Readjudication of mortality information from the FOURIER proceedings suggests a higher hazard for cardiovascular decease with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than primitively reported for the first-in-class PCSK9 inhibitor.
The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this reappraisal successful 2018, citing "significant inconsistencies and misreporting" betwixt accusation successful decease narratives successful the trial's objective survey study (CSR) and the 2017 New England Journal of Medicine (NEJM) work of the superior proceedings results.
"After readjudication, deaths of cardiac root were numerically higher successful the evolocumab radical than successful the placebo radical successful the FOURIER trial, suggesting imaginable cardiac harm," the researchers reason successful the caller study published online December 30 successful BMJ Open. "At the clip the proceedings was terminated early, a non-significantly higher hazard of cardiovascular mortality was observed with evolocumab, which was numerically greater successful our adjudication.
"Our findings bespeak that implicit restoration of each objective outcomes from the FOURIER proceedings is required," they write. "Meanwhile, clinicians should beryllium skeptical astir benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease."
Asked to remark connected the reanalysis, FOURIER pb researcher Marc Sabatine, MD, MPH, a prof of medicine astatine Harvard University and the Lewis Dexter distinguished seat successful cardiovascular medicine astatine Brigham and Women's Hospital, said: "It's hard to telephone this science. I deliberation it lacks each technological rigor and is fundamentally flawed and, due to the fact that their process was flawed, it has led them to erroneous conclusions."
Reached for comment, Sanjay Kaul, MD, a cardiologist and prof of medicine astatine Cedars-Sinai Medical Center successful Los Angeles, who was not progressive with either study, said: "If I were to picture this successful 1 sentence, I would accidental overmuch ado astir nothing. A tempest successful a teapot."
Evaluating Hard Outcomes
The US Food and Drug Administration (FDA) approved evolocumab successful 2015 for lowering LDL-cholesterol levels, but without results from immoderate proceedings evaluating hard outcomes.
As previously reported successful 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL-cholesterol by 59% and was associated with a 15% simplification successful the superior composite cardiovascular (CV) events endpoint compared with placebo but numerically much all-cause and CV mortality.
The NEJM information investigation reported the hazard for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% CI, 0.88 - 1.25), whereas the caller reappraisal recovered a inactive nonsignificant 20% comparative hazard (RR, 1.20; 95% CI, 0.95 - 1.51).
Cardiac deaths were besides numerically higher successful the evolocumab radical (113 vs 88), corresponding to a 28% higher comparative hazard (RR, 1.28; 95% CI, 0.97 - 1.69). Vascular deaths were akin astatine 37 successful some groups (RR, 1.00; 95% CI, 0.63 - 1.58).
For 360 of the 870 deaths, the origin of decease adjudicated by the FOURIER objective events committee differs from that identified by the section objective investigators successful the CSR decease narrative, the authors say.
The RIAT investigators recovered 11 much deaths from myocardial infarction successful the evolocumab radical (36 vs 25 successful the NEJM publication) and 3 less deaths successful the placebo radical (27 vs 30). In addition, their reappraisal indicated that deaths arsenic a effect of cardiac nonaccomplishment successful the evolocumab radical were astir treble those successful the placebo group, astatine 31 vs 16, respectively.
An "Obvious Disconnect"
Thomas L. Perry, MD, a co-author of the BMJ Open insubstantial and a wide internist successful the section of anesthesiology, pharmacology, and therapeutics astatine University of British Columbia-Vancouver, Canada, said successful an interrogation that the squad repeatedly sought accusation from the FOURIER investigators but ne'er received a response.
They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a akin petition with the FDA but were told successful October 2019 it would instrumentality up to 7 years to merchandise the information. Case study forms were besides requested but not received from each 3 agencies.
Perry noted that nary autopsies were performed successful the trial, a assertion Sabatine rejects, and that their reappraisal of the decease narratives successful the CSR recovered 91 deaths classified by the section researcher arsenic "undetermined" but subsequently adjudicated by the FOURIER objective events committee arsenic "sudden cardiac" deaths without immoderate documented grounds to enactment the change.
At his request, Perry said they included 2 lawsuit examples (figures 1 and 2) successful the BMJ Open insubstantial of the "obvious disconnect" successful decease endpoints. Both of these were identified by the section researcher arsenic a myocardial infarction (MI) but aboriginal "misreported" according to Perry, arsenic a sudden cardiac death and noncardiovascular decease (trauma), respectively.
"What's truthful important astir this is not lone that it throws into uncertainty the reliability of what the radical astatine Harvard and elsewhere reported successful the New England Journal of Medicine in 2017, but besides raises a question astir immoderate different ample survey similar this wherever you trust connected supposedly ethical section investigators to tally the proceedings good and to study accurately what happens to people," Perry told theheart.org | Medscape Cardiology.
Although helium ne'er prescribed evolocumab aft the archetypal results were published, Perry said he's adjacent little convinced of a payment now. "Basically, I don't judge that they are telling america the facts," helium said. "I person nary crushed to accidental there's an constituent of deliberately misleading us. I deliberation it's sloppiness, incompetence, laziness."
Perry besides favors readjudication of the mortality information successful the ODYSSEY trial, which showed an all-cause mortality payment with the PCSK9 inhibitor alirocumab (Praluent).
The "Full Picture"
Sabatine explained that erstwhile a diligent had a cardiovascular event, including a death, it triggered the postulation of a afloat dossier containing each disposable root documents, specified arsenic discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by 2 committee certified physicians blinded to treatment. To suggest, arsenic the RIAT investigators have, that nary autopsies were performed is "obviously ridiculous and wrong," helium said.
In contrast, helium said the caller investigation was station hoc, progressive unblinded individuals, and relied connected superior adverse lawsuit (SAE) narratives, which see a tiny substance container that indispensable beryllium filled retired with the site's archetypal content of the lawsuit and sent wrong 24 hours of the event.
Further, erstwhile the FOURIER investigators pulled the dossiers for the 2 much egregious examples cited successful the paper, they recovered that the archetypal diligent died successful his slumber astatine home. "The researcher past conscionable said, 'Oh, I presume it's an MI' but there's nary biochemical data, there's nary ECGs, there's thing to marque the diagnosis of MI. So that's wherefore that is simply a abrupt cardiac decease per the FDA definition," Sabatine said.
When the FOURIER investigators reviewed the afloat dossier for the 2nd lawsuit example, they recovered the diligent had slipped successful his room astatine home, sustained a superior head trauma, was brought into the exigency department, and died.
"That's wherefore we trust connected the root documents. That gives the afloat picture," helium said. The FDA besides reviewed the decease narratives.
"They comment, ironically, that they were amazed astatine the inconsistencies betwixt the investigator-reported causes of decease and the cardinal events committee-adjudicated ones, making it dependable similar thing nefarious has happened. But that's the full constituent of adjudication, right? That you person a cardinal events committee that reviews and past classifies based connected each the data," Sabatine said.
Sabatine said helium sees nary crushed to reevaluate the ODYSSEY mortality information and that the RIAT investigation should not alteration the wide mentation of FOURIER.
"I deliberation this is successful information a disservice to the aesculapian assemblage due to the fact that it's not existent science," helium said. "It's conscionable sensationalism and sends the incorrect message. But I wholly basal by the results that we published, arsenic the FDA has."
Kaul besides thought the caller investigation doesn't materially alteration the wide benefit–risk balance. He observed that determination isn't a large quality betwixt the reanalysis and the archetypal evaluation. Total mortality was akin and, for cardiovascular deaths, the archetypal NEJM insubstantial lists 251 for evolocumab vs 240 for placebo and the reanalysis lists 150 vs 125, respectively.
Undetermined deaths were 164 successful the NEJM insubstantial and 144 successful the reanalysis. "The blimpish attack is to number them arsenic presumed cardiovascular deaths," Kaul said. "So, if you bash the mathematics and adhd those undetermined arsenic cardiovascular deaths, we get a full of 294 vs 289. That's 5 excess deaths with evolocumab."
Open Access
Although the RIAT radical has called for the nationalist merchandise of the FOURIER data, commercialized and ineligible issues volition complicate that process, Steven Grover, MD, prof of medicine and manager of the Comprehensive Health Improvement Program astatine McGill University successful Montreal, Canada, said successful an interview. Amgen is backmost successful tribunal implicit patent protection, filing an appeal with the Supreme Court aft losing successful the little courts successful a protracted battle, Reuters reported.
"One happening that's for definite aft they've raised questions astir the results of this survey [is that] idiosyncratic needs to instrumentality a bully hard look astatine the adjudicated results," said Grover, who co-authored respective iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest successful 2021.
"I deliberation the happening that got truthful galore of america backmost successful 2017 erstwhile the survey was archetypal published is the mortality information stuck retired similar a sore thumb," helium told theheart.org | Medscape Cardiology. "It didn't person to beryllium statistically significant, but it did request to determination successful the aforesaid absorption arsenic the nonfatal coronary events. That's what we've seen hap clip and again and, successful this case, it was going successful the other direction."
Sabatine said helium doesn't cognize whether the information volition beryllium released but that the FOURIER trialists program to taxable a rebuttal to BMJ Open to the RIAT analysis, which has caused a disturbance connected CardioTwitter. "Now that radical unrecorded with Tweets of information, it necessitates past dispelling the misinformation that comes out. So yes, we volition draught a rebuttal pointing retired each the flaws successful this analysis."
Kaul commented that the FDA's effect not to supply the information was "rather curious" and that Sabatine and colleagues had the accidental to code the RIAT group's concerns, but the insubstantial notes they did not adjacent fuss to respond. "You can't beryllium holier than thou successful medicine. You person to dainty each question with respect and humility and can't beryllium dismissive…He could person nipped the evil successful the bud, truthful to speak."
The survey was funded by a assistance from the University of Maryland, Baltimore. The authors, Kaul, and Grover study having nary applicable fiscal relationships.
BMJ Open. Published online December 30, 2022. Full text
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