COLCOT- Colchicine for acute myocardial infarction
If you started to practice after 2011, you likely have no experience with colchicine. Before the FDA began its unapproved drug initiative in 2006 which sought formal regulatory review of medications that previously fell under “grandfather” laws. Since colchicine was available prior to the 1938 Food, Drug, and Cosmetic Act, it was never required to establish safety and efficacy for FDA approved indications.[1,2] The goal of this FDA program was to modernize and test these drugs, without “imposing undue burdens on consumers, or unnecessarily disrupting the market.”
When it came to calling on colchicine to produce safety and efficacy data, most manufacturers dropped the product or were forced to stop producing the drug altogether by 2011, creating catastrophic shortages. The single producer remaining conducted the required research and won regulatory approval for Colcrys. Unfortunately in the process, these actions by the FDA caused the price of colchicine to rise from $0.07 per tablet to more than $5 per tablet. The price increase, coupled with the extended shortage/unavailability forced providers to simply move on from the therapy.
Perhaps because of these regulatory changes, colchicine was looked upon by other providers for various indications. One of which that has recently demonstrated a positive effect in patients was post-myocardial infarction. The COLCOT study which randomized patients to either colchicine or placebo within 30 days after an MI. Colchicine demonstrated a statistically significant improvement in the primary outcome (a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization). Before examining why this may be something we will be seeing in our cardiac patients, let’s remind ourselves of our long-forgotten friend.
Microtubules are important
Colchicine is a tremendously fascinating drug to study. While I’ll expand on some other aspects, particularly the toxicology in a future post, here is a wonderful read about some of its toxic effects in nature.
Colchicine acts by inhibiting the construction of microtubules that compose spindles in metaphase Mind you, this is a rudimentary description of what colchicine actually does.
To understand colchicine, you have to recall the function of a specific intracellular structure: microtubules. We recall that microtubules are composed of repeating alpha and beta-tubulin subunits aligned in such a way that they create a polar structure resembling a hollow tube. These microtubules are created by adding these alpha/beta units at one end and then disassembled at the other.[4,5] In some tissues, microtubules form stable structures, while others exist in a transient state. Transient microtubules, as the name would suggest assemble and disassemble at a much faster rate when compared to stable microtubules (if it occurs at all).
At normal doses, when colchicine binds to its particular site at the end of developing a microtubule, its assembly at the positive end is halted. The normal process of disassembly is unaffected at normal doses. Without the function of transient intracellular microtubules, colchicine causes inhibition of neutrophil activity (chemotaxis, adhesiveness, mobility, degranulation of lysosomes). The inhibition of chemotaxis of leukocytes, inflammatory cytokines, glycoproteins is the primary mechanism for the treatment of gout.
Colchicine also alters the regulation of microtubule formation. Because of the above action, colchicine actually increases the number of available tubulin dimers available, initiating negative feedback by inhibiting further production by binding to ribosomes and halting mRNA production. So while there is no direct effect on the disassembly of microtubules, their disassembly is enhanced while further production is impaired.
When it comes to cardiology, the hypothesis is that colchicine could prevent the negative effects of inflammation and remodeling after an acute MI. Hypothetically, because of its effects on macrophages, adhesion molecules and neutrophils, as well as its ability to reduce cytokine and matrix metalloproteinase production, colchicine could play a role in reducing adverse cardiovascular outcomes. This is the hypothesis that was tested in the COLCOT study.
Role in STEMI
The COLCOT study was a prospective, randomized trial of 4745 patients with a recent MI. Patients were randomized to receive colchicine 0.5 mg daily or placebo within 30 days after MI with the primary outcome of a composite endpoint consisting of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization.
The typical patient enrolled in this study was a 60-year-old male with hypertension who received standard of care treatment (primary PCI) and appropriate secondary prevention drug therapy. Most patients received colchicine or placebo 13 days after the initial MI. The primary outcome occurred in 5.5% of patients receiving colchicine compared to 7.1% receiving placebo (HR 0.77; 95% CI 0.61-0.96; p=0.02). This effect appeared to be driven by the reduction in stroke (HR 0.26, 95% CI 0.1-0.7), and reduction in urgent revascularization (HR 0.5 95% CI 0.31-0.81). More relevant CV related outcomes were not significantly different: CV death (HR 0.84, 0.4-1.52), resuscitated cardiac arrest (HR 0.83, 0.25-2.73), or MI (HR 0.91, 0.68-1.21). From a safety perspective, colchicine was associated with a higher incidence of pneumonia when compared to placebo (p=0.03).
Promising, but still skeptical
While colchicine may hold promise in cardiology, there is sufficient skepticism with this evidence to warrant further study before wide adoption in post-MI care. Aside from the considerably increased cost of care from the drug, it’s not certain what effect the addition to colchicine will have in a larger group of real-world patients.
More from EM PharmD related to COLCOT- Colchicine for acute myocardial infarction:
- Gupta R, Dhruva SS, Fox ER, Ross JS. The FDA Unapproved Drugs Initiative: An Observational Study of the Consequences for Drug Prices and Shortages in the United States. J Manag Care Spec Pharm. 2017 Oct;23(10):1066-1076
- Kesselheim AS, Franklin JM, Kim SC, et al. Reductions in Use of Colchicine after FDA Enforcement of Market Exclusivity in a Commercially Insured Population. J Gen Intern Med. 2015 Nov; 30(11): 1633–1638.
- D. Santos C, Schier CG. Colchicine, Podophyllin, and the Vinca Alkaloids. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank’s Toxicologic Emergencies, 11e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com.ezproxy.uttyler.edu:2048/content.aspx?bookid=2569§ionid=210270571. Accessed December 08, 2019.
- Snow JW, Kao LW, Furbee B. Chapter 71, Antitubulin Agents: Colchicine, Vinca Alkaloids, and Podophyllin. In: J. Brent et al. (eds.), Critical Care Toxicology,DOI 10.1007/978-3-319-17900-1_138
- Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019 Nov 16.
- COLCOT- Colchicine for acute myocardial infarction