Study says drug hailed by Trump is harm­ful

Heart is­sues preva­lent in pa­tients who took hy­drox­y­chloro­quine

The Washington Post - - FRONT PAGE - BY ARI­ANA EUN­JUNG CHA AND LAU­RIE MCGIN­LEY

A study of 96,000 hos­pi­tal­ized coro­n­avirus pa­tients on six con­ti­nents found that those who re­ceived an an­ti­malar­ial drug pro­moted by Pres­i­dent Trump as a “game changer” in the fight against the virus had a sig­nif­i­cantly higher risk of death com­pared with those who did not.

Peo­ple treated with hy­drox­y­chloro­quine, or the closely re­lated drug chloro­quine, were also more likely to de­velop a type of ir­reg­u­lar heart rhythm, or ar­rhyth­mia, that can lead to sud­den car­diac death, it con­cluded.

The study, pub­lished Fri­day in the med­i­cal jour­nal Lancet, is the largest anal­y­sis to date of the risks and ben­e­fits of treat­ing covid-19 pa­tients with an­ti­malar­ial drugs. Like ear­lier smaller stud­ies, it de­liv­ered dis­ap­point­ing news to a world ea­ger for promis­ing treat­ments for the novel coro­n­avirus as the global death toll grows to more than 300,000. While doc­tors have re­fined how they treat the dis­ease, they have yet to dis­cover a magic bul­let against a virus for which hu­mans have no known im­mu­nity.

“It’s one thing not to have ben­e­fit, but this shows dis­tinct harm,” said Eric Topol, a car­di­ol­o­gist and di­rec­tor of the Scripps Re­search Trans­la­tional In­sti­tute. “If there was ever hope for this drug, this is

the death of it.”

David Maron, di­rec­tor of pre­ven­tive car­di­ol­ogy at the Stan­ford Univer­sity School of Medicine, said that “these find­ings pro­vide ab­so­lutely no rea­son for op­ti­mism that these drugs might be use­ful in the pre­ven­tion or treat­ment of covid-19.”

Trump stunned many doc­tors ear­lier this week when he said he was tak­ing hy­drox­y­chloro­quine “every day” — de­spite FDA warn­ings that the use of the drug should be lim­ited to those in a hos­pi­tal set­ting or in clin­i­cal tri­als. He has since said he is close to fin­ish­ing his course of treat­ment and would stop tak­ing the med­i­ca­tion in “a day or two.”

At a White House press brief­ing Fri­day, Deb­o­rah Birx, who is co­or­di­nat­ing the gov­ern­ment’s coro­n­avirus re­sponse, de­flected a ques­tion about the pres­i­dent’s use of the drug, and added the Food and Drug Ad­min­is­tra­tion “has been very clear on their web­site about their con­cerns about hy­drox­y­chloro­quine.”

The Lancet anal­y­sis — by Man­deep Mehra, a Har­vard Med­i­cal School pro­fes­sor and physi­cian at Brigham and Women’s Hos­pi­tal, and col­leagues at other in­sti­tu­tions — in­cluded pa­tients with a pos­i­tive lab­o­ra­tory test for covid19 who were hos­pi­tal­ized be­tween Dec. 20, 2019, and April 14, 2020, at 671 med­i­cal cen­ters world­wide. The mean age was 54 years, and 53 per­cent were men. Those who were on me­chan­i­cal ven­ti­la­tors or who re­ceived remde­sivir, an an­tivi­ral drug made by Gilead Sciences that has shown prom­ise in de­creas­ing re­cov­ery times, were ex­cluded.

Mehra said in an in­ter­view that the widespread use of an­ti­malar­i­als for covid-19 pa­tients was based on the idea of “a des­per­ate dis­ease de­mands des­per­ate mea­sures,” but that we have learned a hard les­son from the ex­pe­ri­ence about the im­por­tance of first do­ing no harm.

In ret­ro­spect, Mehra said, us­ing the drugs without sys­tem­atic test­ing was “un­wise.”

“I wish we had had this in­for­ma­tion at the out­set, as there has po­ten­tially been harm to pa­tients,” he said.

Nearly 15,000 of the 96,000 pa­tients in the anal­y­sis were treated with hy­drox­y­chloro­quine or chloro­quine alone or in com­bi­na­tion with a type of an­tibi­otics known as a macrolide, such as azithromyc­in or clar­ithromycin, within 48 hours of their di­ag­no­sis. The study is a ret­ro­spec­tive anal­y­sis of their med­i­cal records, rather than a con­trolled study in which pa­tients are di­vided ran­domly into treat­ment groups — the method con­sid­ered the gold stan­dard of medicine. But the sheer size of the study was con­vinc­ing to some sci­en­tists.

And the dif­fer­ence be­tween those who re­ceived the an­ti­malar­i­als and those who did not was strik­ing.

For those given hy­drox­y­chloro­quine, there was a 34 per­cent in­crease in risk of mor­tal­ity and a 137 per­cent in­creased risk of a se­ri­ous heart ar­rhyth­mias. For those re­ceiv­ing hy­drox­y­chloro­quine and an an­tibi­otic — the cock­tail en­dorsed by Trump — there was a 45 per­cent in­creased risk of death and a 411 per­cent in­creased risk of se­ri­ous heart ar­rhyth­mias.

Those given chloro­quine had a 37 per­cent in­creased risk of death and a 256 per­cent in­creased risk of se­ri­ous heart ar­rhyth­mias. For those tak­ing chloro­quine and an an­tibi­otic, there was a 37 per­cent in­creased risk of death and a 301 per­cent in­creased risk of se­ri­ous heart ar­rhyth­mias.

Car­di­ol­o­gist Steven Nis­sen of the Cleve­land Clinic said the new data, com­bined with data from smaller pre­vi­ous stud­ies, sug­gests that the drug “is maybe harm­ful and that no one should be tak­ing it out­side of a clin­i­cal trial.”

Jesse Good­man, a for­mer FDA chief sci­en­tist who is now a Ge­orge­town Univer­sity pro­fes­sor, called the re­port “very con­cern­ing.” He noted, how­ever, that it is an ob­ser­va­tional study, rather than a ran­dom­ized con­trolled trial, so it shows cor­re­la­tion be­tween the drugs and cer­tain out­comes, rather than a clear cause and ef­fect.

Peter Lurie, a for­mer top FDA of­fi­cial who now heads the Cen­ter for Sci­ence in the Public In­ter­est, called the re­port “an­other nail in the cof­fin for hy­drox­y­chloro­quine — this time from the largest study ever.”

He said it was time to re­voke the emer­gency use au­tho­riza­tion is­sued by the FDA, which ap­proved the drug for se­ri­ously ill pa­tients who were hos­pi­tal­ized or for whom a clin­i­cal trial was not avail­able.

FDA spokesman Michael Fel­ber­baum said Fri­day the agency gen­er­ally “does not com­ment on third-party re­search” but that an emer­gency use au­tho­riza­tion may be re­vised or re­voked un­der cer­tain cir­cum­stances, such as when there are linked or sus­pected ad­verse events, new data about ef­fec­tive­ness, or changes in the riskben­e­fit as­sess­ment of the drug. Last month, the agency warned against the use of the drug out­side hos­pi­tal set­tings or clin­i­cal tri­als cit­ing re­ports of “se­ri­ous heart rhythm prob­lems.”

There have been at least 13 stud­ies in re­cent months on hy­drox­y­chloro­quine or chloro­quine as a treat­ment for covid-19 pa­tients. They have in­cluded ran­dom­ized con­trolled stud­ies and ob­ser­va­tional analy­ses en­com­pass­ing pa­tients on the con­tin­uum from mild ill­ness to those near death. Ev­i­dence of any ben­e­fit, such as vi­ral clear­ance or im­proved symp­toms, has been al­most nonex­is­tent. But many found an in­creased risk in ad­verse car­diac re­ac­tions

— es­pe­cially when com­bined with the an­tibi­otic azithromyc­in.

Ear­lier this month, back­ers of the pres­i­dent’s views on an­ti­malar­i­als seized on a study out of NYU Lan­gone Health that gave hos­pi­tal­ized coro­n­avirus pa­tients zinc com­bined with hy­drox­y­chloro­quine and azithromyc­in. Those in the treated group had a higher rate of sur­vival, but re­searchers em­pha­sized the study was fo­cused on zinc and whether hy­drox­y­chloro­quine would en­hance the sup­ple­ment’s anti-vi­ral ef­fects. They em­pha­sized their find­ings were ten­ta­tive and could have been due to fac­tors other than the drugs, es­pe­cially since zinc was added to pa­tients’ reg­i­mens later in the pan­demic when hos­pi­tal treat­ments and pro­ce­dures had been re­fined.

Last week, the Na­tional In­sti­tutes of Health an­nounced a ran­dom­ized, placebo-con­trolled clin­i­cal trial of hy­drox­y­chloro­quine and azithromyc­in in­volv­ing 2,000 adults deal­ing with their ill­ness at home. In April, NIH launched a dif­fer­ent ran­dom­ized trial of the drug cock­tail in hos­pi­tal­ized pa­tients.

Topol, of the Scripps Re­search Trans­la­tional In­sti­tute, sug­gested that the re­searchers should re­con­sider the ethics of those tri­als, given the in­creas­ing ev­i­dence of po­ten­tial harm. “It’s very hard to ig­nore that sig­nal, and it’s wor­ri­some to con­tinue giv­ing it,” he said.

Ge­of­frey Barnes, a car­dio­vas­cu­lar spe­cial­ist at the Univer­sity of Michi­gan, said the study’s ap­proach and its find­ings were “strik­ing” in mak­ing the case that “the risk with these drugs is real.” How­ever, he said that due to the en­thu­si­asm some Amer­i­cans have for the drug and the Lancet study’s find­ings, ran­dom­ized tri­als are even more im­por­tant.

“There has been so much dis­cus­sion about this drug that I think the sci­en­tific and med­i­cal com­mu­nity has an obli­ga­tion to de­fine what the po­ten­tial ben­e­fit or risk is in the best way pos­si­ble,” Barnes said.

Some sci­en­tists have ex­pressed alarm at the politi­ciza­tion of sci­ence in the de­bate over the use of an­ti­malar­ial drugs. The Lancet, one of the world’s old­est and best­known jour­nals, also pub­lished an unsigned ed­i­to­rial last week crit­i­ciz­ing Trump’s “in­con­sis­tent and in­co­her­ent na­tional re­sponse” to the pan­demic, and urg­ing Amer­i­cans to “put a pres­i­dent in the White House come Jan­uary, 2021, who will un­der­stand that public health should not be guided by par­ti­san pol­i­tics.”

When the first large wave of sick pa­tients be­gan show­ing up at hos­pi­tals in March, doc­tors had very lit­tle to of­fer them. As a re­sult, many took a gam­ble on hy­drox­y­chloro­quine. The drug had been shown to have strong an­tivi­ral prop­er­ties in cell cul­tures, was widely avail­able and was thought to be rather be­nign in terms of side ef­fects. For years, hy­drox­y­chloro­quine has been con­sid­ered a gen­er­ally safe and ef­fec­tive treat­ment for malaria, lu­pus and rheuma­toid arthri­tis.

But those find­ings of safety were at lower doses than were be­ing used at hos­pi­tals dur­ing the early days of the surge in pa­tients in the United States and mostly in pa­tients who were healthy. The pop­u­la­tion in­fected with covid-19 in hos­pi­tals, it turned out, was al­ready at higher risk of car­dio­vas­cu­lar com­pli­ca­tions be­cause many suf­fer from high blood pres­sure or other heart is­sues. Doc­tors also dis­cov­ered that, to their sur­prise, the novel coro­n­avirus ap­peared to di­rectly or in­di­rectly at­tack the heart, in­clud­ing by re­duc­ing its abil­ity to pump, cre­at­ing an im­bal­ance in its elec­tri­cal rhythms, and at­tack­ing blood ves­sels.

CRAIG LASSIG/REUTERS

Cody Hoff­mann checks the re­sults as re­searchers at the Univer­sity of Min­nesota be­gan a trial to see whether hy­drox­y­chloro­quine could pre­vent or re­duce the sever­ity of covid-19. How did an ob­scure drug be­came a coro­n­avirus “cure?” See video at wapo.st/drug­factcheck.

GE­ORGE FREY/AGENCE FRANCE-PRESSE/GETTY IM­AGES

Pres­i­dent Trump said Mon­day that for the past two weeks he has been tak­ing hy­drox­y­chloro­quine.

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