mahévas M, Tran VT, Roumier M, et al. No evidence of clinical efficacy of hydroxychloroquine   in patients hospitalised for COVID-19 infection and requiring oxygen: results of a study using routinely collected data to emulate a target trial. medRxiv.  April 14, 2020.  https://www.medrxiv.org/content/10.1101/2020.04.10.20060699v1.full.pdf  

(4)    Magagonoli J, Narendran S, Pereira F, et al., Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19.  MedRxiv.  April 23, 2020.  https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v2   

(5)    Liu A. Top COVID-19 aspirants chloroquine, AbbVie's Kaletra and a flu drug disappoint in clinical tests.  FiercePharma. March 24, 2020.  https://www.fiercepharma.com/pharma-asia/top-covid-19-aspirants-chloroquine-abbvie-s-kaletra-and-a-flu-drug-disappoint-clinical  

(6)    Liu A.  Did chloroquine really fail a COVID-19 study-or was the trial design to blame?  FiercePharma. March 26, 2020.  https://www.fiercepharma.com/pharma-asia/did-chloroquine-really-fail-a-covid-19-study-or-was-it-just-trial-design-s-fault     

(7)    Voss A.  Official Statement from International Society of Antimicrobial Chemotherapy (ISAC) Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial (Gautret P et al. PMID 32205204).  April 3, 2020.  https://www.isac.world/news-and-publications/official-isac-statement  

(8)    Therapeutic Options for COVID-19 Currently Under Investigation. NIH. https://covid19treatmentguidelines.nih.gov/therapeutic-options-under-investigation/

(9)    FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems.  FDA.  April 24, 2020.  https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or   

(10) COVID-19 Update with NIAID’s Anthony Fauci, MD; March 18, 2020.   JN (JAMA Network) Learning March 19, 2020.  https://edhub.ama-assn.org/jn-learning/audio-player/18324686    

(11) Kuster GM, Pfister O, Burkard, T, et al.  SARS-CoV2: should inhibitors of the renin–angiotensin systembe withdrawn in patients with COVID-19?  European Heart Journal.  2020.  0:1–3.   https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa235/5810479  

(12)Kuba K., Imai Y, Rao S. et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury.  Nature Medicine. Aug. 2005.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095783/pdf/41591_2005_Article_BFnm1267.pdf   

(13) Imai Y, Kuba K, Rao S, et al.  Angiotensin-converting enzyme 2 protects from severe acute lung failure.  Nature. July 7, 2005.  436:112-116.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094998/

(14) Richardson S. Hirsch JS, Narasimhan M., et al.    Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area.  JAMA Network.   April 22, 2020.   https://jamanetwork.com/journals/jama/fullarticle/2765184?  

(15)  Zhang P, Zhu, L, Cai J, et al.   Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19.  Circulation Research.  April 17, 2020.  https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.120.317134

(16) Li J, Wang X, Chen J.  Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China.  JAMA Cardiology.  April 26, 2020.   https://jamanetwork.com/journals/jamacardiology/fullarticle/2765049   

(17)Nelson D.  Blood-pressure drugs are in the crosshairs of COVID-19 research.  Reuters News Service.  April 23, 2020.  https://uk.reuters.com/article/us-health-conoravirus-blood-pressure-ins-idUKKCN2251GQ