LoDoCo trial: Low-dose colchicine reduces the residual risk of acute coronary syndrome (ACS) events in secondary prevention patients

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1 July 2013

In patients with stable coronary disease receiving best evidence-based therapy, including statins, a low dose of colchicine reduced the residual risk of ACS events.

Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013;61:404-10.

STUDY SUMMARY

Objective

To investigate whether low-dose colchicine (0.5 mg/day) can reduce the residual risk of cardiovascular events in patients with stable coronary disease receiving best evidence-based treatment, including antiplatelet therapy and statins

Study design

Prospective, randomized, observer-blinded endpoint (PROBE) design

Study population

532 patients (mean age 67 years, 89% male) with angiographically-proven coronary disease, stable for at least 6 months, and without major competing morbidities or contraindication to colchicine treatment. Almost all patients were on antiplatelet therapy with aspirin and/or clopidogrel (93%) and on high-dose statins (95%).

Primary variable

• Cardiovascular events, defined as a composite of ACS, out-of-hospital cardiac arrest, or non-embolic ischaemic stroke

Secondary variables

• Individual components of the primary outcome and components of ACS unrelated to stent disease (i.e. nonstent-related acute myocardial infarction and nonstent-related unstable angina)

Methods

Eligible patients were randomized to treatment with colchicine (0.5 mg/day) or not, with no other changes to their medical therapy. Sample size calculations allowed for randomization of 500 patients (250 to each treatment group) who were tolerant of colchicine for at least 4 weeks. The pre-specified study duration was a minimum follow-up of 2 years in all patients. Data were analysed on an intention-to-treat (ITT) basis, including all randomized patients. The primary outcome was analysed using a Cox proportional hazards model including treatment group (control or colchicine).

Main results

After a median follow-up of 36 months (range 24 to 44 months), there was a 67% reduction in the primary outcome with colchicine (15/282 [5.3%] versus 40/250 [16.0%] with control; hazard ratio 0.33, 95% CI 0.18-0.59, p<0.001; number needed to treat =11). The decrease in the primary outcome was mainly driven by a reduction in ACS (Table 1).

Table 1. Primary outcome and individual components; number (%) patients

Outcome	Control (n=250)	Colchicine (n=282)	Hazard ratio (95% CI)	p-value
Primary	40 (16)	15 (5.3)	0.33 (0.18-0.59)	<0.001
ACS	34 (13.6)	13 (4.6)	0.33 (0.18-0.63)	<0.001
OOH cardiac arrest	2 (0.8)	1 (0.35)	0.47 (0.04-5.15)	0.53
Non-cardioembolic stroke	4 (1.6)	1 (0.35)	0.23 (0.03-2.03)	0.18

ACS components
Stent-related	4 (1.6)	4 (1.4)	-	NS
Nonstent-related	30 (12)	9 (3.2)	0.26 (0.12-0.55)	<0.001

ACS: acute coronary syndrome; CI confidence interval; OOH: out of hospital

In a pre-specified secondary on-treatment analysis that excluded 32 patients assigned to colchicine who withdrew within 30 days due to gastrointestinal intolerance and 7 patients who did not start treatment, there was a 71% reduction in the primary outcome (4.5% versus 16.0% with control, hazard ratio 0.29, 95% CI 0.15-0.56, p<0.001).

Author's conclusion

Colchicine 0.5 mg/day administered in addition to statins and other standard secondary prevention therapies appeared effective for the prevention of cardiovascular events in patients with stable coronary disease.

COMMENT

Patients with stable coronary disease remain at high residual risk of cardiovascular events, despite best evidence-based therapy, including antiplatelet and high-dose statin treatment. Accumulating evidence associates low-grade systemic inflammation with the onset of ACS, and locally also implicates neutrophil infiltration of the unstable plaque in the transformation from stable to unstable plaque.1,2 Mechanistically, this is supported by experimental studies showing that activated neutrophils produce and release reactive oxygen species, inflammatory leukotrienes and proteolytic lysosomal enzymes, and may also secrete myeloperoxidase, involved in lipoprotein oxidation.

These data therefore pose the question: Do therapies that target neutrophil function reduce the risk of plaque instability and acute clinical events in the secondary prevention setting? Low-dose colchicine exhibits a range of anti-inflammatory effects, including reduction in C-reactive protein in patients with stable coronary disease, and has been shown to be effective in preventing neutrophil-mediated inflammation, as documented by its efficacy in the treatment of gout.3-5 These findings thereby provide a rationale for testing this agent for prevention of ACS.

The study findings clearly support the hypothesis that targeting neutrophil function with low-dose colchicine may be another strategy to reduce the high residual risk of ACS patients, given that the benefit observed was in addition to current evidence-based therapy, including antiplatelet and high-dose statin treatments. On this basis, further investigation in larger studies, as well as mechanistic studies to explore the effects of colchicine in the ACS setting, is clearly warranted.

However, a limitation of this therapeutic strategy is the tolerability of colchicine. Despite the use of the lowest available dose (0.5 mg/day), 11% of patients discontinued treatment early due to gastrointestinal adverse effects and a further 5% subsequently discontinued treatment due to adverse effects. Furthermore, there is evidence to suggest that the combination of colchicine plus a statin may increase the risk of muscle-related symptoms including myalgia.3,6,7 This is relevant in the context of increasing evidence that the incidence of statin-associated muscle-related adverse events may be higher than previously thought.8,9 Thus, while the LoDoCol study highlights the potential of this strategy to improve clinical outcomes, benefit/risk considerations also need to be taken into account.

In conclusion, the Residual Risk Reduction Initiative believes that this therapeutic strategy may provide an innovative approach to reducing the high residual risk of cardiovascular events that persists despite best evidence-based therapy. Thus a dual approach targeting both lipids/lipoprotein-related and inflammatory mechanisms may offer enhanced capacity to impact this residual vascular risk.

References

1. Ylä-Herttuala S, Bentzon JF, Daemen M, Falk E et al. Stabilisation of atherosclerotic plaques. Position paper of the European Society of Cardiology (ESC) Working Group on atherosclerosis and vascular biology. Thromb Haemost 2011;106:1-19.
2. Della Bona R, Cardillo MT, Leo M et al. Polymorphonuclear neutrophils and instability of the atherosclerotic plaque: a causative role? Inflammation Research 2013;62:537-50.
3. Roubille F, Kritikou E, Busseuil D, Barrere-Lemaire S, Tardif JC. Colchicine: an old wine in a new bottle? Antiinflamm Antiallergy Agents Med Chem 2013;12:14-23.
4. Nuki G. Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr Rheumatol Rep 2008l;10:218-27.
5. Chia EW, Grainger R, Harper JL. Colchicine suppresses neutrophil superoxide production in a murine model of gouty arthritis: a rationale for use of low-dose colchicine. Br J Pharmacol 2008;153:1288-95.
6. Baker SK, Goodwin S, Sur M, Tarnopolsky MA. Cytoskeletal myotoxicity from simvastatin and colchicine. Muscle and Nerve 2004;30:799-802.
7. Clinically significant statin drug interactions. Pharmacist's Letter 2012;28:280606. Available on Internet
8. Zhang H, Plutzky J, Skentzos S et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med 2013;158:526-34.
9.Mansi IA, Mortensen EM, Pugh MJ, Wegner M, Frei CR. Incidence of musculoskeletal and neoplastic diseases in patients on statin therapy: results of a retrospective cohort analysis. Am J Med Sci 2013;345:343-8.