Pharmacology Consult

Colchicine in the cardiology clinic: No longer just for gout

Historical use of colchicine, or its precursors, dates back several thousand years, with reports appearing in records from ancient Egyptians, Greeks and Arabic physicians. Although colchicine has been used for centuries, formal FDA approval of the medication did not occur until 2009, which resulted in colchicine being considered a “new” drug and moving from an inexpensive generic drug to a much more expensive, branded drug with marketing exclusivity for 3 years.

Perhaps equally interesting is that new indications and uses for colchicine continue to be explored. Although the default indication for colchicine in most prescriber’s minds is treatment of gout and familial Mediterranean fever (FMF), the cardiology community may have reason to look at this ancient drug in a different light. In particular, a developing body of evidence supports use, or further evaluation, of colchicine for several CV indications.

Abigail Plummer

Augustus Hough

Although the exact mechanism of action of colchicine has not been definitively established, its effects are thought to be mediated through an interruption in the activation of inflammatory mediators associated with neutrophils and monocytes, as well as disruption of leukocyte function, ultimately resulting in anti-inflammatory effects. Indications for which colchicine have been explored beyond gout and FMF include prevention of pericarditis events and, more recently, prevention of atrial fibrillation and CV events.

Pericarditis prevention

Recurrent pericarditis and post-pericardiotomy syndrome (PPS) are troublesome complications for 25% to 50% of patients after acute pericarditis episodes and 10% to 40% of post-cardiac surgery patients. Both complications have the potential to adversely affect quality of life and increase health care utilization via rehospitalizations and additional diagnostic workup. Colchicine has potential to reduce occurrence of these complications and, since 2005, several trials have evaluated its use in the prevention of recurrent pericarditis episodes and primary prevention of PPS.

The COPE trial was a prospective, randomized, open-label, parallel-group trial that studied colchicine administration for 3 months, besides background therapy of aspirin (or prednisone in those with contraindication to aspirin) in patients with a first episode of acute pericarditis. The trial found a significant reduction in recurrence rate of pericarditis at 18 months with colchicine compared with background therapy alone (10.7% vs. 32.3%; P=.004; number needed to treat=5).

The CORE and CORP trials both studied colchicine administered for 6 months, besides background therapy in patients with recurrent pericarditis. Background therapy in the two trials was similar to COPE and consisted of aspirin or prednisone in NSAID-intolerant patients; however, CORP also allowed use of ibuprofen in place of aspirin. Both CORE and CORP, respectively, showed that the 18-month pericarditis recurrence rate was reduced to 24% vs. 50.6% (P=.02) and 24% vs. 55% (P<.001) with colchicine use compared with background therapy alone.

These three trials, in patients with acute pericarditis of idiopathic, viral, or autoimmune causes, yielded consistently small numbers needed to treat with colchicine (three to five patients) to prevent one episode of recurrent pericarditis, with similar risk for serious adverse events compared with background therapy alone.

The COPPS trial studied 1 month of colchicine therapy, besides background therapy in patients undergoing cardiac surgery. Development of PPS was significantly reduced over 12 months of colchicine therapy, from 21.1% to 8.9% (P=.002). Similar to the previous evaluations, a favorable number needed to treat (NNT) was found (n=8) without a significant difference in adverse events.

These clinical trials were conducted by the same research team in Italy and evaluated colchicine dosed in increments of 0.5 mg. However, in the United States, the only available dosage form is a 0.6-mg tablet; therefore, treatment regimens have to be extrapolated from trials using the currently available tablet strength (eg, 1.2 mg twice daily on day 1, followed by maintenance 0.6 mg twice daily). Finally, doses were halved in patients weighing less than 70 kg or who were intolerant to full doses.

Other potential indications

More recent trials have investigated taking advantage of colchicine’s anti-inflammatory properties to prevent AF in various perioperative settings. Colchicine reduced incidence of post-cardiac surgery AF from 22% to 12% at 1 month and early recurrent AF after ablation with pulmonary vein isolation from 34% to 16% after 3 months. Although interesting, more studies are needed to determine optimal durations of therapy and dosing strategies in these settings before any broad integration into routine clinical practice for AF prevention.

Finally, the recent presentation of results from the LoDoCo trial at the American Heart Association Scientific Sessions in November signals a possible role for colchicine in the prevention of CVD. LoDoCo demonstrated that using low-dose colchicine, 0.5 mg daily, for a minimum of 2 years reduced risk for the primary endpoint (composite of ACS, out-of-hospital cardiac arrest or noncardioembolic ischemic stroke) from 16% to 5.3% (P<.001), a 67% reduction with a NNT of 11. Although more research is needed to determine how these findings will affect clinical practice, the relatively low NNT makes colchicine therapy a thought-provoking treatment option in patients with stable CAD.

To put this possible benefit into perspective, the TNT trial, which showed benefit with more intensive statin therapy, yielded a NNT of 45 for its primary endpoint and 20 for its secondary endpoint of “any coronary event” — an endpoint very similar to that in the LoDoCo trial.

Colchicine safety considerations

It is important to consider the safety aspects of colchicine. Most discontinuations in the pericarditis trials were due to gastrointestinal adverse effects associated with colchicines. The COPE, CORE and CORP trials incorporated a proton pump inhibitor in patients receiving NSAID therapy, and the LoDoCo trial will provide important long-term safety data because patients were followed for a minimum of 2 years.

Colchicine myopathy, which can progress to rhabdomyolysis, may also be an important concern, particularly in patients taking statins. Colchicine use has also been associated with blood dyscrasias and neurologic toxicities.

Although there are no specific recommendations for laboratory monitoring at this time, these adverse effects should be kept in mind, especially when colchicine is used in higher-risk patients (eg, those with renal dysfunction, with concomitant strong CYP3A4 and P-glycoprotein inhibitors, statins or fibrates).

Current use and future directions

Available data support the use of colchicine for prevention of pericarditis episodes and emerging data support further evaluation in the prevention of postprocedure AF and CV events. More data will be needed to solidify these later indications, but add to the conclusion that colchicine is not just for gout anymore.

Colcrys (colchicine, USP) package insert. 2012. Available at: dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=56c130d1-7581-4152-99a2-0014ee9366c0.
Deftereos S. J Am Coll Cardiol. 2012;60:1790-1796.
Imazio M. Arch Intern Med. 2005;165:1987-1991.
Imazio M. Circulation. 2005;112:2012-2016.
Imazio M. Ann Intern Med. 2011;155:409-414.
Imazio M. Circulation. 2011;124:2290-2295.
Imazio M. Heart. 2012;98:1078-1082.
Abigail Plummer, PharmD, is a PGY1 Pharmacy Practice Resident, and Augustus Hough, PharmD, BCPS, is a Clinical Pharmacy Specialist, both at the West Palm Beach VA Medical Center in Florida. Rhonda M. Cooper-DeHoff, PharmD, MS, is associate professor in the department of pharmacotherapy and translational research, College of Pharmacy, and division of cardiovascular medicine, College of Medicine, University of Florida, Gainesville. Cooper-DeHoff is Cardiology Today’s Pharmacology Consult column editor and a member of the CHD and Prevention section of the Editorial Board. She can be reached at the College of Pharmacy at University of Florida, Gainesville, PO Box 100486, Gainesville, FL 32610; email: dehoff@cop.ufl.edu.

Disclosure: Plummer and Hough report no relevant financial disclosures.

Historical use of colchicine, or its precursors, dates back several thousand years, with reports appearing in records from ancient Egyptians, Greeks and Arabic physicians. Although colchicine has been used for centuries, formal FDA approval of the medication did not occur until 2009, which resulted in colchicine being considered a “new” drug and moving from an inexpensive generic drug to a much more expensive, branded drug with marketing exclusivity for 3 years.

Perhaps equally interesting is that new indications and uses for colchicine continue to be explored. Although the default indication for colchicine in most prescriber’s minds is treatment of gout and familial Mediterranean fever (FMF), the cardiology community may have reason to look at this ancient drug in a different light. In particular, a developing body of evidence supports use, or further evaluation, of colchicine for several CV indications.

Abigail Plummer

Augustus Hough

Although the exact mechanism of action of colchicine has not been definitively established, its effects are thought to be mediated through an interruption in the activation of inflammatory mediators associated with neutrophils and monocytes, as well as disruption of leukocyte function, ultimately resulting in anti-inflammatory effects. Indications for which colchicine have been explored beyond gout and FMF include prevention of pericarditis events and, more recently, prevention of atrial fibrillation and CV events.

Pericarditis prevention

Recurrent pericarditis and post-pericardiotomy syndrome (PPS) are troublesome complications for 25% to 50% of patients after acute pericarditis episodes and 10% to 40% of post-cardiac surgery patients. Both complications have the potential to adversely affect quality of life and increase health care utilization via rehospitalizations and additional diagnostic workup. Colchicine has potential to reduce occurrence of these complications and, since 2005, several trials have evaluated its use in the prevention of recurrent pericarditis episodes and primary prevention of PPS.

The COPE trial was a prospective, randomized, open-label, parallel-group trial that studied colchicine administration for 3 months, besides background therapy of aspirin (or prednisone in those with contraindication to aspirin) in patients with a first episode of acute pericarditis. The trial found a significant reduction in recurrence rate of pericarditis at 18 months with colchicine compared with background therapy alone (10.7% vs. 32.3%; P=.004; number needed to treat=5).

The CORE and CORP trials both studied colchicine administered for 6 months, besides background therapy in patients with recurrent pericarditis. Background therapy in the two trials was similar to COPE and consisted of aspirin or prednisone in NSAID-intolerant patients; however, CORP also allowed use of ibuprofen in place of aspirin. Both CORE and CORP, respectively, showed that the 18-month pericarditis recurrence rate was reduced to 24% vs. 50.6% (P=.02) and 24% vs. 55% (P<.001) with colchicine use compared with background therapy alone.

These three trials, in patients with acute pericarditis of idiopathic, viral, or autoimmune causes, yielded consistently small numbers needed to treat with colchicine (three to five patients) to prevent one episode of recurrent pericarditis, with similar risk for serious adverse events compared with background therapy alone.

The COPPS trial studied 1 month of colchicine therapy, besides background therapy in patients undergoing cardiac surgery. Development of PPS was significantly reduced over 12 months of colchicine therapy, from 21.1% to 8.9% (P=.002). Similar to the previous evaluations, a favorable number needed to treat (NNT) was found (n=8) without a significant difference in adverse events.

These clinical trials were conducted by the same research team in Italy and evaluated colchicine dosed in increments of 0.5 mg. However, in the United States, the only available dosage form is a 0.6-mg tablet; therefore, treatment regimens have to be extrapolated from trials using the currently available tablet strength (eg, 1.2 mg twice daily on day 1, followed by maintenance 0.6 mg twice daily). Finally, doses were halved in patients weighing less than 70 kg or who were intolerant to full doses.

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Other potential indications

More recent trials have investigated taking advantage of colchicine’s anti-inflammatory properties to prevent AF in various perioperative settings. Colchicine reduced incidence of post-cardiac surgery AF from 22% to 12% at 1 month and early recurrent AF after ablation with pulmonary vein isolation from 34% to 16% after 3 months. Although interesting, more studies are needed to determine optimal durations of therapy and dosing strategies in these settings before any broad integration into routine clinical practice for AF prevention.

Finally, the recent presentation of results from the LoDoCo trial at the American Heart Association Scientific Sessions in November signals a possible role for colchicine in the prevention of CVD. LoDoCo demonstrated that using low-dose colchicine, 0.5 mg daily, for a minimum of 2 years reduced risk for the primary endpoint (composite of ACS, out-of-hospital cardiac arrest or noncardioembolic ischemic stroke) from 16% to 5.3% (P<.001), a 67% reduction with a NNT of 11. Although more research is needed to determine how these findings will affect clinical practice, the relatively low NNT makes colchicine therapy a thought-provoking treatment option in patients with stable CAD.

To put this possible benefit into perspective, the TNT trial, which showed benefit with more intensive statin therapy, yielded a NNT of 45 for its primary endpoint and 20 for its secondary endpoint of “any coronary event” — an endpoint very similar to that in the LoDoCo trial.

Colchicine safety considerations

It is important to consider the safety aspects of colchicine. Most discontinuations in the pericarditis trials were due to gastrointestinal adverse effects associated with colchicines. The COPE, CORE and CORP trials incorporated a proton pump inhibitor in patients receiving NSAID therapy, and the LoDoCo trial will provide important long-term safety data because patients were followed for a minimum of 2 years.

Colchicine myopathy, which can progress to rhabdomyolysis, may also be an important concern, particularly in patients taking statins. Colchicine use has also been associated with blood dyscrasias and neurologic toxicities.

Although there are no specific recommendations for laboratory monitoring at this time, these adverse effects should be kept in mind, especially when colchicine is used in higher-risk patients (eg, those with renal dysfunction, with concomitant strong CYP3A4 and P-glycoprotein inhibitors, statins or fibrates).

Current use and future directions

Available data support the use of colchicine for prevention of pericarditis episodes and emerging data support further evaluation in the prevention of postprocedure AF and CV events. More data will be needed to solidify these later indications, but add to the conclusion that colchicine is not just for gout anymore.

Colcrys (colchicine, USP) package insert. 2012. Available at: dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=56c130d1-7581-4152-99a2-0014ee9366c0.
Deftereos S. J Am Coll Cardiol. 2012;60:1790-1796.
Imazio M. Arch Intern Med. 2005;165:1987-1991.
Imazio M. Circulation. 2005;112:2012-2016.
Imazio M. Ann Intern Med. 2011;155:409-414.
Imazio M. Circulation. 2011;124:2290-2295.
Imazio M. Heart. 2012;98:1078-1082.
Abigail Plummer, PharmD, is a PGY1 Pharmacy Practice Resident, and Augustus Hough, PharmD, BCPS, is a Clinical Pharmacy Specialist, both at the West Palm Beach VA Medical Center in Florida. Rhonda M. Cooper-DeHoff, PharmD, MS, is associate professor in the department of pharmacotherapy and translational research, College of Pharmacy, and division of cardiovascular medicine, College of Medicine, University of Florida, Gainesville. Cooper-DeHoff is Cardiology Today’s Pharmacology Consult column editor and a member of the CHD and Prevention section of the Editorial Board. She can be reached at the College of Pharmacy at University of Florida, Gainesville, PO Box 100486, Gainesville, FL 32610; email: dehoff@cop.ufl.edu.

Disclosure: Plummer and Hough report no relevant financial disclosures.