Critical Appraisal of a Randomized, Controlled, Double-Blind Trial Entitled“Colchicine in Patients with Chronic Coronary Disease”
Overview
This is a critical appraisal of a randomized, controlled, double-blind trial on the effects of colchicine to patients with chronic coronary disease. A clinical scenario was presented to determine the applicability of the trial to an actual patient from the general population. The evaluation method followed the population (P), intervention (I), comparison (C), outcome (O) design. Overall, the appraisal revealed that all valdiity criteria were met in this study. The trial provide evidence suggesting that inflammation plays a causal role in the pathogenesis of cardiovascular disease and related complications and that interventions to mitigate inflammation, like the colchicine, may reduce the risk of cardiovascular events.
Critical Appraisal of a Randomized, Controlled, Double-Blind Trial
- GENERAL OBJECTIVE
To evaluate a randomized, controlled, double-blind trial entitled “Colchicine in Patients with Chronic Coronary Disease”.
Specifically, this scientific inquiry seeks to:
- Assess the risk of bias, directness, and validity of the results of the study.
- Determine if the effect is significant, generalizable, and applicable to the current clinical scenario.
- CLINICAL SCENARIO
S> A case of a 56-year-old male, diagnosed to have chronic coronary syndrome, known to be hypertensive for 7 years, non-diabetic, with a history of smoking - 10 packs per year, the last attack was 7 months ago, with creatinine of 88, had ACS UA 7 months ago, no previous surgery. , 2D echo revealed EF of 85%, with good systolic and diastolic function, no valvular heart disease. No allergies to food and drugs.
Maintenance medications include:
ASA, clopidogrel, atorvastatin , Losartan, Amlodipine
O> Awake, not in cardiorespiratory distress
BP: 130/70 mmHg
HR: 67 bpm
RR: 19 cpm
T: 36.7
Anicteric sclera, pink palpebral conjunctiva, moist lips, moist oral mucosa
(-) NVE, no palpable cervical lymphadenopathy
O> symmetrical chest expansion, clear breathsounds
- Adynamic precordium, normal rate, regular rhythm
- Flabby, soft nontender abdomen
- Full pulses, no edema
A> Chronic Coronary syndrome, Hypertension stage 2, controlled
- CLINICAL QUESTION
- In adult patients with chronic coronary disease, does daily intake of colchicine or placebo reduce the risk of any cardiovascular event?
Population | Adult patients with chronic coronary syndrome. |
Intervention | Low dose of daily colchicine |
Comparison | No colchicine (placebo) |
Outcome | Reduce the likelihood of poor outcomes (reduced composite of cardiovascular death, spontaneous MI, ischemic stroke, or ischemic-driven coronary revascularization) |
- JOURNAL SEARCH
- METHODS
Design | Double-blind randomized controlled trial |
Setting | 13 centers affiliated with Genesis Care and the Heart & Vascular Research Institute of Sir Charles Gairdner Hospital in Western Australia; 30 centers of the Dutch Network for Cardiovascular Research in the Netherlands |
Patient Population | Adult patients with evidence of coronary disease on invasive coronary angiography or CT angiography or a coronary-artery calcium score of at least 400 Agatston units on a coronary-artery calcium scan. |
Description of Prognostic Factors Considered | Patients must be clinically stable for at least 6 months before the trial. Excluded patients were those who had moderate to severe renal impairment, severe heart failure, severe valvular heart disease, or known side effects from colchicine. |
Analysis | Cox proportional-hazards models (for cause-specific hazard ratios), Fine and Gray sub-distribution hazard models (for analysis of the primary & secondary end points) |
Outcomes | Primary: Composite of cardiovascular death, spontaneous (nonprocedural) MI, ischemic stroke, or ischemic-driven coronary revascularization Secondary: Composite of cardiovascular death, spontaneous (nonprocedural) MI, ischemic stroke (key secondary end point); Composite spontaneous MI or ischemic-driven coronary revascularization; composite cardiovascular death or spontaneous MI; ischemic driven coronary revascularization; spontaneous MI; death from any cause; and CV death. |
Follow-up | One month open-label run-in phase, 60 months since randomization |
- APPRAISING DIRECTNESS
Does the research question of the study correspond that of the clinical question?
Research Question | Clinical Questions | |
Population | Chronic Coronary Syndrome | Chronic coronary syndrome with history of hypertension |
Intervention | Colchicine 0.5 mg/tab | Colchicine |
Comparison | Placebo use | No colchicine use |
Outcome | Reduced cardiovascular event and stroke | Reduced cardiovascular event and stroke |
- APPRAISING VALIDITY
Question 1: Were patients randomly assigned to treatment groups?
Answer: Yes
- Eligible patients entered an open-label run-in phase for 1 month (receive 0.5 mg of Colchicine daily).
- After passing the run-in phase (i.e., stable condition, no side effects, still willing to participate), randomization was conducted in 1:1 ratio (either 0.5 mg Colchicine or placebo)
- Randomization was performed in double-blind manner with the use of a computerized algorithm (i.e., both the patients and the doctors are blinded of the treatment or placebo).
Question #2: Was allocation concealed?
Answer: Yes
- Double-blind randomization was made.
Question #3: Were baseline characteristics similar at the start of the trial?
Answer: Yes
Question #4: Were patients blinded to treatment assignment?
Answer: Yes
- Randomization was performed in a double-blind manners with the use of a computerized algorithm, with stratification according to country.
Question #5: Were caregivers blinded to treatment assignment?
Answer: Yes
- Double-blind randomization was made.
Question #6: Were outcome assessors blinded to treatment assignment?
Answer: Yes
- The academic and clinical investigators designed the study, collected and managed the data, performed the statistical analysis, and drafted the manuscript. The members of the steering committee & the trial statisticians vouched for the completeness and accuracy of the data & analyses and for the fidelity of the trial.
Question #7: Were all patients analyzed in the groups to which they were originally randomized?
Answer: Yes
Question #8: Was follow-up rate adequate?
Answer: Yes
- Clinical evaluations were scheduled before the run-in phase, at the time of the randomization, and at 6-month intervals until the completion of the trial. All follow-up assessments were performed in person, if person, or by telephone. The trial regimens were continued until the completion of the trial. Moreover, clinical follow-up was continued until the date of trial completion regardless of premature discontinuation of colchicine or placebo.
Were all validity criteria met?
ACHIEVED | |
Randomization | Yes |
Allocation concealment | YEs |
Similar baseline data | Yes |
Patients blinded | Yes |
Assessors blinded | Yes |
Caregivers blinded | Yes |
Analyzed to original random group | Yes |
Adequate follow-up | Yes |
- APPRAISING RESULT
How likely are the outcomes during a specified period of follow-up?
The primary composite end-point event of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization occurred in 187 patients (6.8%) in the colchicine group and in 264 patients (9.6%) in the placebo group, with incidence rates of 2.5 and 3.6 events, respectively, per 100 person-years (hazard ratio, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P<0.001).
- With a hazard ration of 0.69, this indicate that people in the colchicine group at any individual time along the study are 31% less likely to develop a cardiovascular event than the people in the placebo group.
How likely are the outcomes during a specified period of follow-up?
In the prespecified hierarchical testing of the ranked secondary end points, the rates of the first five secondary end points, including spontaneous myocardial infarction, were significantly lower in the
colchicine group than in the placebo group
Colchicine did not result in a lower incidence of death from any cause than placebo (73 vs. 60 fatalities; incidence, 0.9 vs. 0.8 events, respectively, per 100 person-years; hazard ratio, 1.21; 95% CI, 0.86 to 1.71).
- Colchicine has not significant benefit in reducing death from any cause than placebo. A hazard ration of 1.21 indicates that people in the colchicine group at any individual time along the study are 121% more likely to develop death from any cause than the people in the placebo group.
How precise is the likelihood estimates?
- The trial was designed to accrue a minimum of 331 primary end-point events and to have a minimum follow-up of 1 year. On the basis of a target enrollment of 6053 patients in the open-label run-in phase, with 5447 undergoing randomization after screening, we estimated that the trial would have more than 90% power, at a two-sided alpha level of 0.05, to detect a 30% lower rate (i.e., a hazard ratio of 0.70) of a primary composite end-point event in the colchicine group than in the placebo group, assuming a 10% rate of discontinuation of colchicine or placebo and an annual rate of the primary end point in the control group of 2.6%.
- The main analysis was based on the time from randomization to the first occurrence of any component of the primary composite end point. If the incidence of the primary end point was significantly lower in the colchicine group than in the placebo group (P<0.05) then the ranked secondary end points were tested in a hierarchical fashion at a significance level of 0.05 in order to preserve the alpha level.
- The main analysis was performed according to the intention-to-treat principle and included all adjudicated end-point events that occurred between randomization and the end-of-trial date in all patients who had undergone randomization, regardless of whether they adhered to their assigned regimen. Cause-specific hazard ratios in the colchicine group, as compared with the placebo group, and 95% confidence intervals were determined with the use of Cox proportional hazards models, stratified according to country. If an end-point event had not occurred, follow-up data were censored at the time of the competing risk event (death from non-cardiovascular causes or death from any cause, as appropriate) or at the end of the trial. Two-sided P values for superiority were calculated with the use of log-rank tests, as governed by the rules of hierarchical testing. The prespecified subgroup analyses were performed with the use of the Cox proportional-hazards method.
- ASSESSING APPLICABILITY
Biologic Consideration
Inclusion Criteria | Exclusion Criteria |
Age: 35-82 years old | With moderate to sever renal impairment |
Had any evidence of coronary disease on invasive coronary angiography or CT angiography or a coronary-artery calcium score of at least 400 Agatston units on a coronary-artery calcium scan. | With severe heart failure |
Clinically stable for at least 6 months | With severe valvular heart disease |
With known sided effects from colchicine |
- Non-cardiovascular deaths occurred more frequently among the patients who received colchicine than among those who received placebo, with incidence rates of 0.7 and 0.5 events, respectively, per 100 person-years (hazard ratio, 1.51; 95% CI, 0.99 to 2.31) . Similar rates were observed of cancer diagnosis, hospitalization for infection, hospitalization for pneumonia, and hospitalization for a gastrointestinal reason in the two trial groups, in both the intention-to-treat analysis and the on-treatment analysis. Gout occurred in 38 patients (1.4%) in the colchicine group and in 95 patients (3.4%) in the placebo group (cumulative incidence ratio, 0.40; 95% CI, 0.28 to 0.58). Neutropenia and myotoxic effects were uncommon in both trial groups. Among the patients from the Netherlands, myalgia was reported in 384 (21.2%) in the colchicine group and 334 (18.5%) in the placebo group (cumulative incidence ratio, 1.15; 95% CI, 1.01 to 1.31). Dysesthesia was reported in 143 patients (7.9%) in the colchicine group and in 150 patients (8.3%) in the placebo group (cumulative incidence ratio, 0.95; 95% CI, 0.76 to 1.18).
Assessing Applicability
Patient’s Characteristics:
- 56-year-old male,
- diagnosed to have chronic coronary syndrome,
- hypertensive for 7 years,
- non-diabetic,
- with creatinine of 88,
- had ACS UA 7 months ago, no previous surgery. ,
- 2D echo revealed EF of 85%,
- with good systolic and diastolic function,
- no valvular heart disease
- no allergies to food and drugs.
Socioeconomic Consideration
- Colchicine is an anti-inflammatory drug originally extracted from the autumn crocus (Colchicum autumnale) and was used by the ancient Greeks and Egyptians.
- Usual price of Colchicine in the Philippine market ranges from P2.50 to P4.50
- CONCLUSION
- The trial provided evidence suggesting that inflammation plays a causal role in the pathogenesis of cardiovascular disease and related complications and that interventions to mitigate inflammation may reduce the risk of cardiovascular events.
- REVIEWER’S APPRAISAL
- In scrutinizing the validity of the trial, the results, and its applicability, the study is acceptable. The trial design is appropriate, there was a true randomization of assignment of participants, treatment groups are concealed, both the patients and the care providers were blinded to treatment assignment, the outcomes were measured and analyzed adequately using an appropriate statistical tool. Hence, the effects of treatments were consistent across the majority of clinical subgroups examined.
Article:
Nidorf, S. M., Fiolet, A. T. L., Mosterd, A., Eikelboom, J. W., Schut, A., Opstal, T. S. J., The, S. H. K., Xu, X. F., Ireland, M. A., Lenderink, T., Latchem, D., Hoogslag, P., Jerzewski, A., Nierop, P., Whelan, A., Hendriks, R., Swart, H., Schaap, J., Kuijper, A. F. M., van Hessen, M. W. J., … LoDoCo2 Trial Investigators (2020). Colchicine in Patients with Chronic Coronary Disease. The New England journal of medicine, 383(19), 1838–1847. https://doi.org/10.1056/NEJMoa2021372