What evidence supports the use of colchicine for secondary prevention after an acute myocardial infarction?

Introduction

Heart disease is the leading cause of death for men and women in the United States and accounts for approximately 647,000 deaths each year.1 The most prevalent form of heart disease is coronary artery disease (CAD)­­­­­ which is caused by atherosclerosis.1,2 Atherosclerosis leads to plaque formation, which can potentially block the affected artery and cause an acute coronary syndrome (ACS).3 An ACS event is classified as ST-segment-elevation myocardial infarction (STEMI), non-ST-segment-elevation myocardial infarction (NSTEMI) or unstable angina (UA).4,5 The diagnosis of the type of ACS is made based on cardiac biomarkers (ie, troponin) and electrocardiogram (ECG) findings. Inflammation is known to have a role in atherosclerosis, including in plaque formation, progression, and rupture.2 Despite patients being placed on the standard of care after the initial ACS event, residual inflammation contributes to an increased risk of a secondary cardiovascular (CV) event. Recurrent CV events are associated with higher morbidity and mortality than the initial ACS event, so prevention with an anti-inflammatory medication may be beneficial.2

Guideline recommendations

The 2013 STEMI and 2014 NSTEMI guidelines recommend that all patients without contraindications receive aspirin indefinitely after a myocardial infarction (MI).4,5 Patients should receive anti-platelet therapy with either clopidogrel, ticagrelor or prasugrel for up to 1 year or more. The duration of dual anti-platelet therapy and choice of anti-platelet medication depends on the type of MI, stent placement and whether fibrinolytic therapy was used. All patients without contraindications are recommended to receive a beta-blocker and a high-intensity statin indefinitely after an MI. After an NSTEMI, select patients who have a left ventricular ejection fraction (LVEF) less than 40%, hypertension, diabetes mellitus, or stable chronic kidney disease should receive an angiotensin-converting enzyme inhibitor (ACE-I) indefinitely. After a STEMI, select patients who have an LVEF less than or equal to 40% or heart failure (HF) should receive an ACE-I indefinitely. Of note, colchicine is mentioned in the STEMI guidelines for the management of pericarditis if aspirin is not effective.

Discussion of colchicine

Attempts to systematically analyze certain anti-inflammatory medications in CAD, such as non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, have been limited by a lack of benefit and the unsafe CV safety profile of these medications, with the exception of aspirin.2 There is interest in finding an alternative anti-inflammatory medication that can be used safely in patients with CV disease. Due to its unique anti-inflammatory mechanism of action, colchicine is a drug of interest. Colchicine is hypothesized to reduce inflammation through a variety of mechanisms.6 Colchicine enters endothelial cells and leukocytes, mostly neutrophils and macrophages, to irreversibly bind to tubulin and disrupt a variety of proteins that are responsible for proper cell functioning. Assembly of pro-inflammatory mediators in macrophages is disrupted, such as metalloproteinase and tumor necrosis factor α (TNF-α). Also, colchicine impairs the ability of the NOD-like receptor protein 3 (NLRP3) inflammasome to assemble which reduces the release of pro-inflammatory interleukins (IL) such as IL-1β and IL-6. Formation and release of superoxide and certain proteolytic enzymes in neutrophils are disrupted by colchicine, and IL-1β production and E-selectin in endothelial cells are decreased, which is necessary for neutrophil adhesion. It also decreases the interaction between platelets and leukocytes, which is responsible for worsening atherothrombosis. In anti-inflammatory macrophages, colchicine increases the release of anti-inflammatory cytokines, such as IL-10 and transforming growth factor β (TGF- β) which may reduce pro-inflammatory mechanisms and promote favorable healing. Colchicine is FDA-approved for the prevention of gout and the treatment of gout and familial Mediterranean fever (FMF).7 The most common side effects are diarrhea, nausea and vomiting. Colchicine should be used cautiously in patients with renal impairment, hepatic impairment and bone marrow suppression. The purpose of this review is to summarize data on the use of colchicine as an adjunct to standard of care for secondary prevention in patients after ACS, due to its proposed anti-inflammatory effects. The trial of focus is the Colchicine Cardiovascular Outcomes Trial (COLCOT), which studies CV events as the primary outcome. Prior to discussing COLCOT, the initial studies of colchicine and markers of inflammation will be discussed. Trials focusing strictly on stable CAD were excluded.

Literature review of initial studies of markers of inflammation

There have been numerous trials studying the use of colchicine after an acute MI focusing on markers of inflammation as the primary endpoint.8-13 The main outcomes studied were C-reactive protein (CRP), plaque stability, inflammatory cytokines and myocardial cell wall injury. Most of the patients in these trials were on the standard of care post-MI, which included dual-anti-platelet therapy with aspirin, a statin and a beta-blocker. The results of these trials were mixed and have led to further trials involving colchicine after an acute MI that focus on adverse CV event outcomes as the primary endpoint. The initial trials are summarized below (Table).

Table. Summary of evidence of colchicine and markers of inflammation.8-13
Study design and durationSubjects

InterventionsOutcomesConclusions
Hennessy 20198 (LoDoCo-MI study)

Randomized, single-center, double-blind, placebo-controlled trial		N=237 adults admitted to the hospital within the past 7 days for acute MIColchicine (n=119) 0.5 mg once daily for 30 days

Placebo (n=118) for 30 days		·     The percentage of patients who had a hs-CRP ≥2 mg/L at 30 days was 44% in the colchicine group and 50% in the placebo group (p=0.35)·    Colchicine started within 7 days of acute MI did not reduce the proportion of patients with a CRP ≥2 mg/L compared to placebo
Vaidya 20189

Prospective, single-center, open-label, observational study		N=80 adults admitted to the hospital within the past 1 month with ACSColchicine (n=40) 0.5 mg once daily for 12 months

No colchicine (n=40)		·     The mean LAP volume* of the coronary CTA plaque at follow-up was -15.9 mm3 from baseline (-40.9%) in the colchicine group and -6.6 mm3 from baseline (-17.0%) in the no colchicine group (p=0.008)·    Colchicine started within 1 month of ACS reduces LAP volume more compared to no colchicine
Akodad 201710

Randomized, controlled, single-center, open-label trial		N=44 adults admitted to the hospital with STEMI treated with PCIColchicine (n=23) 1 mg once daily for 30 days

No colchicine (n=21)		·     The mean peak CRP during hospitalization was 29.03 mg/L in the colchicine group and 21.86 mg/L in the no colchicine group (p=0.36)·    Colchicine started after hospital admission in patients with STEMI post-PCI did not lead to lower peak CRP values compared to no colchicine
Martinez 201511

Randomized, single-center trial (blinding not specified)		N=83 adults admitted to the hospital with an indication for cardiac catheterization and grouped into either ACS, stable CAD, or a control groupACS group (n=40):
Colchicine (n=21) 1.5 mg loading dose (1 mg then 0.5 mg one hour later) 6 to 24 hours before coronary angiography

No colchicine (n=19)

Stable CAD group (n=33)
Colchicine (n=13) 1.5 mg loading dose (1 mg then 0.5 mg one hour later) 6 to 24 hours before coronary angiography

No colchicine (n=20)

No ACS or stable CAD group (n=10)
No colchicine (n=10)		ACS group only:
·     The coronary sinus gradient† for IL-1β was 0.87 in the colchicine group and 3.75 in the no colchicine group (p=0.028)
·     The coronary sinus gradient for IL-18 was 22.85 in the colchicine group and 38.20 in the no colchicine group (p=0.032)
·     The coronary sinus gradient for IL-6 was 6.02 in the colchicine group and 53.90 in the no colchicine group (p=0.032)		·    Colchicine started 6 to 24 hours before coronary angiography in patients with ACS led to significantly lower release of 3 pro-inflammatory cytokines when compared to no colchicine
Deftereos 201512

Randomized, multi-center (2 centers), double-blind, placebo-controlled trial		N=151 adults admitted to the hospital with STEMI (within 12 hours from pain onset) treated with PCIColchicine (n=77) 2 mg loading dose (1.5 mg then 0.5 mg one hour later) followed by 0.5 mg twice daily (0.5 mg once daily if < 60 kg) for 5 days

Placebo (n=74) for 5 days		·     The AUC of CK-MB fraction concentration‡ over 72 hours after hospital admission was 3144 ng∙hr/mL in the colchicine group and 6184 ng∙hr/mL in the placebo group (p<0.001)·    Colchicine started after hospital admission in patients with STEMI post-PCI leads to a smaller AUC of CK-MB fraction when compared to placebo
Raju 201213

(COOL study)

Randomized, single-center, double-blind, placebo-controlled trial		N=80 adults admitted to the hospital with either an ACS or acute ischemic strokeColchicine (n=40) 1 mg once daily for 30 days

Placebo (n=40) for 30 days		·     The median hs-CRP at 30 days follow-up was 1.0 mg/L (-7.0 mg/L from baseline) in the colchicine group and 1.5 mg/L (-7.1 from baseline) in the placebo group (p=0.64)·    Colchicine started after hospital admission in patients with acute atherothrombotic vascular event did not reduce hs-CRP when compared to placebo
*Presence of LAP on coronary CTA is an indicator of plaque stability and future CV events.
†Measure of transcoronary release of cytokines.
‡CK-MB is an enzyme released from the heart that signals myocardial cell wall injury.14
Abbreviations: ACS=acute coronary syndrome; AUC=area under the curve; CAD=coronary artery disease; CK-MB=creatine kinase-myocardial brain; CTA= computed tomography angiography; CV=cardiovascular; hs-CRP=high-sensitivity C-reactive protein; IL=interleukin; LAP=low attenuation plaque; MI=myocardial infarction; PCI=percutaneous coronary intervention; STEMI=ST-segment-elevation myocardial infarction.

Literature review of COLCOT

The Colchicine Cardiovascular Outcomes Trial (COLCOT) was conducted to identify an alternative anti-inflammatory medication as secondary prevention after an MI.15 COLCOT was a randomized, multi-center, double-blind and placebo-controlled trial. Relevant inclusion criteria included an MI within 30 days of enrollment and treatment according to national post-MI guidelines. Relevant exclusion criteria included LVEF less than 35%, class III or IV HF, stroke in the past 3 months, inflammatory bowel disease (IBD) or chronic diarrhea, and severe renal or hepatic disease. Eligible patients received either colchicine 0.5 mg once daily or placebo once daily. The primary outcome was a composite of death from CV causes, resuscitated cardiac arrest, MI, stroke or angina leading to revascularization. A key exploratory outcome was change in CRP from baseline to 6 months. All serious adverse events were recorded, while non-serious adverse events were only recorded if they were related to the gastrointestinal system or determined to be related to colchicine or placebo. As an event-driven trial, treatment was stopped once 301 primary outcome events occurred.

A total of 4745 adults were randomized after being admitted to the hospital with an ACS within the past 30 days.15 There were 2366 adults in the colchicine group and 2379 adults in the placebo group. The mean time to enrollment after MI was 13.5 days and it was not specified if patients had an NSTEMI or STEMI. At baseline most patients were 60 years old, white (~72.6%), male (~80.9%) and had a body mass index  of ~28. Patients were on the standard of care prior to starting the trial, including aspirin (~98.8%) and another antiplatelet medication (~97.9%), a statin (~99.0%) and a beta-blocker (~88.9%).  Patients were treated for a median of 19.6 months in the colchicine group and 19.5 months in the placebo group and the median follow-up time of both groups was 22.6 months. The discontinuation rate was 18.4% in the colchicine group and 18.7% in the placebo group. The primary outcome and its components are summarized below:

  • The number of composite CV events was 131 (5.5%) in the colchicine group and 170 (7.1%) in the placebo group (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.61 to 0.96; p=0.02).
  • The number of patients experiencing individual components of the primary outcome in the colchicine and placebo groups, respectively, were:
    • Death from CV causes: 20 (0.8%) vs 24 (1.0%) (HR, 0.84; 95% CI, 0.46 to 1.52)
    • Resuscitated cardiac arrest: 5 (0.2%) vs 6 (0.3%) (HR, 0.83; 95% CI, 0.25 to 2.73)
    • MI: 89 (3.8%) vs 98 (4.1%) (HR, 0.91; 95% CI, 0.68 to 1.21)
    • Stroke: 5 (0.2%) vs 19 (0.8%) (HR, 0.26; 95% CI, 0.10 to 0.70)
    • Angina events leading to revascularization: 25 (1.1%) vs 50 (2.1%) (HR, 0.50; 95% CI, 0.31 to 0.81)

There was no difference between colchicine and placebo in terms of change in CRP from baseline to 6 months.15 CRP in the colchicine group decreased from 4.27 mg/L at baseline to 1.37 mg/L at 6 months (-70% change) and CRP in placebo group decreased from 5.09 mg/L at baseline to 1.60 mg/L at 6 months (-66.6% change). Treatment-related adverse events occured in 16% in the colchicine group and 15.8% in the placebo group, while serious adverse events occurred in 16.4% in the colchicine group and 17.2% in the placebo group. Adverse events that occurred more with colchicine compared to placebo were nausea (1.8% vs 1.0%; p=0.02), flatulence (0.6% vs 0.2%; p=0.02), and pneumonia (0.9% vs 0.4%; p=0.03).

Colchicine started within 30 days of an ACS led to a lower number of composite CV events when compared to placebo.15 However, of the 5 components of the primary outcome, only stroke and angina events leading to revascularization led to a statistically significant lower number of events when compared to placebo. Although this trial was well-designed and the majority of patients were on the standard of care post-MI, there were several limitations. The long-term safety and efficacy of colchicine in this patient population was not captured with a relatively short follow-up time of 22.6 months. Also, some factors which may weaken the external validity are that colchicine 0.5 mg tablets are not available in the United States and patients with certain significant comorbidities (eg, certain types of HF, severe hepatic or renal disease, inflammatory bowel disease, chronic diarrhea) were excluded. Furthermore, most patients were white, which may not accurately represent the average patient with heart disease. African Americans have a higher risk of death from heart disease compared to white Americans and other ethnicities.16

Conclusion

Initial studies of colchicine analyzing markers of inflammation in patients with ACS had mixed results, which led to researchers conducting COLCOT. This study found that use of colchicine after MI significantly reduced composite CV events; however, the results of the primary outcome was driven by stroke and angina leading to revascularization. While only 2 of the 5 components of the primary outcome were statistically significant, these findings suggest colchicine may have benefit in reducing the risk of CV events after an MI within the past 30 days. Colchicine is not yet mentioned in the guidelines of NSTEMI or STEMI for secondary prevention, likely because most studies on colchicine and ACS were completed after the guidelines were published. The success of colchicine in some of these studies have led to continued interest in colchicine for use in CV disease. There are ongoing clinical trials studying colchicine in ACS, stable CAD and atrial fibrillation.17 Until more large-scale, long-term and randomized-controlled trials are conducted, colchicine should not routinely be used in patients post-MI for secondary prevention. However, the results from COLCOT appear promising and warrant further studies of colchicine and ACS to be conducted.

References

  1. Heart disease statistics and facts. Centers for Disease Control and Prevention. Updated December 2, 2019. Accessed March 13, 2020. https://www.cdc.gov/heartdisease/facts.htm
  2. Vaidya K, Martinez G, Patel S. The role of colchicine in acute coronary syndromes. Clin Ther. 2019;41(1):11-20. doi: 10.1016/j.clinthera.2018.07.023.
  3. Timmis A. Acute coronary syndromes. 2015;351:h5153. doi: 10.1136/bmj.h5153.
  4. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64(24):e139-e228. doi: 10.1016/j.jacc.2014.09.017.
  5. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guidelines for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4):e78-e140. doi: 10.1016/j.jacc.2012.11.019.
  6. Nidorf SM, Thompson PL. Why colchicine should be considered for secondary prevention of atherosclerosis: an overview. Clin Ther. 2019;41(1):41-48. doi: 10.1016/j.clinthera.2018.11.016.
  7. Package insert. Takeda Pharmaceuticals; 2015
  8. Hennessy T, Soh L, Bowman M, et al. The low dose colchicine after myocardial infarction (LoDoCo-MI) study: a pilot randomized placebo controlled trial of colchicine following acute myocardial infarction. Am Heart J. 2019;215:62-69. doi: 10.1016/j.ahj.2019.06.003.
  9. Vaidya K, Amott C, Martinez GJ, et al. Colchicine therapy and plaque stabilization in patients with acute coronary syndrome: a CT coronary angiography study. JACC Cardiovasc Imaging. 2018;11(2):305-316. doi: 10.1016/j.jcmg.2017.08.013.
  10. Akodad M, Lattuca B, Nagot N, et al. COLIN trial: value of colchicine in the treatment of patients with acute myocardial infarction and inflammatory response. Arch Cardiovasc Dis. 2017;110(6-7):395-402. doi: 10.1016/j.acvd.2016.10.004.
  11. Martinez JG, Robertson S, Barraclough J, et al. Colchicine acutely suppresses local cardiac production of inflammatory cytokines in patients with an acute coronary syndrome. J Am Heart Assoc. 2015;4(8):e002128. doi: 10.1161/JAHA.115.002128.
  12. Deftereos S, Giannopoulos G, Angelidis C, et al. Anti-inflammatory treatment with colchicine in acute myocardial infarction. 2015;132(15):1395-1403. doi: 10.1161/CIRCULATIONAHA.115.017611.
  13. Raju NC, Yi Q, Nidorf SM, Fagel ND, Hiralal R, Eikelboom JW. Effect of colchicine compared with placebo on high sensitivity C-reactive protein in patients with acute coronary syndrome or acute stroke: a pilot randomized controlled trial. J Thromb Thrombolysis. 2012;33(1):88-94. doi: 10.1007/s11239-011-0637-y.
  14. Cabaniss DC. Creatine kinase. In: Walker HK, Hall WD, Hurst JW, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd Butterworths; 1990: chapter 32. Accessed March 20, 2020. https://www.ncbi.nlm.nih.gov/books/NBK352/.
  15. Tardif J, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381(26):2497-2505. doi: 10.1056/NEJMoa1912388.
  16. African americans and heart disease. The Heart Foundation. Published September 7, 2018. Accessed March 26, 2020. https://theheartfoundation.org/2018/09/07/african-americans-and-heart-disease/
  17. Colchicine | recruiting, not yet recruiting, active, not recruiting, enrolling by invitation Studies. ClinicalTrials.gov. Accessed March 20, 2020. https://clinicaltrials.gov/ct2/results?term=colchicine&Search=Apply&recrs=b&recrs=a&recrs=f&recrs=d&age_v=&gndr=&type=&rslt=

Prepared by:
Richard Daniel, PharmD Candidate Class of 2020
University of Illinois at Chicago College of Pharmacy

Reviewed by:
Patricia Hartke, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

May 2020

The information presented is current as of March 20th, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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