Any cardiovascular protection from
colchicine in heart attack survivors seemed to be debunked with a
better-powered randomized trial, researchers found.
Between acute MI patients randomized to colchicine or placebo right
after percutaneous coronary intervention (PCI) in the CLEAR OASIS 9
trial, there were statistically indistinguishable rates of combined
cardiovascular death, myocardial infarction (MI), stroke, or
ischemia-driven revascularization at 5 years (9.1% vs 9.3%, HR 0.99, 95%
CI 0.85-1.16), according to Sanjit Jolly, MD, of Hamilton Health
Sciences and McMaster University in Ontario, at the Transcatheter Cardiovascular Therapeutics (TCT) meetingopens in a new tab or window.
The only clinically significant signal his group reported was more diarrhea with colchicine (10.2% vs 6.6%, P<0.001).
"I was a believer in colchicine," Jolly revealed during a TCT press
conference. He shared his experience putting his own father (a retired
cardiologist) on colchicine and only recently taking him off the drug,
given the results of CLEAR OASIS 9. "As a patient you can decide for
yourself, would you want to take this therapy? I decided to stop it in
my parent."
As this is the largest trial of routine long-term colchicine in acute
MI to date -- boasting 649 primary outcome events -- "the role of
colchicine post myocardial infarction long term is uncertain," he
concluded.
Available generically, colchicine is derived from the autumn crocus plant used medicinally for thousands of years in Egypt.
Last year, the FDA approved brand-name colchicine (Lodoco)opens in a new tab or window
as the first anti-inflammatory agent indicated for cardiovascular
prevention in adults with established atherosclerotic disease or
multiple risk factors. Colchicine currently stands at a class IIb
recommendation in American guidelines and IIa in the European ones.
TCT
session discussant Roxana Mehran, MD, of Mount Sinai Health System in
New York City, said she believed that colchicine's place in the
guidelines may be re-evaluated based on the new data. "I would say
there's some evidence to downgrade, but that would be up to the
guideline group."
"Colchicine may be considered in patients under optimal medical
therapy who remain at very high risk for ischemic events. It's not for
everyone," Mehran said.
CLEAR OASIS 9 contradicts two major trials on the anti-inflammatory drug. In 2019, the COLCOTopens in a new tab or window
group had found that low-dose colchicine worked for secondary
prevention after MI, with the most substantial reductions observed for
stroke and revascularization in follow-up of nearly 2 years. Colchicine
again reduced cardiovascular events, this time in stable ischemic heart
disease, in the LoDoCo2 trialopens in a new tab or window from 2020.
Jolly pointed out COLCOT's 301 primary endpoint events and LoDoCo2's 451 -- both lower than the present report.
"We
had double the events, so I think it's just regression to the mean," he
explained. "As time goes on, with more data, the truth may be there is
no effect or a very modest effect [of colchicine]."
"This medicine is not well tolerated ... I would not want to start it
in a patient. I never did, and now there's good rationale not to,"
commented Ajay Kirtane, MD, of New York-Presbyterian/Columbia University
Irving Medical Center in New York City, as a panelist during the press
conference.
The sentiment was echoed by fellow panelist Wayne Batchelor, MD, MHS,
of Inova Health System in Fairfax, Virginia. However, Batchelor warned
against "throwing the baby out with the bathwater" as the concept of
suppressing inflammation may still prove clinically beneficial with a
different drug such as an interleukin 6 inhibitor.
CLEAR OASIS 9 was a 2x2 factorial randomized trial that included
7,000 acute MI patients. Within 72 hours following PCI, participants
were randomly assigned colchicine (0.5 mg once daily) versus placebo and
spironolactone (25 mg once daily) vs placebo.
The
overall cohort had a mean age just over 60 years, with only one in five
being women. Reflecting the study having initially been limited to
patients with ST-segment elevation myocardial infarction (STEMI) until a
protocol amendment to ease enrollment, the study population ended up
presenting with 95% STEMI and 5% large non-ST elevation MI. The
prevalence of diabetes was around 18%, and prior MI around 9%.
For the index PCI, operators used the Synergy stent when available.
The procedure consisted of a median one stent per patient, the stent
averaging 23.8 mm long and having a diameter of 3.2 mm. Nearly half of
patients had multivessel coronary disease, the vast majority of whom had
staged procedures.
Medications at discharge were standard fare including aspirin,
statins, and ticagrelor (Brilinta; 45%) as the preferred P2Y12 inhibitor
over clopidogrel (Plavix; 42%) or prasugrel (Effient; 11%).
Colchicine's lack of benefit was consistent in on-treatment analysis
and in the individual components of the composite primary endpoint:
- Cardiovascular death: 3.3% with colchicine vs 3.2% with placebo
- MI: 2.9% vs 3.1%
- Stroke: 1.4% vs 1.2%
- Ischemia-driven revascularization: 4.6% vs 4.7%
This was irrespective of the patient's MI type and whether they had multivessel disease, Jolly noted.
All-cause mortality was statistically similar between colchicine and
placebo groups (4.6% vs 5.1%), while there was a signal of significant
reduction in non-cardiovascular death by colchicine (1.3% vs 1.9%) that
Jolly downplayed as a statistical anomaly.
In any case, colchicine did reduce inflammation better than placebo
(-1.3 mg/L mean difference in CRP between groups at 3 months).
The medication was also not associated with excess serious adverse events (6.7% vs 7.4%).
Mehran pointed out that limitations of CLEAR OASIS 9 include its
conduct during the COVID-19 pandemic and deviations from the original
study protocol. She also highlighted the underrepresentation of women as
a limitation of the trial, though she acknowledged that many women may
have been missed due to the cutoff of acute MIs within 72 hours.
Jolly noted that the full CLEAR OASIS 9 manuscript has been accepted at the New England Journal of Medicine
and will be published when the spironolactone arm of the 2x2 factorial
trial is presented at the American Heart Association meeting later this
month.
This is not the first negative trial for colchicine.
Cardiovascular benefits apparently did not extend to colchicine administered at the time of PCIopens in a new tab or window in an older trial, nor did the drug work as a perioperative treatmentopens in a new tab or window
to reduce atrial fibrillation and myocardial injury after major
non-cardiac thoracic surgery. Additionally, the CONVINCE trial had been
stopped before investigators could show whether long-term colchicine use
had cardiovascular benefits in stroke survivorsopens in a new tab or window.
-
Nicole Lou is a reporter for MedPage Today, where she covers cardiology news and other developments in medicine. Follow
Disclosures
The trial was funded
by grants from the Canadian Institutes of Health Research, Population
Health Research Institute, and Boston Scientific.
Jolly disclosed relationships with Boston Scientific, Teleflex, Asahi, Shockwave, and Abiomed.
Mehran reported various personal ties to industry and professional societies.
Kirtane
disclosed grant support from Medtronic, Abbott, Boston Scientific,
Amgen, CathWorks, Siemens, Philips, Recor Medical, Spectranetics,
Cardiovascular Systems, Chiesi, Opens, Zoll, Regeneron, Neurotronic,
Biotronik, Bolt Medical, Magenta Medical, Canon, SoniVie, Shockwave
Medical, and Abiomed.
Batchelor reported grant support from Abbott
and Boston Scientific on top of personal fees from Medtronic, Edwards
Lifesciences, Abiomed, Chiesi, and Recor Medical.
Primary Source
Transcatheter Cardiovascular Therapeutics
Source Reference: opens in a new tab or windowJolly
S "A 2x2 factorial randomized controlled trial of colchicine versus
placebo and spironolactone versus placebo in patients with myocardial
infarction: results of the colchicine factorial" TCT 2024.
![author['full_name']](https://clf1.medpagetoday.com/media/images/author/nicoleLou_188.jpg)
