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CE: Old Dogs Gout New Tricks: Exploring New Indications for Gout Medications

03 Aug 2021 10:42 AM | MSHP Office (Administrator)

By: Nicole Diveley, PharmD
CoxHealth | Springfield, MO  

Program Number: 2021-07-01
Approval Dates: August 1, 2021 – February 1, 2022
Approved Contact Hours: 1 hour

Learning Objectives

  • Describe the epidemiology of myocardial infarction.
  • Describe the mechanism of action of colchicine.
  • Discuss approved indications for colchicine.
  • Examine current literature for new indications for colchicine.
  • Investigate a place in therapy for new indications.
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Introduction
Every forty seconds, someone within the United States has a myocardial infarction (MI), according to the Centers for Disease Control and Prevention (CDC).1 In the United States, 655,000 deaths are from heart disease annually.2  Of the 805,000 heart attacks that occur annually, 200,000 happen to individuals who have already had a heart attack. Due to the high incidence of recurrent MIs, preventing a second myocardial infarction from occurring is a priority.

Myocardial infarction is defined as cell death of myocardial tissue due to loss of blood flow leading to oxygen deprivation.3 Patients may experience a large amount of inflammation due to the damage and lack of oxygen. Patients experiencing an MI may feel chest pain or pressure; light-headedness; pain in the jaw, neck, or back; pain or discomfort in one or both arms; and shortness of breath.1 Women may experience non-traditional symptoms such as unexplained fatigue, nausea or vomiting.

Modifiable and non-modifiable risk factors exist for myocardial infarctions.4 Diseases such as hypertension, hyperlipidemia, diabetes mellitus and obesity can contribute to heart disease and increase the chance of having an MI. Other risk factors such as smoking, family history, and age can contribute to the chance of experiencing an MI.

Myocardial Infarction Treatment and Secondary Prevention
There are a multitude of diagnostic tests that can be run to verify if an MI has occurred. Some of these tests are more specific than others, and which ones are utilized will likely depend on the health system that the patient presents to. Typically, one of the first tests to be completed is a twelve-lead electrocardiogram, which measures the heart’s electrical system and can be used to verify if an MI has occurred and which type occurred.5 If patient is being transported by ambulance, this test is typically run while en route to the health care facility.

Blood tests can be utilized to assess the severity of an MI, as well as to assess how severe an infarction was.6 One enzyme that may be measured is creatine kinase – mb (CK-MB). Creatine kinase is an enzyme found within the heart and the muscles and can be released when there is damage. CK-MB is more specific to the heart muscle and increases when there is damage or inflammation of the cardiac tissue. CK-MB does not tend to stay elevated for more than 24 to 48 hours, so use is limited when trying to determine if an event occurred in a delayed presentation. C-reactive protein (CRP) is another marker of inflammation that may be measured.7 It is not specific to cardiac muscle, so it may be elevated due to inflammation elsewhere within the body. Troponin is a marker that is frequently measured in the setting of chest pain or suspected MI.6 Troponin is a protein released into the blood from contraction of the heart muscle and can be used to detect damage. Cardiac troponin has the highest sensitivity to the heart muscle and is also beneficial due to the prolonged elevation of the enzyme after an acute event.

Goals of therapy between the acute stage of an MI and the post-MI stage are vastly different. During the acute phase of an infarction, the goal of therapy is to prevent cell death by oxygen restoration.8 This can be done in a number of ways depending on the facility the patient presents to. Reperfusion therapy is recommended for any patient presenting with an MI who meets eligibility. Reperfusion therapy should be recommended when symptom onset began twelve hours or less from presentation. When available, percutaneous coronary intervention (PCI) therapy is the preferred method of reperfusion, particularly for ST-elevated MI (STEMI). The goal for symptom onset to treatment with PCI is 90 minutes or less for STEMI. When a patient arrives to a facility that is unable to perform PCI, the preferred method of reperfusion is fibrinolytic therapy if the patient is having a STEMI, with a door-to-fibrinolytic therapy (or door-to-needle) time of 30 minute. 

Post reperfusion treatment, maintenance therapy is started. The goal of treatment in this phase is to prevent another acute coronary syndrome event and to prevent further damage to the cardiac muscle. While therapy is patient dependent, the majority of patients are started on a routine regimen including dual antiplatelet therapy, a statin, a beta-blocker, and an angiotensin-converting enzyme inhibitor (ACE-I). Low-dose aspirin should be started daily post-PCI and should be continued indefinitely. A P2Y12 inhibitor should be loaded and then continued post-hospitalization. The length of therapy for dual antiplatelet therapy is dependent upon whether or not a stent is placed, the type of stent the patient receives, and other independent patient factors. Beta-blocker therapy is recommended to start within 24 hours of an MI for patients without contraindications. An ACE-I is recommended to be started within 24 hours post-MI in patients with a reduced ejection fraction less than 40%. In patients unable to tolerate an ACE-I, an angiotensin receptor blocker (ARB) can be given instead. High-intensity statin therapy should also be started within 24 hours of patient presentation. The above regimens are vital in preventing another acute coronary syndrome event.

Review of colchicine indications and cardiovascular outcomes in trials
Colchicine currently has FDA-approved indications for use in the prophylaxis and treatment of gout and in familial Mediterranean fever.9 Colchicine exhibits its action through binding to tubulins which block the assembly and polymerization of microtubules. Colchicine is currently being examined for its use in both the acute MI and as secondary prevention.10 It is being evaluated for benefit when used in acute coronary syndrome and as secondary prevention due its anti-inflammatory effects. A summary of the colchicine doses used in the trials investigating colchicine’s role in MI and coronary artery disease can be viewed in Figure 1.

The COLCOT trial was a randomized, double-blind trial which compared low-dose colchicine at a dose of 0.5 milligrams (mg) once daily versus placebo in patients within 30 days after myocardial infarction.10 The primary outcome was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke or urgent hospitalization for angina leading to coronary revascularization. This trial randomized 4745 patients which were followed for a median of 22.6 months. The primary outcome occurred in 5.5% of patients in the colchicine cohort and 7.1% in the placebo cohort. This finding had a HR of 0.77 (95% confidence interval 0.61 to 0.96) and a p-value of 0.02, which was statistically significant. When compared to placebo, patients that received low-dose colchicine also had a lower risk of ischemic cardiovascular events.

Another study, LoDoCo-MI, was conducted to investigate colchicine’s use post-MI.11 This was a randomized, double-blind, placebo controlled trial. This study evaluated 237 patients that were admitted with an acute MI. Patients were randomized to receive colchicine 0.5 mg once daily or placebo for thirty days. To be included, patients had to be enrolled within 7 days of the MI. The primary outcome was the amount of patients with a CRP level ≥2 mg/L after 30 days of treatment. This value was chosen as it had been determined that levels greater than two were associated with worse prognosis. This study found that after 30 days of treatment with low dose colchicine or placebo, 44% of patients treated with colchicine versus 50% of patients treated with placebo had a CRP level greater than 2 mg/L. This finding was not statistically significant with a p-value of 0.35. In conclusion, this study found that when treated with low dose colchicine for 30 days post-MI, there is a trend toward more participants meeting a CRP level less than 2 mg/L.

Colchicine has not only been studied post-MI but has also been studied in the acute phases of MI.12 A trial titled “Anti-inflammatory treatment with colchicine in acute myocardial infarction” was conducted to assess if colchicine had any effect during the acute phase of an MI. 151 patients who presented less than 12 hours from onset of pain with a STEMI were included. Patients were randomized to receive either colchicine (1.5 mg loading dose followed by 0.5 mg one hour later and then continued with 0.5 mg twice daily for 5 days) versus placebo for 5 days. In addition to colchicine or placebo, patients received standard of care treatment for the acute MI and standard medical therapy post-MI. The trial studied the area under the curve of CK-MB fraction concentration for the primary outcome. This trial found that in the colchicine cohort, the area under the curve for CK-MB was 3144 ng/h/mL with an interquartile range (IQR) of 1754-6940 ng/h/mL versus 6184 ng/h/mL with an IQR of 4456-6980 ng/h/mL. These findings were statistically significant with a p-value of <0.001. This study had positive findings for colchicine’s use in acute MI; however it was not adequately powered, so the findings should be further investigated with larger trials.

Additionally, colchicine’s use has been investigated for coronary artery disease. In the randomized, prospective, observer-blinded LoDoCo study, patients were randomized to receive either colchicine 0.5 mg once daily or placebo.13 532 patients underwent randomization. To be included, patients had to have a diagnosis of stable coronary artery disease, defined as no changes in the previous six months. The majority of the patients in this trial were also on aspirin and/or clopidogrel in addition to a statin medication. Participants in this trial were followed for a median of three years. The primary outcome of this trial was the composite incidence of acute coronary syndrome, cardiac arrest outside of a hospital, or non-cardioembolic ischemic stroke. This composite outcome occurred in 5.3% of the colchicine cohort and 16% of the placebo cohort. The hazard ratio for these findings was 0.33 with a confidence interval of 0.18 to 0.59 and a p-value of < 0.001, which was statistically significant. These findings suggest a number needed to treat of 11. This trial found that when compared with placebo, patients treated with low dose colchicine had a lower risk of cardiovascular events.

An additional trial, LoDoCo2, was conducted to compare colchicine 0.5 mg once daily versus placebo.14 This trial was a randomized, controlled, double-blind study in which 5522 patients with stable coronary artery disease were randomized to receive colchicine or placebo. Patients were followed for a median of 28.6 months. The primary outcome was a composite of death from cardiovascular causes, spontaneous myocardial infarction, ischemic stroke or ischemia-driven coronary revascularization. This study found that the composite endpoint occurred in 6.8% of participants in the colchicine cohort and 9.6% of participants in the placebo cohort. These findings have a hazard ratio of 0.69, with a 95% confidence interval of 0.57 to 0.83 and a p-value <0.001, which was a statistically significant finding. In conclusion, the LoDoCo2 study found that when colchicine at 0.5 mg once daily was taken, it resulted in a lower risk of cardiovascular events versus placebo.

The above studies also studied adverse effects within the population receiving colchicine. The largest reported side effects were gastrointestinal in nature.10,12,14 This aligns with the package insert labeling.9 For adverse effects, diarrhea, nausea, and abdominal pain had the highest incidence.

Figure 1. Summary of the colchicine trials and the doses used.

Trial Name

Colchicine Dose

Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction (COLCOT)

0.5 mg once daily

Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease (LoDoCo)

0.5 mg once daily

Colchicine in Patients with Chronic Coronary Disease (LoDoCo2)

0.5 mg once daily

Low Dose Colchicine after Myocardial Infarction study: a pilot randomized placebo controlled trial of colchicine following acute myocardial infarction

0.5 mg once daily

Anti-Inflammatory Treatment with Colchicine in Acute Myocardial Infarction

1.5 mg loading dose then 0.5 mg one hour later, followed by 0.5 mg twice daily

Mechanism of Colchicine in MI
It has been proposed that colchicine is effective post-MI due to the anti-inflammatory properties it exhibits. It is thought that colchicine potentially exhibits actions on cellular adhesion molecules, inflammatory chemokines and the inflammasome.10 Colchicine’s use in coronary artery disease was largely investigated due to its anti-inflammatory properties.15 Colchicine exerts its anti-inflammatory properties in a slightly different way than typical anti-inflammatory agents. It is different from typical non-steroidal anti-inflammatory agents in the fact that it does not have any action on the arachidonic acid pathway but instead exhibits anti-inflammatory action through microtubule depolymerization. The anti-inflammatory properties are beneficial in acute coronary syndrome due to inflammation resulting from plaque formation and the dislodging of the plaque during the plaque rupture. Additionally, the cardiac tissue suffers damage when deprived from oxygen, which also leads to inflammation. While colchicine’s exact mechanism and role in therapy is being evaluated, the current studies have provided guidance for the continued research.

Due to the unique anti-inflammatory mechanism, colchicine has also been evaluated for additional cardiac disorders. When evaluated for benefit in pericarditis, some positive outcomes have been found. Colchicine was also evaluated for its use in atrial fibrillation, but the findings were not as compelling for potential benefit in this disease state.

Conclusion
MIs and cardiac disease account for 655,000 deaths each year within the United States.2 While current therapy shows benefit, there is still room for improvement. Studies involving low-dose colchicine show promising results for use during the acute phase of an MI as well as post-MI.10,11,12,13,14 It is thought that colchicine’s benefits are due to its anti-inflammatory effects.15 While the potential new benefits of colchicine are exciting, there are some other factors that need to be considered prior to implementation into practice. A major consideration should be the available dosage forms in the United States. While colchicine is generic in the United States making it fairly cost-affordable in comparison to brand name drugs, it is only available in 0.6 mg tablets and a liquid formulation.9 The current literature with positive cardiac outcomes for colchicine use dosing in increments of 0.5 mg tablets, which is not currently available in the United States. Additionally, a majority of medical treatment is typically driven by insurance preferences. It is uncertain how insurance will cover the new use of colchicine for indications other than gout. Colchicine would be a useful treatment in patients especially high-risk for cardiac events post-MI as it has proven beneficial at preventing cardiac events when used at low doses. It does however have adverse effects that may be intolerable to patients and need to be a consideration when determining therapy.

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References

  1. Centers for Disease Control and Prevention. What is a heart attack? https://www.cdc.gov/heartdisease/risk_factors.htm. Jan 11, 2021. Accessed April 2, 2021.
  2. Fryar CD, Chen T-C, Li X. Prevalence of uncontrolled risk factors for cardiovascular disease: United States, 1999–2010. NCHS data brief, no. 103. Hyattsville, MD: National Center for Health Statistics; 2012. Accessed April 2, 2021.
  3. Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. J Am Coll Cardiol. 2007;50(22):2173-2195. doi:10.1016/j.jacc.2007.09.011
  4. Centers for Disease Control and Prevention. Know your risk for heart disease. https://www.cdc.gov/heartdisease/risk_factors.htm. Dec 9, 2019. Accessed April 2, 2020.
  5. American Heart Association. Electrocardiogram (ECG or EKG). https://www.heart.org/en/health-topics/heart-attack/diagnosing-a-heart-attack/electrocardiogram-ecg-or-ekg. Jul 31, 2015. Accessed May 7, 2021.
  6. Haldeman-Englert C, Turley K, Foley M. Cardiac biomarkers (blood). University of Rochester Medical Center Health Encyclopedia. https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=cardiac_biomarkers. Access May 29, 2021.
  7. Mayo Clinic Staff. C-rective protein test. Mayo Clinic. https://www.mayoclinic.org/tests-procedures/c-reactive-protein-test/about/pac-20385228. Nov 21, 2017. Accessed May 15, 2021.
  8. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline 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 [published correction appears in Circulation. 2013 Dec 24;128(25):e481]. Circulation. 2013;127(4):e362-e425. doi:10.1161/CIR.0b013e3182742cf6
  9. Colchicine [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2012.
  10. Tardif JC, 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
  11. Deftereos S, Giannopoulos G, Angelidis C, et al. Anti-Inflammatory Treatment With Colchicine in Acute Myocardial Infarction: A Pilot Study. Circulation. 2015;132(15):1395-1403. doi:10.1161/CIRCULATIONAHA.115.017611
  12. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013;61(4):404-410. doi:10.1016/j.jacc.2012.10.027
  13. 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
  14. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020;383(19):1838-1847. doi:10.1056/NEJMoa2021372
  15. Deftereos S, Giannopoulos G, Papoutsidakis N, et al. Colchicine and the heart: pushing the envelope. J Am Coll Cardiol. 2013;62(20):1817-1825. doi:10.1016/j.jacc.2013.08.726

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