Syed Raza Shah, MD,1,* Richard Alweis, MD, FACP,2 Syed Arbab Shah, MBBS,3 Mohammad Hussham Arshad, MD,4 Adil Al-Karim Manji, Pre-Medical Students,5 Arham Amir Arfeen, Pre-Medical Students,5 Maheen Javed, Pre-Medical Students,5 Syed Muhammad Shujauddin, Pre-Medical Students,6 Rida Irfan, Pre-Medical Students,6 Sakina Shabbir, Pre-Medical Students,6 and Shehryar Shaikh, Pre-Medical Students7
Colchicine, extracted from the colchicum autumnale plant, used by the ancient Greeks more than 20 centuries ago, is one of the most ancient drugs still prescribed even today. The major mechanism of action is binding to microtubules thereby interfering with mitosis and subsequent modulation of polymorphonuclear leukocyte function. Colchicine has long been of interest in the treatment of cardiovascular disease; however, its efficacy and safety profile for specific conditions have been variably established in the literature. In the subset of pericardial diseases, colchicine has been shown to be effective in recurrent pericarditis and post-pericardiotomy syndrome (PPS). The future course of treatment and management will therefore highly depend on the results of the ongoing large randomized placebo-controlled clinical trial to evaluate the efficacy and safety of colchicine for the primary prevention of several postoperative complications and in the perioperative period. Also, given the positive preliminary outcomes of colchicine usage in pericardial effusions, the future therapeutical use of colchicine looks promising. Further study is needed to clarify its role in these disease states, as well as explore other its role in other cardiovascular conditions.
Keywords: Colchicine, Pericardial, Diseases, Pericardium, Cardiac, Review
Colchicine, an ancient drug prescribed even today, comes from a plant named colchicum (1). It is not only the drug of choice in inflammatory diseases like gout but also is prescribed in diseases like Behcet's disease, an anti-inflammatory disease (2, 3). The main mechanism of action of colchicine is by binding to microtubules which interferes with mitosis ultimately leading to dysfunctional polymorphonuclear leukocyte (3, 4). Other proven hypothesis regarding colchicine mechanism includes inhibiting the production of chemotactic factors and affecting the transcellular movement of collagen (3). Some studies also suggest that colchicine maybe involved in changing the binding characteristics of several membrane proteins, thereby making the proteins non-functional (3). Colchicine has long been of interest in the treatment of cardiovascular disease; however, its efficacy and safety profile for specific conditions have been variably established in the literature. In this review, we examine the literature and current evidences behind the most common usages in pericardial diseases.
PericarditisAcute pericarditis is a common, benign disease (Table 1). Presence of a pericardial friction rub, pleuritic chest pain with positional changes, and characteristic findings on ECG are specific for diagnosing pericarditis in the clinical setting. However, in developed countries like the United States, more than 80% of cases of pericarditis are idiopathic (5).
Acute/Chronic and Recurrent Pericarditis
In 2005, the results of two important studies were made available, the CORE (COlchicine for REcurrent pericarditis) trial and the COPE (COlchicine for PEricarditis) trial (9). In the CORE trial, the effect of aspirin alone (or prednisone when aspirin was contraindicated) or aspirin plus colchicine was investigated in patients with first time recurrent pericarditis. The patients were randomly assigned to anti-inflammatory drugs, which were given for 3–5 weeks (progressively tapered), and colchicine (1 mg per day) for 6 months. The results were impressive with a significant effect. Recurrence rates at 18 months for the conventional treatment group was 50.6% while the rates for conventional treatment plus colchicine group was 24% (p=0.022). This explained an important clinical benefit of colchicine over conventional treatment in patients with first time episode of recurrent pericarditis. In the same year, the COPE trial recommended prescribing colchicine not only for recurrent pericarditis but also after the first pericarditis attack (10). This trial conducted on 120 patients with a mean follow-up of 1.5 years reported significant recurrence rate reductions in patients with a first episode of acute pericarditis being treated with conventional treatment plus colchicine group (10.7%) to conventional group (32.3%) (p=0.004). These results confirmed those of a preliminary French study of 19 patients published in 1991 (11).
Since, then, multiple studies testifying for the efficacy of colchicine have been performed. The Colchicine for Recurrent Pericarditis (CORP) trial, done on 120 Italian patients with a first recurrence of pericarditis, reported a recurrence rate of 24 and 55% with colchicine group and placebo group, respectively. There was a significant relative risk reduction of 0.56 [CI, 0.27 to 0.73] when both groups were compared (12). Imazio and Adler, the scientists who have been working tirelessly since the past decade on colchicine and anti-inflammatories later suggested that aspirin and NSAIDs (non-steroidal anti-inflammatories) should be the mainstay of treatment for acute and recurrent pericarditis with the possible adjunct of colchicine, especially for recurrences (13). Their past trials also showed that colchicine use was associated with a reduced risk of pericarditis during follow-up either for primary or secondary prevention without a significant higher risk of adverse events compared with a placebo (14).
In the recent years, Imazio et al. concluded that the data from controlled clinical studies supported the use of colchicine as effective, efficient, and safe means of treatment in recurrent pericarditis. They, however, suggested that there was less evidence that supported the use of colchicine in the treatment of acute pericarditis (15). Similar studies evaluating the current evidence from different prospective, randomized, controlled trials suggested a role for colchicine in the secondary prophylaxis for recurrent pericarditis (16). A recently concluded trial and a continuation of the CORP trial (CORP-2) with 240 patients who were being treated in colchicine and placebo groups (120 patients in each group) reported recurrent pericarditis in 26 (21.6%) and 51 (42.5%) patients, respectively, with a significant clinical difference (relative risk 0.49; p=0.0009), which spoke highly of the use of colchicine in these patients (17). Conversely, in other trials, pretreatment with corticosteroids substantially attenuated the efficacy of colchicine, leading to significantly longer therapy periods and more recurrences (18). This hypothesis was tested in a large multicenter all-case analysis. The results suggested that there were significantly more relapses after colchicine treatment as compared to those with previous corticosteroid treatment. The authors of the study suggested that pretreatment with corticosteroids exacerbates and extends the course of recurrent pericarditis (19). However, over the recent years, large randomized controlled trials have shown that colchicines had statistically significant beneficial effect on the hospitalization rate (p=0.02), on symptom persistence at 72 h (p=0.001), and the number of recurrences per patient (20). Thus, this has been the main topic of debate – whether to use colchicine with or without anti-inflammatories in recurrent pericarditis? While colchicine should be recommended for the prevention of recurrent pericarditis, questions concerning the long-term usage of colchicine in patients having pretreatment with corticosteroids need to be further elucidated.
In conclusion, many recent trials evaluating the role of colchicine with and without addition of aspirin or NSAIDs in the treatment of acute pericarditis and prevention of recurrence are still pending. Till then, colchicine should probably be regarded as a first-line treatment in the absence of contraindications (21).
Postpericardiotomy syndromePostpericardiotomy syndrome (PPS), occurring in 10–45% of patients after a cardiac surgery, is a common complication, developing in days to months after pericardial injury which can often lead to disability (Table 2) 22–25.
The future course of treatment and management will therefore highly depend on the results of the COPPS-2 trial (COlchicine for prevention of the Post-pericardiotomy Syndrome and Post-operative Atrial Fibrillation) which will be the first large randomized placebo-controlled clinical trial to evaluate the efficacy and safety profile of colchicine for the prevention of several postoperative complications and in the perioperative period. This trial will evaluate the possible benefit of the early use of colchicine, starting before cardiac surgery, potentially providing stronger evidence to support the use of preoperative colchicine without a loading dose to prevent several postoperative complications (31). Given these positive preliminary outcomes, the future therapeutical use of colchicine looks promising and deserves to be studied further.
EffusionsPostoperative effusions (including pleural or pericardial) are relatively common after cardiac surgery complication (Table 3). Most of these effusions are perioperative, occurring within the first week as a direct consequence of the surgical procedure (‘non-specific effusions’). They usually follow a benign course 32–34. Nevertheless, large symptomatic effusions may require medical therapy. As with PPS, use of colchicine in postoperative effusions have not yet been well studied. However, there have been some trials that have studied these uses to a limited scale.
ConclusionColchicine is an old drug with a well-established safety profile used in a variety of diseases that is becoming a drug of interest in cardiovascular diseases. In the subset of pericardial diseases, colchicine has been shown to be effective in recurrent pericarditis and to some extent in PPS. The future course of treatment and management will therefore highly depend on the results of the ongoing large randomized placebo-controlled clinical trial to evaluate the efficacy and safety of colchicine for the primary prevention of several postoperative complications and in the perioperative period. Given the positive preliminary outcomes of colchicine usage in pericardial effusions, the future therapeutical use of colchicine looks promising. Further studies are needed to clarify the role of colchicine in these disease states, as well as to explore its other roles in different cardiovascular conditions.
Conflict of interest and fundingThe authors have not received any funding or benefits from industry or elsewhere to conduct this study.
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