New use for an old drug: The potential of colchicine in CVD
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Secondary prevention of CVD with colchicine is a major focus for the cardiology community, especially after recent presentations of the COLCOT and COLCHICINE-PCI trials at the American Heart Association Scientific Sessions in November.
Repurposing of drugs for CV applications has become more common, as researchers have learned how the mechanisms of certain drugs may offer benefit for various conditions.
“The revolution going on is trying to think about drugs that are traditionally used to treat rheumatoid arthritis can now actually be used to treat atherosclerosis. This repurposing process is really very interesting,” Paul M. Ridker, MD, MPH, FACC, FAHA, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital and Eugene Braunwald Professor of Medicine at Harvard Medical School, told Cardiology Today.
Colchicine, which has been investigated for CV applications for more than a decade, is a prominent example of this trend.
In the COLCOT trial, researchers found adults with a recent MI were less likely to experience an ischemic CV event over 2 years when assigned 0.5 mg per day of colchicine, an anti-inflammatory medication, compared with those assigned placebo. In addition, colchicine was associated with a 74% reduction in stroke risk and a 50% reduction in risk for angina hospitalization leading to revascularization. In the COLCHICINE-PCI trial, in patients with suspected ischemic heart disease or ACS referred for coronary angiography with possible PCI, acute preprocedural administration of 1.8 mg of colchicine did not reduce PCI-related myocardial injury or major adverse CV events compared with placebo. A secondary analysis showed attenuation of the inflammatory biomarker response.
“COLCOT demonstrated clinical efficacy of colchicine for cardiovascular risk reduction in patients with recent myocardial infarction,” Aruna D. Pradhan, MD, MPH, associate physician at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, said during a discussant presentation at the AHA Scientific Sessions. “It was a large, simple and well-designed event-driven trial which aimed to answer one core question. This will be a landmark study. These results provide confirmation that inflammation management reduces cardiovascular risk, and it was an example of successful repurposing of a broadly available and relatively safe generic drug for a new application.”
In an interview with Cardiology Today, Jean-Claude Tardif, MD, director of research at the Montreal Heart Institute, principal investigator of COLCOT, said that “by repurposing well-known medications like colchicine, we can help address the major public health issue of subsequent CV events after an MI in a cost-effective manner, to help patients worldwide overcome the cost barriers of their treatment.”
In the COLCHICINE-PCI trial, Tardif and colleagues found that colchicine reduced levels of biomarkers of vascular inflammation compared with placebo. This was not shown in the COLCOT trial, perhaps because only a small subset of its patients had biomarkers analyzed.
“COLCHICINE-PCI showed for the first time that colchicine can prevent a rise in blood markers of vascular inflammation during an acute injury,” Binita Shah, MD, MS, associate director of research in the cardiac cath lab and assistant professor of medicine at VA New York Harbor Healthcare System and NYU Langone Health and a Cardiology Today Next Gen Innovator, who presented the results at the AHA Scientific Sessions, said in an interview. “More work is needed to determine the optimal dosing and timing regimen of colchicine administration in patients with coronary artery disease and patients undergoing PCI. We saw inflammatory markers decrease around the 24-hour time point post-PCI, so an earlier start to preprocedural colchicine regiment warrants further investigation.”
History of colchicine
Colchicine is derived from a plant called autumn crocus. The plant, along with its derivatives, has been used since ancient times for the treatment of inflammatory issues including joint disease. The active ingredient of colchicine was purified in the 19th century and was ultimately utilized for the acute treatment of gout and the prophylactic treatment of patients with frequent gout attacks.
In 1974, research conducted by Charles A. Dinarello, MD, professor of medicine at the University of Colorado School of Medicine, and colleagues and published in The New England Journal of Medicine found that a daily dose of colchicine was effective in preventing attacks in patients with Familial Mediterranean Fever, a condition characterized by recurrent episodes of polyserositis and fever. Dinarello also led other investigations on the mechanism of colchicine and found that it was inhibiting the function of inflammatory blood cells, which potentially opened the doors for its use in the CV arena, experts said.
At the present time, colchicine is being used by cardiologists as a treatment for pericarditis, based in part on the results of trials such as ICAP, published in NEJM, and CORP-2, published in The Lancet, conducted by Massimo Imazio, MD, from Maria Vittoria Hospital, Turin, Italy, and colleagues.
“[Pericarditis is] an inflammatory disease, and it has been treated in the latter half of the 20th century since the introduction of corticosteroids as anti-inflammatory drugs in clinical practice,” Cardiology Today Vascular Medicine Section Editor Peter Libby, MD, cardiovascular specialist at Brigham and Women’s Hospital and Mallinckrodt Professor of Medicine at Harvard Medical School, said in an interview. “It has been treated with glucocorticoids like prednisone. Those treatments are pretty effective for initial bouts of pericarditis but weaning of steroids often proved devilishly difficult, and often led to recurrent bouts of pericarditis, a real vexing problem for us in cardiology. Colchicine proved quite effective in treating pericarditis, and led to many fewer recurrent episodes than we saw with glucocorticoids.”
The issue that remains with the use of colchicine is how to wean patients off the medication, experts said.
“With gout, we tend to limit the chronic use of colchicine because once we get rid of all the uric acid deposits using urate-lowering drug therapy, we do not need it to treat the gouty arthritis,” Brian Mandell, MD, PhD, professor and chairman of academic medicine at Cleveland Clinic, said in an interview. “But [COLCOT] says, maybe we should leave them on it longer because we know that the population of patients with gout also have more coronary disease. So that is a population in which I think it is not unreasonable to change our practice patterns and say, those patients who have tolerated colchicine when it was given as prophylaxis against gout attacks, if they have multiple risk factors for coronary disease, why not continue therapy at a low dose? Notably, in earlier smaller studies of colchicine and cardiovascular events, an even greater benefit was seen in patients who had not received prior coronary stenting (93% of patients in the COLCOT study had received stents).”
Revisiting colchicine for CV applications
The idea of using colchicine for secondary prevention of CVD emerged after the LoDoCo trial was published in the Journal of the American College of Cardiology in 2013. The study enrolled 532 patients with stable coronary disease who were receiving aspirin and/or clopidogrel and statins in an open-label design. Patients assigned 0.5 mg of colchicine per day had a lower incidence of the primary outcome — composite incidence of ACS, noncardioembolic ischemic stroke and out-of-hospital cardiac arrest — compared with those assigned no colchicine (5.3% vs. 16%; HR = 0.33; 95% CI, 0.18-0.59), with a number needed to treat of 11.
“This suggested colchicine reduced MACE in patients with CAD; however, LoDoCo was a small study, so larger studies are being done,” Sanjit S. Jolly, MD, MSc, FRCPC, interventional cardiologist at Hamilton Health Sciences and professor of medicine at McMaster University, both in Hamilton, Ontario, Canada, told Cardiology Today.
Another study was published in 2013 on the use of colchicine to prevent bare-metal stent restenosis in patients with diabetes who underwent PCI. In this study, patients were assigned 0.5 mg of colchicine twice per day or placebo for 6 months. The rate of in-stent restenosis was lower in patients assigned colchicine vs. placebo (16% vs. 33%; OR = 0.38; 95% CI, 0.18-0.79), with a number needed to treat of 6 (95% CI, 3.4-18.7).
Now, with the addition of COLCOT and COLCHICINE-PCI to this growing evidence base, questions remain on how to use colchicine for CV indications, particularly related to long-term use, mechanisms, dose and timing if used after PCI.
Cost can also play a role in whether colchicine, a generic drug, is widely used. The cost is higher in the United States compared with other countries such as the United Kingdom. One brand name of colchicine, Colcrys (Takeda), can cost approximately $228 for a 30-day supply of 0.6 mg tablets, according to its listing on drugs.com. Pre-FDA approval for branding, generic colchicine cost a few cents per pill.
“We need to wait to see the results of a second major colchicine trial,” Ridker said. “If they’re both positive, then I think this discussion about cost can be revisited.”
Nonetheless, the idea of a drug that acts differently from other CV medications but is not cost-prohibitive is starting to generate excitement.
“We now have a drug that is already available, and the question for the guideline writers that they will have to wrestle with is, is this the sixth drug in our cocktail for post-MI patients?” Donald M. Lloyd-Jones, MD, ScM, associate dean for clinical and translational research, chair of the department of preventive medicine and director of Northwestern University Clinical and Translational Sciences Institute, said during a press conference at the AHA Scientific Sessions. “We have now one trial, modestly sized, but with a significant reduction in endpoints. This is going to start a very important conversation in understanding: Should we be using this for everyone? When you have a safe drug that is easily available, it is going to be hard to hold it back.”
Connection to inflammation hypothesis
The inflammation hypothesis that has been researched over the last 35 years appears to explain the role of colchicine for secondary prevention of CVD.
“For a long time, the independent role of inflammation on major adverse cardiovascular events was a hypothesis,” Shah said. “The only data we had to link the lowering of inflammation with lowering of adverse cardiovascular events was with statins, leading some to debate that it is the lowering of LDL cholesterol that lowers inflammation and adverse events.”
The CANTOS trial played a large role in solidifying that inflammation plays a role in CV risk. In the trial, published in The New England Journal of Medicine in 2017, Ridker, Libby and colleagues found that patients with a history of MI and an elevated high-sensitivity C-reactive protein level treated with canakinumab (Ilaris, Novartis), an interleukin (IL)-1 beta neutralizing antibody, had a lower rate of recurrent CV events compared with those assigned placebo.
Ridker also led the CIRT trial, published in NEJM in February 2019, in which low-dose methotrexate did not reduce risk for CV events vs. placebo. The drug, used to treat rheumatoid arthritis and psoriatic arthritis, may not have worked for CV event reduction because the drug does not lower IL-1, IL-6 or CRP, Ridker said.
“The fundamental mechanism by which colchicine works as an anti-inflammatory drug includes a variety of pathways,” Ridker said. “There is a canonical pathway between what’s called the NLRP3 inflammasome, which generates interleukin-1 beta, which augments production of interleukin-6, which ultimately produces CRP as a biomarker. That pathway is what my group figured out was beneficial for atherosclerotic risk.”
Libby’s laboratory discovered the induction of IL-6 by IL-1 in vascular cells decades ago, uncovering a key node in this central inflammatory pathway.
Ridker noted colchicine indirectly impacts that pathway, as it is a microtubule inhibitor that appears to inhibit the assembly of the inflammasome, a multiprotein structure necessary for IL-1 beta activation.
Findings from the CANTOS and CIRT trials, in addition to other research to develop the hypothesis, helped focus on what should be targeted in treatment.
“Together, the data suggest that we should target the IL-1 beta, IL-6, hsCRP pathway,” Shah said.
As more information is discovered on the connection between CVD and inflammation, it seems that more cardiologists are starting to accept the hypothesis.
“Inflammation offers a whole new spectrum of therapeutic targets which is orthogonal to those aimed at more traditional risk factors,” Libby said. “I think now the community is really being prepared to accept the importance of inflammation in atherothrombosis. COLCOT is a welcome buttress to the inflammation hypothesis championed by me and by Dr. Ridker. The clinical trial results now buttress and support the basic science observation.”
Trials underway
The next trial likely to make an impact is LoDoCo2, which may be presented in late 2020, experts said. The trial will focus on secondary prevention of CVD in patients with established, stable CVD and will compare 0.5 mg per day of colchicine with placebo. The primary outcome is the time to first occurrence of a composite of CV death, ischemic stroke, MI and ischemia-driven coronary revascularization.
The CONVINCE trial is being conducted in patients aged 40 years and older with an ischemic stroke or transient ischemic attack. Patients will be assigned 0.5 mg per day of colchicine plus the usual care or the usual care alone. The primary outcome is the prevention of nonfatal recurrent ischemic stroke, vascular death and coronary events. Secondary outcomes include each component of the primary outcome.
The CLEAR SYNERGY OASIS 9 trial is also in the works, which is spearheaded by Jolly and colleagues.
“It’s a 4,000-patient randomized trial that takes patients within 72 hours of their ST-elevation MI and randomizes them in a two-by-two factorial design of colchicine vs. placebo and spironolactone vs. placebo,” he said. “It also has a Synergy stent (Boston Scientific) within the trial, so it’s actually testing three different interventions. We’re really trying to maximize the patient population.”
Tardif said in an interview that more research is needed to assess the benefits of colchicine in other high-risk groups. A new trial, COLCOT-T2D, will randomly assign 10,000 individuals with type 2 diabetes but without known coronary disease to receive colchicine 0.5 mg or placebo, Tardif said.
Even with the current knowledge about colchicine and what is to come, the process of understanding the role of colchicine in CVD prevention is in some ways just beginning, Libby said.
“I quote Sir Winston Churchill, where at a certain turning point during the second world war, he said, ‘This is not the end, it is not even the beginning of the end, but it is perhaps the end of the beginning,’” Libby said. “That’s where I think we are with anti-inflammatory therapy and atherosclerosis today.”
Excitement behind findings
The use of colchicine for secondary prevention of CVD may introduce a new therapeutic pathway, especially with upcoming research potentially releasing data in the next couple years. As the inflammation hypothesis becomes more accepted, more focus will be placed on how to reduce inflammation in this patient population.
“If we have affirmation of the benefit of colchicine, I think it’s going to really impact our clinical practice and could be an enormously important addition to our therapeutic armamentarium,” Libby said. “Colchicine affects a different pathway which is not really attacked by the other therapies; therefore, we should be able to add it on without harm. We have to be concerned about drug-drug interactions and renal function, but we can handle those by adjusting doses and being aware. I think it could be really transformative to clinical practice.” – by Darlene Dobkowski, with additional reporting by Regina Schaffer
- References:
- Australian New Zealand Clinical Trials Registry. The LoDoCo2 Trial: Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease. Available at: www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363771. Accessed Dec. 13, 2019.
- ClinicalTrials.gov. Colchicine for Prevention of Vascular Inflammation in Non-cardio Embolic Stroke. Available at: www.clinicaltrials.gov/ct2/show/NCT02898610. Accessed Dec. 13, 2019.
- Deftereos S, et al. J Am Coll Cardiol. 2013;doi:10.1016/j.jacc.2013.01.055.
- Dinarello CA, et al. N Engl J Med. 1974;doi:10.1056/NEJM197410312911804.
- Drugs.com. Colcrys Prices, Coupons and Patient Assistant Programs. Available at: www.drugs.com/price-guide/colcrys. Accessed Dec. 17, 2019.
- Imazio M, et al. Lancet. 2014;doi:10.1016/S0140-6736(13)62709-9.
- Imazio M, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1208536.
- Nidorf SM, et al. J Am Coll Cardiol. 2013;doi:10.1016/j.jacc.2012.10.027.
- Ridker PM, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1707914.
- Ridker PM, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1809798.
- Shah B, et al. Late Breaking Science IV: State of the Art Interventional Management for ACS Patients. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.
- Tardif JC, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1912388.
- For more information:
- Sanjit S. Jolly, MD, MSc, FRCPC, can be reached at sanjit.jolly@phri.ca; Twitter: @sanjitsjolly.
- Peter Libby, MD, can be reached at plibby@bwh.harvard.edu.
- Donald M. Lloyd-Jones, MD, ScM, can be reached at dlj@northwestern.edu.
- Brian Mandell, MD, PhD, can be reached at mandelb@ccf.org.
- Aruna D. Pradhan, MD, MPH, can be reached at apradhan@partners.org.
- Paul M. Ridker, MD, MPH, FACC, FAHA, can be reached at pridker@bwh.harvard.edu.
- Binita Shah, MD, MS, can be reached at binita.shah@nyulangone.org; Twitter: @binitashahmd.
- Jean-Claude Tardif, MD, can be reached at jean-claude.tardif@icm-mhi.org.
Disclosures: The COLCHICINE-PCI trial was funded by a VA Career Development Award and an AHA Mentored Clinical Research Award, and the drug was supplied by Takeda Pharmaceuticals and the Manhattan VA Hospital Research Pharmacy. Jolly, Libby, Lloyd-Jones and Mandell report no relevant financial disclosures. Pradhan reports she receives research grants from Denka Seiken and Kowa Research Institute. Ridker reports he was the principal investigator for the CANTOS trial, which was funded by Novartis, and for the CIRT trial, which was funded by the NHLBI, and has consulted for CiviBio, Corvidia, Inflazome, Janssen and Novartis. Shah reports she received grant funding from the VA Office of Research and Development and the NIH/NHLBI to study colchicine in acute MI and PCI. Tardif reports he has received grants or personal fees from Amarin, AstraZeneca, DalCor, Esperion, Ionis, Pfizer, Sanofi and Servier, and has a patent for genetic markers predicting responsiveness to therapy with HDL-raising agents.
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Australian New Zealand Clinical Trials Registry. The LoDoCo2 Trial: Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease. Available at:www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363771. Accessed Dec. 13, 2019.
ClinicalTrials.gov. Colchicine for Prevention of Vascular Inflammation in Non-cardio Embolic Stroke. Available at: www.clinicaltrials.gov/ct2/show/NCT02898610. Accessed Dec. 13, 2019.
Deftereos S, et al.J Am Coll Cardiol. 2013;doi:10.1016/j.jacc.2013.01.055.
Dinarello CA, et al.N Engl J Med. 1974;doi:10.1056/NEJM197410312911804.
Drugs.com. Colcrys Prices, Coupons and Patient Assistant Programs. Available at: www.drugs.com/price-guide/colcrys. Accessed Dec. 17, 2019.
Imazio M, et al. Lancet. 2014;doi:10.1016/S0140-6736(13)62709-9.
Imazio M, et al.N Engl J Med. 2013;doi:10.1056/NEJMoa1208536.
Nidorf SM, et al. J Am Coll Cardiol. 2013;doi:10.1016/j.jacc.2012.10.027.
Ridker PM, et al.N Engl J Med. 2017;doi:10.1056/NEJMoa1707914.
Ridker PM, et al.N Engl J Med. 2019;doi:10.1056/NEJMoa1809798.
Shah B, et al. Late Breaking Science IV: State of the Art Interventional Management for ACS Patients. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.
Tardif JC, et al.N Engl J Med. 2019;doi:10.1056/NEJMoa1912388.
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