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In diabetic patients, a daily regimen of low-dose colchicine after bare-metal stent (BMS) implantation halves the risk of in-stent restenosis at 6 months, according to a randomized study published online April 10, 2013, ahead of print in the Journal of the American College of Cardiology. The anti-inflammatory and antiproliferative agent, typically used to treat gout, also reduces other measures of neointimal formation.

Investigators led by Georgios Giannopoulos, MD, PhD, of Athens General Hospital “G. Gennimatas” (Athens, Greece), looked at angiographic and IVUS results from 196 diabetic patients with contraindications to DES who instead received BMS and were randomized to receive colchicine (0.5 mg twice daily, n = 100) or a placebo (n = 96) for 6 months. The treatment arms were well balanced with regard to demographic and clinical characteristics.

In-Stent Restenosis Halved

At 6 months, the rate of angiographic in-stent restenosis (primary endpoint) in the colchicine group was half that in the control group, resulting in an odds ratio of 0.38 (95% CI 0.18-0.79), and a number-needed-to-treat to avoid 1 case of 6 (95% CI 3.4-18.7). Angiographic parameters of neointimal formation including late lumen loss and minimum lumen diameter (MLD) were also favorable for colchicine (table 1).

Table 1. Angiographic Parameters at 6 Months

 
IVUS results showed the same pattern, with a 44% relative reduction in the rate of in-stent restenosis in the colchicine group (OR 0.42; 95% CI 0.22-0.81) and a number-needed-to-treat of 5 (95% CI 3.2-18.1). In-stent lumen area loss was also lower in the colchicine arm (1.6 mm² vs. 2.9 mm²; P = 0.002).

During follow-up, 1 patient in the treatment group died (due to stroke), as did 1 patient in the control group (due to pulmonary edema). Nine patients (4 in the treatment group, 5 in the placebo group) underwent reintervention.

GI complaints were the most common adverse events in the colchicine group, with 16% reporting diarrhea or nausea vs. 7% in the placebo group (P = 0.058). Similar proportions of colchicine and placebo patients experienced myalgia and muscle cramps (15% vs. 10%; P = 0.336). No cases of liver or blood toxicity were reported.

Overall, 17% of colchicine patients and 9% of controls discontinued the study medications before completing 180 days of treatment (P = 0.116). However, colchicine patients discontinued treatment earlier than controls (mean duration of 26 days vs. 47 days; P = 0.03). Moreover, in the colchicine group, late lumen loss was higher among patients who stopped treatment prematurely compared with those who completed treatment (0.8 mm vs. 0.3 mm; P = 0.025). Dropouts also saw a trend toward higher angiographic in-stent restenosis (29.4% vs. 13.3%; P = 0.141).

Double the Antirestenotic Punch

The authors note that inflammation plays a prominent role in the molecular mechanisms of restenosis, and colchicine has a potent anti-inflammatory effect, acting on several cellular components of the immune process. This is paired with an anti-hyperplastic effect, mediated through disruption of the mitotic spindle and inhibition of microtubules.

Based on these properties, colchicine would be expected to help prevent restenosis, Dr. Giannopoulos and colleagues observe. They attribute the drug’s failure in an earlier study of balloon angioplasty (O’Keefe JH Jr, et al. J Am Coll Cardiol. 1992;19:1597-1600) to the different mechanisms of restenosis in the setting of angioplasty (recoil and vessel remodeling in addition to neointimal hyperplasia) as opposed to stenting (almost exclusively neointimal formation).

In the current study, the marked disparity between the rate of TLR (4% overall) and that of angiographic restenosis (24%) is probably due to the fact that a large proportion of patients with in-stent restenosis were asymptomatic, the authors say. The reasons for the latter, they explain, are threefold: Ischemia is often silent in diabetics, all patients were on optimized medical therapy, and about two-thirds of those with in-stent restenosis had an obstruction of less than 70%.

BMS Not So Restenosis Prone?

In an accompanying editorial, Bradley H. Strauss, MD, PhD, of Sunnybrook Health Sciences Centre (Toronto, Canada), recommended caution in use of colchicine in diabetic patients receiving BMS, noting that more studies are needed to confirm its clinical benefit in that setting.

Such hesitation is all the more warranted in light of recent data suggesting that reintervention rates for BMS restenosis in non-insulin-dependent diabetics may be lower than previously thought and similar to those of nondiabetic patients, he added.

Looking beyond use of systemic antiproliferative agents, Dr. Strauss said, “the paclitaxel drug-eluting balloon appears to be an attractive option to prevent restenosis, either when combined with a chromium cobalt BMS during the initial revascularization procedure or as a treatment to prevent a further recurrence of restenosis in patients in whom restenosis developed with either a BMS or DES.” 

In an e-mail communication with TCTMD, Stephen G. Ellis, MD, of the Cleveland Clinic (Cleveland, OH), said the mechanism behind colchicine’s angiographic effect is biologically plausible and the same holds for a variety of other anti-inflammatory and antiproliferative agents. He referenced a recent meta-analysis which found that steroids significantly reduced rates of restenosis and TVR in BMS patients (Sardar P, et al. J Invasive Cardiol. 2012;24:96-103). However, he added, many of such drugs are fairly toxic, and it is surprising that there were not more dropouts in the colchicine arm due to side effects.

Dr. Ellis said he would expect colchicine to confer the same angiographic benefit in both nondiabetic and diabetic patients implanted with BMS. Moreover, only 3 to 4 months’ worth of the drug may suffice to prevent restenosis, he added, although shorter durations would have to be studied.

But if drug-coated balloons prove effective against restenosis in this setting, Dr. Ellis noted, they would trump BMS plus oral colchicine in part due to reduced systemic side effects.

Study Details 

All stents were postdilated with an appropriately sized noncompliant balloon. IVUS was used postimplantation to optimize stent expansion and apposition and identify significant edge dissections or residual plaque burden at the stent edges. 

2. Strauss BH. Diabetic patients receiving bare-metal stents: No option patients? J Am Coll Cardiol. 2013;Epub ahead of print.

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