A single dose of the anti-inflammatory drug colchicine before percutaneous artery intervention (PCI) failed to significantly reduce PCI-related myocardial injury or 30-day major adverse cardiovascular events (MACE) compared with placebo in an investigator-initiated, double-blind, randomized trial.
However, colchicine was associated with significant reductions in some inflammatory markers following PCI, including interleukin (IL)-6 and high-sensitivity C-reactive protein (hsCRP).
“The study dose of colchicine used in our trial given 1 to 2 hours pre-procedure did not lower the rates of microdamage to the heart but did, for the first time, show that colchicine can prevent a rise in vascular inflammation during an acute injury,” lead study author Binita Shah, MD, told theheart.org | Medscape Cardiology.
The Colchicine-PCI study findings were reported during a late-breaking research session at the American Heart Association (AHA) Scientific Sessions 2019.
Paucity of Data Around PCI
“We know that opening up a coronary artery blockage with balloons and stents can cause vascular inflammation and microdamage to the heart,” added Shah, assistant professor of medicine and associate director of research, Cardiac Catheterization Laboratory, Leon H. Charney Division of Cardiology, New York University School of Medicine in New York City.
“We also know that reducing inflammation after a heart attack improves outcomes, but there are no currently available drugs to rapidly reduce vascular inflammation,” he said.
The CANTOS trial demonstrated a reduction in recurrent MACE after MI with anti-IL-β antibody, and findings of the COLCOT study, also presented here at the AHA Scientific Sessions 2019, show the agent holds promise for secondary prevention of events after MI compared to placebo.
“Colchicine may be particularly applicable to the PCI setting due to its rapid onset of action and excellent side-effect profile at low doses,” the researchers note. “However, data on colchicine use in patients with coronary disease is extremely limited, and no studies to date have evaluated the use of colchicine in patients undergoing PCI.”
Single-Dose Colchicine vs Placebo
To address this gap in the literature, Shah and colleagues assessed 1429 adults suspected of having ischemic heart disease or acute coronary syndromes referred for coronary angiography with possible PCI. After exclusions and withdrawals, they studied 709 participants. They randomly assigned 348 participants to placebo and another 366 people to treatment with 1.2 mg colchicine 1 to 2 hours before PCI and 0.6 mg 1 hour later.
Mean age in the PCI cohort was 66 years, 93% of patients were men, and the population was ethnically/racially diverse: 57% white non-Hispanic, 21% Hispanic, and 17% black non-Hispanic.
Approximately 50% of patients presented with acute coronary syndrome as their indication for PCI. More than one third, 38%, had a history of coronary revascularization; tobacco use was reported by 71%, and 54% had diabetes mellitus.
Peri-procedural myocardial injury within 24 hours after PCI was the primary endpoint. Researchers measured this as IL-6 concentrations at 30 minutes to 1 hour after PCI. A total 118 people in the colchicine group vs 122 in the placebo group met this endpoint, so there was no significant difference between cohorts.
In addition, the secondary outcome of 30-day MACE did not differ significantly between groups, occurring in 24 colchicine and 25 placebo recipients. MACE “was largely driven by type 4a MI,” Shah said.
Furthermore, the secondary outcome of PCI-related MI also did not differ between the two groups.
Nested Inflammatory Marker Substudy
The investigators also performed a nested biomarker substudy among 280 of the patients who underwent PCI. They measured systemic inflammation markers and neutrophil activity, particularly IL-6 levels.
“When looking at the percent change in IL-6 concentration vs baseline, we don’t see an attenuation with colchicine at 1 or at 6 to 8 hours,” the researchers note. “However, at 22 to 24 hours post-procedure, we see a significant attenuation in the rise in IL-6 with colchicine compared to placebo.”
Although IL-1β levels did not different between groups, the percentage change in hsCRP concentration compared to baseline at 22 to 24 hours was attenuated with colchicine vs placebo.
Reported adverse events were low in the overall randomly assigned cohort of 714 patients, Shah said. These events did not significantly differ between the two groups, with the exception of gastrointestinal symptoms, which were more prevalent in the colchicine group than the placebo group: 9% vs 3%. In addition, hemodynamic instability was more prevalent in the placebo group.
Additional research to determine optimal dosing and timing of colchicine administration is warranted among PCI patients, the researchers note. They added, “In this study, we saw inflammatory markers decrease around the 24-hour time point post-PCI, so an earlier start to pre-procedural colchicine regimen warrants further investigation.”
Shad said that additional studies, including the COLCOT and CLEAR SYNERGY trials, “will provide further insight into how daily colchicine may improve outcomes after a myocardial infarction, and may provide important information to guide future studies of colchicine for patients undergoing PCI.”
Shah is working with Sanjit Jolly, MD, at McMaster University in Hamilton, Ontario, Canada, principal investigator of the CLEAR SYNERGY (OASIS 9) trial. She has also received National Institutes of Health funding to evaluate blood samples from CLEAR trial participants “to try to better understand which patients may benefit from colchicine use after a heart attack — and which patients would not — with the hope of further advancing the field of precision medicine.”
A Neutral Outcome, Some New Questions
“It is a very important study and a very important question,” invited discussant Subodh Verma, MD, PhD, a cardiac surgeon at St. Michael’s Hospital and Professor of Surgery and Pharmacology & Toxicology at the University of Toronto, Ontario, Canada, said at the conference.
The primary outcome of Colchicine-PCI “showed a neutral effect of colchicine with respect to PCI-related myocardial injury,” Verma said. “And when you look at biomarkers, the primary change early was not statistically significant, and there was a modest, statistically significant change in IL-6 seen at 22 to 24 hours.” IL-1β levels did not significantly change, he added.
The study population was a mixed population of patients undergoing diagnostic angiography and others presenting with an acute coronary syndrome, Verma noted. “That has important implications, as people with an acute coronary syndrome often have variable biomarker responses.”
The absolute baseline levels of inflammatory markers were not reported, he said, “but they are important. We learned from CANTOS that patients with increased baseline inflammation have greater benefit.”
“It is reassuring, though, that there was biological efficacy witnessed by a reduction in hsCRP at 24 hours post-PCI,” Verma said. “That provides me with confidence that the therapies were onboard and at least inflammation was being affected.”
“What is the bottom line for colchicine at this point?” Verma asked. “If you had a recent MI, I think the answer is a resounding yes based on what I heard from Dr Tardif [the COLCOT study]. If you had an acute peri-STEMI presentation, I think we still have to await results from CLEAR Synergy.”
“What about pre- or peri-PCI? I don’t think we’re there yet based on what I heard today,” Verma said. “More studies are needed that target residual inflammatory risk and potentially couple this acute loading dose with chronic, ongoing treatment.”
Future Research Should ID Best Candidates
“One of the things the discussant brought up, which I agree with, is that even though these were somewhat elective or urgent PCIs, there was a wide variability in baseline inflammatory markers,” session co-moderator Jinnette Dawn Abbott, MD, director of the Interventional Structural Heart Disease Fellowship at Rhode Island and Miriam Hospitals, Providence, told theheart.org | Medscape Cardiology when asked to comment on the study.
“We just don’t know if there are going to be subgroups that have more of a change,” added Abbott, who is also affiliated with the Warren Alpert Medical School, Brown University.
“It’s encouraging to see that CRP, which is a generic marker of multiple inflammation pathways, was reduced,” she said. “We can say that this study adds to the evidence that this drug will work to reduce inflammation. We just have to figure out which of the patients to give it to.”
Shah dedicated the study to the memory of Steven Sedlis, MD, who served as chief of the cardiology section at the Manhattan Veterans Affairs Medical Center and professor of medicine at New York University School of Medicine for more than 20 years. Sedlis “was a mentor and played a pivotal role in my career development as well as the design and conduct of this study.”
Shah, Abbott, and Verma had no relevant financial disclosures. The AHA National Clinical Research Program and a VA Career Development Award funded the study.
Presented during a late-breaking research session at the American Heart Association (AHA) Scientific Sessions 2019.