A randomized multicentre open-label clinical trial with 2 parallel groups was conducted at 3 Spanish tertiary teaching centers. The study compared the efficacy of 2 treatment regimens in patients with a first episode of AIP to avoid recurrent pericarditis: conventional anti-inflammatory treatment with aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) plus colchicine (1 mg/12 h for patients who weighed more than 70 kg or 0.5 mg/12h in patients with a weight <70kg) for 3 months (group A) vs conventional antiinflamatory treatment (group B).

The inclusion criteria were: a) AIP evident at the time of inclusion, and b) agreement to participate in the study with provision of informed consent. The exclusion criteria were: a) pregnant or nursing women or women of childbearing potential not protected by a contraception method; b) life expectancy of less than 18 months; c) current treatment with corticosteroids or underlying diseases requiring treatment with corticosteroids; d) tuberculosis, malignancy, or bacterial pericarditis; e) postcardiac injury pericarditis; f) creatinine levels greater than 2.5mg/dl; g) liver disease or transaminase> 1.5 the upper limit of the normal; h) blood dyscrasia; i) contraindication or hypersensitivity to colchicine.

The trial included 110 patients, of whom 50% were assigned to receive aspirin or NSAIDs and the other 50% to receive aspirin, NSAIDs, and colchicine for months.

This study complies with the Declaration of Helsinki. The study was approved by the Vall d’Hebron University Hospital Institutional Review Board and was registered in the EU Clinical Trials Register (EudraCT Number: 2009-011258-16). Prior to participating in this study, each investigator obtained local ethics committee approval and patients gave their written informed consent.

All patients received conventional treatment consisting of aspirin at initial doses of 1g every 6 or 8 hours, ibuprofen 600 mg every 8hours or indometacin 50mg every 8hours for 2 to 10 days with tapering over 3 to 4 weeks. In the group assigned to colchicine (group A), in addition to conventional treatment, colchicine was started at diagnosis of AIP. In all patients, treatment was started within the first week of symptom onset. Colchicine was administered at a dose of 1 mg/12h in patients> 70 kg or 0.5mg/12h in patients <70 kg for 3 months, reduced to half the dose if there was diarrhea. Corticosteroids were not administered in any of the patients. Other cardiac medications were prescribed at the discretion of the attending physician. Relapses were treated with aspirin or ibuprofen at the same doses as those used in the first episode. We strongly advised against the use of steroids. Colchicine was maintained for 3 months irrespective of the presence of recurrences. All patients received a proton pump inhibitor as gastroduodenal prophylaxis.

In addition to hematological and biochemical determinations, serial measurements of CK-Mb and troponin T were performed. Echocardiography was performed during patient admission. If pericardial effusion was documented, echocardiographic monitoring was performed according to clinical judgment.

Patients were deemed to have withdrawn from the study under 2 circumstances: a) no adherence with 24 months follow-up, b) following the patient's wishes or if violations of the monitoring protocol were evident. Patients who discontinued colchicine treatment due to adverse effects were followed up until the 24-month follow-up protocol was complete.

Acute pericarditis is diagnosed on the basis of the presence of 2 of the following criteria: typical pericarditic chest pain, pericardial rub and/or evolving repolarization abnormalities typical of acute pericarditis in an electrocardiogram (ECG). Idiopathic pericarditis is diagnosed when no underlying disease, previous cardiac injury or specific infectious etiology are identified after the applications of a protocol for management of pericardial diseases.19Recurrent pericarditis is diagnosed by a documented first episode of acute pericarditis, a symptom-free interval of 6 weeks or longer, and evidence of subsequent recurrence of pericarditis. Patients with persistent pericarditis or those with a symptom-free interval of less than 6 weeks are diagnosed with incessant pericarditis. Recurrence is diagnosed by recurrent typical pericarditic chest pain and 1 or more of the following signs: pericardial friction rub, evolving ECG changes, or echocardiographic evidence of a new pericardial effusion.

The primary end point of the study was to assess whether early administration of colchicine in the first episode of AIP may be effective in preventing recurrent episodes of pericarditis. The secondary study end point was to evaluate the time to the first recurrence and whether the potential beneficial effect of colchicine was limited to the period of its administration or was maintained after discontinuation of the treatment.

The safety of colchicine was assessed by the registering all the adverse events that appeared during its administration.

The expected rate of recurrences in the group not exposed to colchicine was assumed to be 30%. Expected absolute reduction in the number of recurrences was 20%. Assuming a type I error of 5% and type II error of 20%, 49 patients per arm were required to obtain a power of 80%. Estimating a 10% loss to follow-up, the required sample size was calculated to be of 110 patients.

Patients who met a*ll the inclusion criteria and none of the exclusion criteria were randomized in consecutive order of qualification to receive colchicine in addition to conventional antiimflammatory treatment or only conventional antiimflammatory treatment (1:1). Overall, randomization was conducted in permuted blocks with a block size of 4, through a web-based system (computer-generated sequence allocation), which was also used for electronic data capture throughout the study. Time zero was defined as the time of randomization. Patients were considered enrolled in the study and eligible for final intention-to-treat analysis.

All patients were followed up for at least 24 months after inclusion in the study. Follow-up visits to the outpatient clinic were scheduled at 6 weeks, 3, 6 and 12 months and thereafter until the end of the study. A minimum follow-up of 24 months for all patients was predetermined and the follow-up ended at December 2013. Each visit was performed through a structured interview (questionnaire) where the occurrence of symptoms or signs of a possible new episode of pericarditis were recorded. Assessment of treatment adherence was asked from each patient. Currently, there are no analytical methods that allow measuring levels of colchicine in serum or other body fluids. During follow-up, testing of each visit included basic vital signs and a general physical examination. All adverse events were monitored and recorded.

All analyses were carried out by intention-to-treat. Quantitative variables are expressed as mean±standard deviation and category variables are expressed as the absolute value of cases and the percentage (%). For mean comparisons, the Student t test was used, and the Mann-Whitney U statistic was used when necessary. Comparative proportions analysis was performed using the chi-square test, and the Fisher test was used when necessary. Statistical significance was considered for a value <.05. The distribution of events (recurrent pericarditis) was estimated by Kaplan-Meier analysis and compared groups by log-rank test. A logistic regression analysis was carried out to assess possible contribution of other risk factors for recurrences including sex, previous use of colchicine, and pericardial effusion at presentation. All analyses were performed using SPSS 21.0.

From February 2004 to May 2010, 110 patients (83.6% men, mean age 44.4±18.3 years; median age 40 [range, 24-67] years) with a first episode of AIP who were candidates to participate in the current study were randomized to each treatment group. Group A comprised 59 patients who received conventional treatment plus colchicine for 3 months and group B comprised 51 patients who received conventional treatment alone. Of the 110 randomized patients, 102 (92.7%) completed the follow-up and were analyzed. Three patients died before the first year of follow-up because of sudden cardiac death (1 patient from group A) and neoplasia of the colon and pancreas respectively (2 patients from group B), and 5 patients (1 from group A and 4 from group B) were lost during follow-up (Figure 1). No differences were found in baseline demographic characteristics or in the clinical features of the index pericarditis episode (Table 1). Conventional treatment was similar in both groups, with aspirin alone (67.3%) or in combination with other analgesic and/or anti-inflammatory drugs (17.3%) as the main treatment (Table 2). No patient received corticosteroid treatment.

Figure 1.

Trial profile. All patients assigned to each treatment.

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Overall, the average follow-up was 30.2±17.0 [range, 24-145] months. No differences were found in the mean follow-up (group A vs group B, 28.4±15.3 vs 30.5±18.6 months; P=.5) or in the percentage of patients who ended the 2 year follow-up in each group (group A vs group B, 93.2% vs 92.1%; P=.88).

Recurrent pericarditis occurred in 12 patients (10.9%). No episodes of incessant pericarditis occurred in any of the patients. The main results for each group are summarised in Table 3. No statistically significant differences in recurrence rate were found between groups (group A vs group B, 13.5% vs 7.8%; P=0.34). Among the 12 patients who had recurrence of pericarditis, 7 occurred during the first 3 months (4 in group A and 3 in group B) (Table 1), 2 at 6 months, 1 at 12 months, 1 at 18 months, and 1 at 24 months of follow-up. The time to the first recurrence did not differ between groups (group A vs group B, 9.6±9.0 vs 8.3±10.5 months; P=.80). Colchicine administration did not result in a lesser severity of the index episode of pericarditis, as measured by pericardial effusion, cardiac tamponade, or episode duration (Table 1). No patient had more than 1 recurrence. Symptom severity (symptom duration, presence of pericardial effusion or tamponade) of the recurrent episodes of pericarditis were no different between the groups (Table 2). No patient experienced a severe pericardial effusion or cardiac tamponade during episodes of recurrence. Kaplan-Meier survival curves showed no significant differences for subsequent recurrences (Figure 2). Multivariate analysis showed no predictors for episodes of recurrences.

Figure 2.

Kaplan-Meier survival curves for recurrent pericarditis. 95%CI, 95% confidence interval.

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Adverse effects related directly to colchicine were observed in 8 patients (13.5% of the colchicine group); all of them had diarrhea. In 2 patients, diarrhea was resolved by reducing the colchicine dose but it had to be discontinued in 6 patients. In 1 additional case, the patient decided to discontinue colchicine of his own initiative, although no adverse effect was observed. In the conventional treatment group, gastrointestinal disorders occurred in 4 patients (8.5%) with no patient with diarrhea and no need for treatment discontinuation because of adverse effects. No serious adverse effects where observed in either group.