Trial design and population
The present study was a prospective double-blinded placebo-controlled randomized trial which included a total of 361 ACS patients (40–70-year-old adults) who visited a tertiary healthcare heart hospital affiliated to Shiraz University of Medical Sciences from October 2019 till March 2020. All the patients underwent coronary angiography (explained as ≥ 50% luminal stenosis in any epicardial vessel of ≥ 2.5 mm luminal diameter) and were managed with either PCI or medical therapy. ACS patients were included as three groups with either elevated troponin or ECG changes: unstable angina (UA), non-ST segment elevation myocardial infarction (NSTEMI) and STEMI. Patients with unstable angina had typical chest pain and ECG alteration without elevated troponin and elevated ST segment. NSTEMI patients were those who had elevated troponin without ST-segment elevation, and STEMI patients exhibited ST elevation in ECG and had a positive troponin test. The exclusion criteria were any history of long-term colchicine use or hypersensitivity to it, moderate renal dysfunction (glomerular filtration rate ˂50), hepatic dysfunction, thrombocytopenia, leukemia, left ventricular ejection fraction ˂30%, surgical revascularization and lactation or the risk of pregnancy.
We randomly assigned patients with a 1:1 aspect ratio to receive either colchicine (at a single dose of 0.5 mg once daily), plus standard medical therapy and standard medical therapy plus placebo. We used a computer-based program with block randomization protocol as well as the method of block size factor obtained from the study investigators. Preparing packages of study medications was performed by an independent packaging team that was not involved in the rest of the study. All the investigators, patients and follow-up team members were unaware so as to devise a non-biased controlled study, whereas unbinding was performed in exceptional cases of unwell patients wherein the knowledge of treatment allocation was necessary The present study was also registered at (irct.ir) with a registration number of IRCT20201117049420N1.
Trial procedures
All the patients obtained standard medical treatments in accordance with the local ACS management guidelines. Patients who were placed in the intervention group received 0.5 mg/daily colchicine, whilst the control group members were given placebo tablets. Screening, randomization, and administration of colchicine were performed on the first day of ACS occurrence. Considering shape, size, color and packaging, placebo tablets were the same as colchicine. The follow-up was carried out seven days after the patients were discharged from hospital by means of structured telephone interviews. Moreover, the follow-up process continued monthly to control patients` tolerability, adherence to study and major adverse cardiac events (MACE). For further confidence, all the patients were checked every two months by investigators. This follow-up was performed by investigators who were unaware of the study groups' allocation. We kept the patients under scrutiny for a period of six months after ingestion of first colchicine or placebo tablets. During these six months, the blinding of the research team to outcome of the study was maintained.
Trial outcomes
The primary outcomes were death from any cause, non-cardio-embolic ischemic stroke, hospital admission due to typical chest pain (UA, STEMI/NSTEMI), urgent need for revascularization and decompensated heart failure. The secondary end points consisted of the components of the primary efficacy end point; a combination of hospitalization for chest pain, death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, or stroke; and total mortality in time-to event analyses.
Statistical analysis
The collected data was placed into the statistical package for social sciences version 18 (SPSS Inc., Chicago, IL, USA). Descriptive statistics including mean (standard deviation) for quantitative variables and number (%) for qualitative variables were used to describe the data. Data analysis was conducted using independent sample T-test and Chi-square test. The use of independent T makes it possible to measure the average of the parameters before and after, as well as the difference between the changes. Furthermore, t-test was used to compare the mean of parameters in each of the two groups. The Chi-square test was also employed to make a comparison between the qualitative variables and qualities for the two groups. Normality of distributions was evaluated using the frequency histograms and the Shapiro-Wilkes test. The primary outcome was a time to event analysis via the logrank test. A sensitivity analysis accounted for multiple correlated events within in an individual by using a Cox regression with group assignment as the independent variable, clustering over individual and reporting robust standard errors. Results of this study are reported as hazard ratios (HR) with 95% confidence intervals (95%CI). A P-value less than 0.05 (two-tailed) was regarded as statistically significant.
Sample size justification
Given the goals and the type of this study, the citation was based on the previous studies [9] in this field while taking into account the assumptions: the error of 5%, the power of 80%, the effect size of about 40% or the risk ratio of about three percent in the two groups, and the ratio of one to one in two groups were all measured by means of the following formula:
$$n = \frac{{2\overline{p}(1 - \overline{p})(z_{{1 - {\raise0.7ex\hbox{$\alpha $} \!\mathord{\left/ {\vphantom {\alpha 2}}\right.\kern-\nulldelimiterspace} \!\lower0.7ex\hbox{$2$}}}} + z_{1 - \beta } )^{2} }}{{(\partial )^{2} }}$$
Considering a five percent drop in total amount obtained from the computations, a total of at least 120 patients in each group and a total of 240 patients are needed. It should be noted that the sampling method is purposeful sampling method which is easily based on the purpose of the study. Accordingly, the investigators were present at the time of the study and started sampling from accessible referral patients to obtain the total sample size.
Trial oversight
This study was approved by the institutional review board of Shiraz University of Medical Sciences and won the approval of the Ethical Committee (IR.SUMS.MED.REC.1398.409). Likewise, the present study was also registered at (irct.ir) with a registration number of IRCT20201117049420N1. It should be noted that written informed consents were obtained from all the participants in the study. The patients’ MACE was evaluated by two independent cardiologists who were blinded to (unaware of) the treatment allocation.