What Is the CADTH Reimbursement Recommendation for Myinfla?:

CADTH recommends that Myinfla should not be reimbursed by public drug plans for the reduction of atherothrombotic events in adults with coronary artery disease.

Additional Information

Clinician Input

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for colchicine:

• Considerations for initiation of therapy.
• Considerations for discontinuation of therapy.
• Considerations for prescribing of therapy.
• Generalizability of trial populations to the broader populations in the jurisdictions.
• Care provision issues.

The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.

The drug programs requested input on the patients most likely to be prescribed colchicine, the longer-term safety and tolerance of colchicine, and the potential for off-label use of colchicine 0.6 mg dosage form as secondary prevention therapy. In response, the clinical experts expect that colchicine will be used primarily in patients with a history of MI, including some patients who were excluded from the clinical trials (e.g., low ejection fraction, prior bypass surgery). A large number of patients are potentially eligible for treatment with colchicine, as the drug could be initiated irrespective of how much time has elapsed since a prior myocardial ischemic event. Colchicine is associated with gastrointestinal adverse effects, and a portion of patients will discontinue therapy due to intolerance. Based on previous experience with colchicine, the frequency of discontinuation due to adverse effects is expected to be similar to other secondary prevention drugs.

The clinical expert stated that colchicine may be beneficial as primary prevention therapy however, direct evidence is lacking as no clinical trials have been conducted in this population. Primary prevention is outside the Health Canada indication for colchicine. The experts state that some clinicians have prescribed colchicine 0.6 mg tablets for secondary prevention therapy, and it is possible that off-label use may continue after the 0.5 mg dosage formulation is available in Canada. There is some uncertainty in regards to long-term safety of colchicine in patients with coronary artery disease and additional data are required.

Description of Studies

Four randomized controlled trials (RCTs) met the inclusion criteria for the systematic review, including 3 double-blind placebo-controlled studies (COLCOT, COPS, LoDoCo2) and 1 open-label, observer-blinded trial (LoDoCo). The trials enrolled adults with an acute MI (COLCOT), ACS (COPS), or stable coronary artery disease (LoDoCo2, LoDoCo), and had a sample size that ranged from 532 to 5,522 patients. Patients received colchicine 0.5 mg daily versus placebo or no treatment as add-on therapy to standard secondary prevention therapies. In the LoDoCo2 study, all patients received open-label colchicine during a 1-month run-in period and those who were tolerant and adherent to therapy were randomized. The primary outcome in all trials was the time to first occurrence of a composite outcome that included several major cardiovascular events. The median follow-up duration ranged from 1 to 3 years.

The mean age of patients enrolled ranged from 59.7 years (standard deviation [SD] 10.2) to 67 years (SD 9.2), and 78% to 89% of patients per treatment group were male. Approximately half of the patients enrolled had a history of hypertension (50% to 52%), 18% to 33% had diabetes, and 4% to 37% were smokers. In the LoDoCo2 and LoDoCo studies, 84% and 24% of patients, respectively, had a history of ACS. In the COLCOT study, patients were enrolled a mean of 13.5 days following their MI, and in the COPS study, patients were enrolled during their hospital admission for ACS.

Efficacy Results

The COLCOT study reported a similar number of deaths in the colchicine (43 patients, 1.8%) and placebo groups (44 patients, 1.8%) over a median follow-up period of 22.6 months (hazard ratio [HR] 0.98; 95% CI, 0.64 to 1.49, P = 0.93) (total N = 4,745). For the primary composite outcome, 131 patients (5.5%) in the colchicine group and 170 patients (7.1%) in the placebo group experienced an adjudicated event of cardiovascular death, resuscitated cardiac arrest, acute MI, stroke, or urgent revascularization. The unadjusted HR for the time to first occurrence of the primary composite end point was 0.77, 95% CI, 0.61 to 0.96 (P = 0.02) for colchicine versus placebo.

In the 1-year COPS study, 8 patients who received colchicine died (2.0%), compared with 1 patient in the placebo group (0.3%) (HR 8.20, 95% CI, 1.03 to 65.61, P = 0.047, not adjusted for type I error rate). In this trial, 24 patients in the colchicine group (6.1%) and 38 patients (9.5%) in the placebo group experienced a primary adjudicated end point of either death, ACS, ischemia-driven urgent revascularization, or non-cardioembolic ischemic stroke by 12 months (P = 0.09 log-rank test). The estimated HR for the time to first adjudicated primary end point was 0.65, 95% CI, 0.38 to 1.09 (total N = 795).

The LoDoCo2 study reported 73 deaths (2.6%) in the colchicine group and 60 (2.2%) deaths in the placebo group after a median follow-up of 28.6 months (HR 1.21 95% CI, 0.86 to 1.71) (total N = 5,522). The primary composite outcome was time to first occurrence of an adjudicated cardiovascular death, non-procedural MI, ischemic stroke, or ischemia-driven revascularization. In the colchicine group, 187 patients (6.8%) experienced an adjudicated primary end point compared with 264 patients (9.6%) in the placebo group, with a cause-specific HR of 0.69 95% CI, 0.57 to 0.83, P < 0.001.

A total of 4 patients died (1.4%) in the colchicine group and 10 patients (4.0%) died in the control group of the LoDoCo study, which had a median follow-up duration of 36 months (total N = 532). Fifteen patients (5.3%) in the colchicine group and 40 patients (16.0%) in the control group experienced an adjudicated primary end point event of ACS, fatal or non-fatal out of hospital cardiac arrest or non-cardioembolic stroke (unadjusted HR 0.33 95% CI, 0.18 to 0.59, P < 0.001).

In the LoDoCo2 and LoDoCo studies, the treatment effects for the primary composite end point were similar in the subgroup of patients with a history of ACS, as in the overall population.

Across all 4 trials, the time to event analyses of the individual components of the primary composite end point showed point estimates for the HR that favoured colchicine versus control, however the 95% CI did not exclude the null for all outcomes. Of the major cardiovascular events included in the composite end points, MI, and revascularization procedures were the most frequently reported, with resuscitated cardiac arrest, stroke, and death reported less frequently. Only the LoDoCo2 study used a hierarchical testing procedure to control the type I error rate for secondary outcomes, which included the time to ischemia-driven revascularization (HR 0.75 95% CI 0.60 to 0.94; P = 0.01), MI (HR 0.70 95% CI, 0.53 to 0.93, P = 0.01), ischemic stroke (HR 0.66 95% CI 0.35 to 1.25, P = 0.20) and cardiovascular death (0.80 95% CI, 0.44 to 1.44; P value not reported as statistical testing was stopped). Of note, the experts consulted for this review indicated that not all end points in the composite were of equal importance. A significant reduction in revascularization, while important from a health care resource perspective, may be considered of lesser relevance to patients than death, or potentially disabling stroke or MI. These differences in clinical importance of the end points should be considered when interpreting the results of the composite outcomes.

Harms Results

The collection and reporting of harms data were incomplete for all studies. No studies collected data on the overall frequency of adverse events and only the COLCOT study reported the number of patients with 1 or more serious adverse events (16% in the colchicine group and 17% in the placebo group).

The overall frequency of gastrointestinal adverse effects was 17% per treatment group in the COLCOT study, and 21% to 23% in the COPS study. Gastrointestinal adverse effects were the reason for treatment discontinuation for 4% of colchicine-treated patients in the COLCOT study, 9% in the COPS study, and 14% in the LoDoCo study. During the run-in period of the LoDoCo2 study 9% of patients withdrew due to intolerance, and during the double-blind phase another 3% of patients per group stopped treatment.

Generally, the frequency of neoplasms and serious infections appeared to be numerically similar between groups in the COLCOT and LoDoCo2 studies. Myalgia was reported in 21.2% of patients in the colchicine group compared with 18.5% of patients in the placebo group, based on data from a subgroup of the LoDoCo2 study.

Critical Appraisal

No major sources of bias were identified for the pivotal COLCOT and LoDoCo2 studies. Potential limitations include unclear allocation concealment in the LoDoCo2 study, and lack of control of multiplicity in the COLCOT study.

Several limitations were identified for the 2 other trials. This included the sample size (532 and 795) and lack of statistical power (COPS), as well as poor reporting of methods to maintain blinding of all participants in the double-blind COPS study or outcome assessors in the open-label, assessor blinded LoDoCo study. In the COPS study, follow-up was incomplete for many patients (number not reported) at the time of the pre-planned primary analysis. The randomization process was potentially biased in the LoDoCo study, and some imbalances in patient characteristics were noted at baseline; thus, it is unclear if all prognostic and effect modifiers were balanced between groups. Due to the open-label design, the LoDoCo study may also be subject to performance bias, outcome ascertainment bias, and reporting bias.

Of note, the trials were designed and powered to detect differences in the primary composite outcome, not the individual outcomes of the composite, or for mortality. None of the trials collected data on health-related quality of life, and limited hospitalization data were reported in the COPS study.

The safety data available were limited by the sample size and study duration of the key trials, which may have been insufficient to detect infrequent adverse events or those that require a longer time to develop. Moreover, the collection and reporting of adverse event data was incomplete. Although colchicine has been available in Canada for decades, some uncertainty remains regarding its comparative longer-term safety in patients with coronary artery disease.

With regard to external validity, the LoDoCo2 study enrolled an enriched population that was tolerant and adherent to colchicine, and thus, may overestimate the treatment effects in an unselected patient population. The pivotal trials excluded patients with more severe heart failure, valvular heart disease or prior coronary bypass graft, as well as those with renal or hepatic impairment. As a result, the findings may not be generalizable to these patients. Although the patients enrolled may not reflect the gender, racial or ethnic diversity of the Canadian population, the experts had no major concerns with the generalizability of the study populations.

Budget Impact

CADTH identified the following key limitations with the sponsor’s analysis: the number of individuals eligible for public drug plan coverage is underestimated; the cost of colchicine is underestimated; there is a high degree of uncertainty in assumptions around the market share and uptake rate of colchicine; and the cost of prolonged survival on colchicine is not captured in the estimated budget impact. The CADTH reanalysis included using the proportion of patients eligible for coverage to calculate market size and assuming full colchicine adherence.

Although the sponsor suggested colchicine would be associated with a budget impact of $24,421,794 over the 3-year time horizon, based on CADTH reanalyses, the estimated budget impact to the public drug plans of reimbursing colchicine for the full Health Canada–indicated population (patients with CAD) is $7,650,184 in year 1, $15,021,976 in year 2, and $30,254,348 in year 3, for a 3-year total of $52,926,508. The estimated budget impact is sensitive to the proportion of patients eligible for public drug plan coverage and treatment adherence.

Members of the Committee

Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed.