535907

research-article2014

AOPXXX10.1177/1060028014535907Annals of PharmacotherapyNorrid and Oliphant

Review Article-Drug Information Rounds

Colchicine for the Treatment of Acute and Recurrent Pericarditis

Annals of Pharmacotherapy 2014, Vol. 48(8) 1050­–1054 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014535907 aop.sagepub.com

Sarah E. Norrid, BS1, and Carrie S. Oliphant, PharmD, BCPS1,2

Abstract Objective: To evaluate the literature with colchicine for the acute treatment of pericarditis and prevention of recurrent pericarditis. Data Sources: Searches of MEDLINE (1966-March 2014) and Cochrane Database (1993-March 2014) were conducted using the search terms pericarditis and colchicine. Limits were set for articles written in English with human subjects. Additional data were identified through bibliographic reviews. Study Selection and Data Extraction: Case series and clinical trials identified from the data sources were evaluated. Data Synthesis: A total of 16 case series and 5 prospective controlled trials were identified in the search. Early observational studies examined the use of colchicine, as an adjunct to aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs), in patients with multiple cases of recurrent pericarditis. These studies showed decreased rates of recurrence after the initiation of colchicine therapy and formed the basis of the only available guidelines for the treatment of pericarditis. Since then, 5 randomized controlled trials have been published; 3 trials studied colchicine therapy for 6 months in patients with recurrent pericarditis, and the other 2 studied colchicine therapy for 3 months in patients with acute pericarditis. All 5 trials showed decreased rates of recurrence and symptom persistence, with similar rates of adverse events between study groups. Conclusions: Clinical controlled trials have shown that colchicine, as an adjunct to aspirin or NSAIDs, is effective in the prevention of recurrent pericarditis and in the management of acute symptoms. Colchicine was generally well tolerated with a low incidence of adverse events. Keywords colchicine, pericarditis

Request Is colchicine an effective therapy to manage patients with pericarditis?

Response Background Inflammation of the pericardium, the thin sac-like covering surrounding the heart, is a condition known as pericarditis. The diagnosis of pericarditis occurs in 0.1% of total hospital admissions and 5% of emergency department admissions for chest pain.1 In developed countries, more than 80% of cases of acute pericarditis are idiopathic and often presumed to be viral. Common viral infections associated with pericarditis include coxsackievirus A and B, echovirus, and adenovirus.1 Other causes include systemic inflammatory or autoimmune diseases, postcardiac injuries, and neoplasms.1-3 Acute pericarditis is diagnosed by the presence of 2 or more of the following: pleuritic chest pain (sharp pain exacerbated by inspiration), pericardial friction rub, widespread ST-segment elevation on electrocardiogram (ECG), and pericardial effusion.1,3

The most common complication of acute pericarditis is recurrence of symptoms after resolution of the initial attack. Recurrent pericarditis may occur in 15% to 32% of patients.4 Diagnostic criteria for recurrent pericarditis include documentation of acute pericarditis and pleuritic chest pain plus 1 or more of the following features: fever, pericardial rub, ECG changes, new or worsening pericardial effusion, or elevation in white blood cell count, C-reactive protein, or erythrocyte sedimentation rate.1 Recurrent pericarditis may occur at any point but typically develops within 18 months of the initial attack.3 Incessant pericarditis, on the other hand, is the persistence of symptoms within 6 weeks of the initial attack.4 Other severe, but rare, complications are constrictive pericarditis and cardiac tamponade.1 The management of pericarditis includes treatment of the acute phase and prevention of recurrence. In 2004, the 1

The University of Tennessee College of Pharmacy, Memphis, TN, USA Methodist Healthcare–University Hospital, Memphis, TN, USA

2

Corresponding Author: Carrie S. Oliphant, Department of Pharmacy, Methodist Healthcare– University Hospital, 1265 Union Avenue, Memphis, TN 38104, USA. Email: [email protected]

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Norrid and Oliphant European Society of Cardiology published the only available guidelines on the subject.5 The mainstay of therapy for acute pericarditis is aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs; class I recommendation) at antiinflammatory doses (eg, aspirin 2 to 4 g daily, ibuprofen 1600 to 3200 mg daily, or indomethacin 75 to 250 mg daily). Colchicine is listed as a second-line medication for treatment of acute pericarditis (class IIa recommendation) and first-line for prevention of recurrence (class I recommendation) at doses of 2 mg daily for 1 to 2 days followed by a 1 mg daily maintenance dose. This recommendation was limited to findings from small studies and expert opinion because large clinical trials had yet to be published. Corticosteroids are only recommended in cases related to autoreactive, autoimmune, or connective tissue diseases or intolerance, contraindication, or failure of aspirin or NSAIDs. Corticosteroids are linked to increased rates of recurrence and decreased efficacy of colchicine in recurrent pericarditis prevention.6,7 The effect of colchicine in the management of acute and recurrent pericarditis may be explained on examination of the pathophysiology governing these separate phases of the disease. Recurrent pericarditis is presumed to be an immune-mediated process.2,3,8 Colchicine concentrates in leukocytes, where it inhibits tubulin polymerization, decreases cell migration, and decreases metabolic activity, resulting in disruption of the inflammatory cycle.4,8 Therefore, the unique anti-inflammatory properties of colchicine make it an ideal drug to reduce the incidence of recurrence. In contrast, the etiology of acute pericarditis is typically attributed to infectious causes. It has been proposed that colchicine’s interference with leukocyte function may theoretically deter the clearance of infection, thus exacerbating the acute phase.2,8 Noting these differences, it is important to examine the potential utility of colchicine in both phases of pericarditis. Whereas gastrointestinal intolerance, including nausea, vomiting, and diarrhea is common, chronic administration of colchicine usually occurs without significant long-term adverse effects.9 Rare toxicities associated with colchicine include liver failure, bone marrow suppression, and myotoxicity. The risk of colchicine toxicity is increased in renal dysfunction and concomitant administration of cytochrome P450 3A4 and P-glycoprotein (P-gp) inhibitors.8 Growing evidence supporting the use of colchicine in pericarditis has been released since the publication of the guidelines a decade ago. The purpose of this review is to summarize and evaluate the safety and efficacy of colchicine for the acute treatment and prevention of pericarditis.

Literature Review A total of 16 case series and 5 prospective controlled trials were identified in the search. Initially, colchicine therapy was directed at prevention of recurrent pericarditis in

patients with multiple recurrences. These studies led to prospective controlled trials that examined colchicine for prevention of recurrence and treatment of acute symptoms in the setting of recurrence and the initial attack of pericarditis, summarized in Table 1.

Recurrent Pericarditis In 1987, Rodriguez de La Serna et al10 first reported using colchicine in 3 patients with at least 3 episodes of recurrence. Patients received colchicine 1 mg daily as an adjunct to corticosteroids, which were tapered over 2 months. No recurrence was reported during 15 to 35 months of followup.10 Guindo et al11 later studied a similar patient population consisting of 9 patients, with a minimum of 3 recurrences. Colchicine 1 mg daily was prescribed in addition to a corticosteroid taper. All patients had discontinued corticosteroids at 2 to 6 weeks (mean = 26.33 ± 10.9 days). During 10 to 54 months of follow-up, there were no reports of recurrence while receiving colchicine. The symptom-free interval was extended from 3.33 ± 4.3 months to 24.3 ± 16.1 months after colchicine initiation (P < 0.002).11 Several other small studies showed similar results of reduced recurrence with colchicine.7,12-14 In a 10-year multicenter retrospective study conducted by Adler et al,4 51 patients received colchicine 1 mg daily for an average of 12 months. Patients had 3.58 ± 3.64 recurrences despite treatment with NSAIDs, corticosteroids, or pericardiocentesis. New recurrences occurred at a rate of 14% (7 of 51 patients) during 1004 patient-months of colchicine therapy. The symptom-free interval increased from 3.1 months to 43 months after colchicine initiation (P < 0.0001). During 2333 patient-months of follow-up, 60.7% of patients had no reports of recurrence. Throughout the study, colchicine was discontinued in 39 patients (76.5%), and 14 of those patients (35.8%) relapsed. However, subsequent recurrences were generally mild and resolved by restarting colchicine. These promising results in early studies prompted initiation of the COlchicine for REcurrent pericarditis (CORE) trial followed by the COlchicine for Recurrent Pericarditis (CORP) trial.15,16 Both trials compared conventional therapy alone with conventional therapy in addition to weightadjusted colchicine dosing in patients with a first episode of recurrent pericarditis. Patients who weighed 70 kg received a 2 mg loading dose followed by 0.5 mg twice daily. The CORE trial was a prospective, randomized, openlabel study evaluating colchicine as an adjunct to conventional therapy for treatment of the first episode of recurrent pericarditis.15 In this trial, 84 patients were randomized to receive aspirin (prednisone as an alternative if contraindicated or intolerant) or aspirin plus weight-adjusted colchicine for 6 months. The primary outcome was rate of

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Annals of Pharmacotherapy 48(8)

Table 1.  Summary of Prospective Clinical Trials Clinical Trial Patient population Study groups: Colchicine + CT vs CTa; colchicine regimen Primary outcomec: recurrence rate (colchicine + CT vs CT) Other significant end points

Adverse events (colchicine + CT vs CT)

CORE15 (n = 84)

CORP16 (n = 120)

CORP217 (n = 240)

COPE18 (n = 120)

ICAP19 (n = 240)

First case of recurrent pericarditis LD: 1 to 2 mgb; MD: 0.5 to 1 mg dailyb; duration: 6 months (open-label) 24% vs 50.6% (P = 0.02, NNT 4)

First case of recurrent pericarditis LD: 1 to 2 mgb; MD: 0.5 to 1 mg dailyb; duration: 6 months (blinded) 24% vs 55% (P < 0.001, NNT 3)

Multiple recurrences of pericarditis (≥2) LD: None; MD: 0.5 to 1 mg dailyb; duration: 6 months (blinded)

Acute pericarditis

Acute pericarditis LD: None; MD: 0.5 to 1 mg dailyb; duration: 3 months (blinded)

21.6% vs 42.5% (P = 0.0009, NNT 5)

LD: 1 to 2 mgb; MD: 0.5 to 1 mg dailyb; duration: 3 months (open-label) 10.7% vs 32.3% (P = 0.004, NNT 5)

Significant reduction: symptom persistence at 72 hours

•• Significant reduction: symptom persistence at 72 hours, median number of recurrences per patient •• Significant increase: remission rate at 1 week, time to subsequent recurrence 7% vs 7% (P = 0.99)

•• Significant reduction: symptom persistence at 72 hours, recurrences per patient, diseaserelated hospitalizations •• Significant increase: remission rate at 1 week

16.7% vs 37.5% (P < 0.001, NNT 4); 9.2% vs 20.8% (P = 0.02, NNT 9) •• Significant reduction: •• Significant reduction: symptom persistence at symptom persistence 72 hours, recurrences at 72 hours per patient, diseaserelated hospitalizations •• Significant increase: remission rate at 1 week, time to first recurrence

8.3% vs 6.7% (P = NS)

11.7% vs 10% (P = 0.84)

7% vs 14% (P = 0.48)

11.7% vs 8.3% (P = 0.519)

Abbreviations: CORE, COlchicine for REcurrent pericarditis; CORP, COlchicine for Recurrent Pericarditis; COPE, COlchicine for PEricarditis; ICAP, Investigation on Colchicine for Acute Pericarditis; CT, conventional therapy; LD, loading dose; MD, maintenance dose; NNT, number needed to treat. a CT by study: CORE: aspirin 800 mg every 6 to 8 hours for 7 to 10 days, with gradual tapering over 3 to 4 weeks; or prednisone 1 to 1.5 mg/kg daily for 4 weeks, then gradually tapered for aspirin contraindication. All patients received gastroduodenal prophylaxis with omeprazole 20 mg daily. CORP: aspirin 800 to 1000 mg or ibuprofen 600 mg every 8 hours for 7 to 10 days, with gradual tapering over 3 to 4 weeks. If aspirin intolerant or contraindicated, prednisone 0.2 to 0.5 mg/kg daily for 4 weeks, then gradually tapered. All patients received gastroduodenal prophylaxis with a proton pump inhibitor. CORP2: aspirin 800 mg, ibuprofen 600 mg, or indomethacin 50 mg every 8 hours for 7 to 10 days, with gradual tapering over 3 to 4 weeks. If already taking corticosteroids or aspirin intolerant or contraindicated, prednisone 0.2 to 0.5 mg/kg daily for 4 weeks, then gradually tapered. All patients received gastroduodenal prophylaxis with a proton pump inhibitor. COPE: aspirin 800 mg every 6 to 8 hours for 7 to 10 days with gradual tapering over 3 to 4 weeks or prednisone 1 to 1.5 mg/kg daily for 2 to 4 weeks, then gradually tapered for aspirin intolerance or contraindication. All patients received gastroduodenal prophylaxis with omeprazole 20 mg daily. ICAP: aspirin 800 mg or ibuprofen 600 mg every 8 hours for 7 to 10 days, with gradual tapering over 3 to 4 weeks. If aspirin intolerant or contraindicated, prednisone 0.2 to 0.5 mg/kg daily for 2 weeks, then gradually tapered. All patients received gastroduodenal prophylaxis with a proton pump inhibitor. b Patients weighing 0.99), or constrictive pericarditis (P > 0.99). The rate of adverse events was similar between study groups, with the most common being gastrointestinal intolerance (colchicine 7% vs placebo 5%, P = 0.84). The rate of colchicine discontinuation was 8%. Although small studies supported the use of colchicine in cases of multiple recurrences, the CORE and CORP trials did not address this patient population. The Colchicine for

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Norrid and Oliphant Recurrent Pericarditis 2 (CORP-2) trial was conducted to assess the efficacy and safety of colchicine in 240 patients with 2 or more recurrences.17 In this randomized, placebocontrolled, double-blind study, patients were assigned to receive colchicine 0.5 to 1 mg daily or placebo for 6 months in combination with aspirin, ibuprofen, or indomethacin. Prednisone was given to patients already taking corticosteroids or as an alternative if contraindicated or intolerant to NSAIDs. The same weight-adjusted colchicine dosing seen in CORE and CORP was used, but the loading dose was eliminated. The primary outcome was the rate of recurrence, with the same secondary outcomes as the CORP trial. Patients were followed for a minimum of 18 months, with a mean follow-up of 20 months. Recurrence occurred in 21.6% of colchicine patients versus 42.5% of placebo patients (P = 0.0009; NNT = 5). Colchicine also decreased symptom persistence at 72 hours (19.2% vs 44.2%; P = 0.0001), number of recurrences per patient (0.28 vs 0.63; P = 0.0004), and disease-related hospital admissions (1.7% vs 10.0%; P = 0.013) as well as improved remission rates at 1 week (83.3% vs 59.2%; P = 0.0001). There was no statistically significant difference in time to first recurrence (P = 0.22), cardiac tamponade (P = 0.478), or constrictive pericarditis (P = 0.097). There was a similar rate of adverse events in each group (colchicine 11.7% vs placebo 8.3%, P = 0.519), with gastrointestinal intolerance reported most frequently.

Acute Pericarditis In a preliminary open-label study in acute pericarditis, 19 patients received colchicine (3 mg on day 1, 2 mg on days 2 and 3, followed by 1 mg daily) alone for 3 months. The recurrence rate was 10.5% after a mean follow-up of 5 months, which was less than the population observed rate of 15% to 32%.13 Based on the promising results from this preliminary study, subsequent prospective trials were designed to test this hypothesis. The COlchicine for PEricarditis (COPE) trial was a single-center, prospective, randomized, open-label trial evaluating colchicine as an adjunct to conventional therapy for the treatment of the first episode of acute pericarditis and prevention of recurrence.18 Here, 120 patients were randomly assigned to receive aspirin (prednisone as an alternative if contraindicated or intolerant) or aspirin plus colchicine for 3 months. The same weight-adjusted colchicine dosing seen in CORE and CORP was used. The primary outcome was rate of recurrence, and the secondary outcome was rate of symptom persistence at 72 hours. Patients were followed for a minimum of 8 months, with a mean follow-up of 24 months. During 2873 patient-months of follow-up, colchicine significantly reduced the rate of recurrence. At 18 months, 10.7% of colchicine patients and 32.3% of patients

receiving conventional therapy alone had recurrence (P = 0.004; NNT = 5). Colchicine significantly reduced symptom persistence at 72 hours (11.7% vs 36.7%, P = 0.003; NNT = 4) and resulted in a longer symptom-free interval compared with conventional therapy alone (22.9 ± 10.3 months vs 17.2 ± 12.3 months, P = 0.007). The rate of adverse events was similar between groups. Colchicine was discontinued in 5 cases (8.3%) because of diarrhea, with 2 patients experiencing relapse after discontinuation. The largest study to date, the Investigation on Colchicine for Acute Pericarditis (ICAP) trial was a multicenter, prospective, randomized, double-blind, placebo-controlled trial enrolling 240 patients.19 The purpose of the study was to evaluate colchicine for the treatment of the first episode of acute pericarditis and prevention of recurrence. Patients were randomly assigned to receive colchicine 0.5 to 1 mg daily or placebo for 3 months in combination with aspirin or ibuprofen (prednisone as an alternative if contraindicated or intolerant). The same weight-adjusted colchicine dosing seen in CORE and CORP was used, but the loading dose was eliminated. The primary outcome was the composite rate of incessant or recurrent pericarditis. Secondary outcomes were the same as those in the CORP trial. Patients were followed for a minimum of 18 months, with a mean follow-up of 22 months. The primary outcome occurred in 20 of 120 colchicinetreated patients and 45 of 120 placebo patients (16.7% vs 37.5%, P < 0.001; NNT = 4). Colchicine significantly reduced the rate of recurrent pericarditis alone (9.2% vs 20.8%, P = 0.02; NNT = 9). Other end points favoring colchicine included decreased symptom frequency at 72 hours (19.2% vs 40%, P = 0.001; NNT = 4), number of recurrences per patient (0.21 vs 0.52, P = 0.001), and diseaserelated hospitalizations (5% vs 14.2%, P = 0.02; NNT = 11). Colchicine also improved remission rates at 1 week (85% vs 58.3%, P < 0.001) and prolonged the time to first recurrence (24.7 weeks vs 17.7 weeks, P < 0.001). There was a low incidence of cardiac tamponade and constrictive pericarditis, with no significant difference between groups. The rate of adverse events was similar (colchicine 11.7% vs placebo 10%, P = 0.84), with gastrointestinal disturbances occurring most frequently.

Discussion In CORE, CORP, CORP-2, COPE, and ICAP, weightadjusted colchicine added to conventional therapy had similar rates of adverse events compared with conventional therapy alone. The overall incidence of colchicine discontinuation or dose reduction occurred in ~8% of colchicinetreated patients, largely as a result of gastrointestinal intolerance, in contrast to early studies with non-weightadjusted colchicine, with a discontinuation or dose reduction rate of 10% to 14%. The initial use of weight-adjusted

1054 dosing appears to almost halve the rate of colchicine discontinuation or dose reduction resulting from adverse events.8,15-19 In CORP-2 and ICAP, eliminating the colchicine loading dose had no effect on the efficacy or the rate of adverse events; therefore, a loading dose may not be necessary.17,19 Although these trials demonstrate positive results, there are several limitations to consider. Patients with a serum creatinine >2.5 mg/dL, severe liver disease, or aminotransferase levels >1.5 times the upper limit of normal were excluded because of safety concerns.15-19 In addition, patients with neoplastic or bacterial pericarditis were also excluded.15-19 All the prospective studies are relatively small, and the earliest studies (COPE, CORE) had an openlabel study design.15,18 Another limitation is the fact that all the prospective trials were conducted in Northern Italy using colchicine 0.5 mg tablets, which are not commercially available in the United States. Despite these limitations, the benefits of colchicine have been consistent in all the prospective trials.

Summary The recurrence of pericarditis creates a high disease burden and worsening quality of life. Clinical trials have shown that patients treated with colchicine have faster resolution of symptoms and lower rates of recurrence, thereby reducing the overall burden of disease and improving quality of life. Weight-adjusted colchicine is generally well tolerated, with low rates of adverse events, and should be continued for 3 months in the setting of acute pericarditis and for 6 months after recurrent pericarditis. Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The authors received no financial support for the research, authorship, and/or publication of this article.

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