1 A Review of Pericarditis Steven Du LMPS Resident January 21 st, 2013

2 Objective Discuss the etiology, clinical presentation, and diagnostic evaluation of pericarditis Discuss the treatment options and monitoring for acute pericarditis

Our Patient – SF 3 ID56 year old female admitted on Jan 10 th 2014 to CCU CCPleuritic chest pain 7/10 HPINew onset of pleuritic chest pain in last 2 days that worsened when reclined. AllergiesNKA SocialNonsmoker, social EtOH

Background Pericardium: double layer membrane over the heart Functions –Promotes efficiency by limiting acute dilation –Barrier against infections and external friction –Fixed position anatomically Acute inflammation of the pericardial sac –Increased production of pericardial fluid –Chronic inflammation can lead to fibrosis 4

Etiology Majority of acute pericarditis is of viral or idiopathic origin. Other causes –Autoimmune –Tuberculosis –Uremia –MI or secondary to cardiac trauma 5

Clinical features Pleuritic chest pain Pericardial friction rub ECG changes: diffuse ST elevation present in most leads New or worsening pericardial effusion Diagnostic criteria: at least 2 of 4 6

Laboratory and Imaging Echocardiogram: look for pericardial effusion and tamponade Troponins may be elevated if there is myocardial involvement Signs of inflammation: elevated WBC, ESR, CRP 7

Prognosis and complications Generally a self limited disease responsive to medical therapy Pericardial effusion and tamponade Constrictive pericarditis (<1%) Recurrent pericarditis –Reports of incidence vary from 15-50% –Use of glucocorticoids and poor response to initial NSAID therapy predictor of recurrence 8 j.amjcard

Myocardial Involvement: Myopericarditis Inflammation of heart muscle itself Often subclinical, may present as symptoms of heart failure. Generally treated as pericarditis if ventricular function is preserved Specific therapy aimed at treating underlying cause and HF if applicable 9

Standard Care: Acute Pericarditis Nonpharmacological therapy –Strenuous physical activity should be avoided until symptom resolution –Unclear exact role of physical activity in recurrence of pericarditis, but some patients report worsening of symptoms provoked by exercise 10

Standard Care: Acute Pericarditis NSAIDs –First line for pain relief and inflammation –No evidence they alter the course of disease –90% patients experience symptom relief within 7 days of treatment –No strong RCT evidence, dosing based on cohort studies and expert consensus 11 Mayo Clin Proc June; 85(6): 572–593.

Standard Care: Acute Pericarditis Corticosteroids –Second line for symptomatic patients refractory to standard therapy –Use for known autoimmune etiology e.g. SLE, vasculitis –Corticosteroids independent risk factor for recurrent pericarditis 12

Colchicine Recurrent pericarditis thought to be an idiopathic immune mediated inflammatory condition Colchicine first tested in 1987 in patients with persistent recurrence due to success with FMF Proposed mechanism: inhibition of microtubule self assembly by binding to b-tubulin in leukocytes and disrupting leukocyte motility and phagocytosis 13 Eur Heart J (2009) 30 (5):

Review of Systems VitalsBP: 110/75 HR: 105 RR: 19 O2 Sat: 97% RA Temp: 37.5 CNS/HEENTA/O X3 RespiratorySOBOE, mild crackles CVSNormal S1, S2. Pericardial rub present. JVP 2cm, Ø peripheral edema. Pleuritic chest pain Troponin <0.05 ECG: Sinus rhythm Echocardiogram: Normal biventricular function. Mild pericardial effusion present GI/GUUnremarkable Liver/EndoUnremarkable ChemistryNa 138 K 3.8 Cl 102 HCO3 28, Cr 71, BUN 3 CBCWBC 12.9, Neutrophils 9.1, Hgb 126, Platelets

PMH and Medications PMHMPTA Ulcerative ColitisIn remission AsthmaFluticasone/Salmeterol Inh 500/50 BID Salbutamol Inh 200 ug q4-6h prn DepressionSertraline 25mg QHS Trazodone 100mg QHS InsomniaZopiclone 22.5mg daily PericarditisASA 650mg po QID GI protectionPantoprazole 40mg daily 15

Goals of therapy Symptom management Reduce recurrence Reduce complications Minimize ADR 16

Drug Therapy Problems Patient is experiencing pericarditis and would benefit from reassessment of her drug therapy 17

Clinical Question P 56 year old female with first episode of pericarditis I NSAIDs + Colchicine C NSAIDs alone O Symptom control Time to remission Recurrent pericarditis Complications such as constrictive pericarditis or tamponade 18

Literature Search Searched: Medline, Embase Terms: pericarditis, NSAIDs, colchicine, Limits: Humans, English, RCT, Meta- analysis, Systematic review Results: 4 RCT, 1 meta analysis 19

CORE: Imazio et al Trial DesignOpen label RCT performed in Italy. PatientsN=84 Adults with first recurrent episode of pericarditis of idiopathic, viral, or autoimmune etiology Exclusion: tuberculosis, neoplastic, or purulent pericarditis, severe renal or hepatic dysfunction Intervention Comparator Colchicine 1-2mg stat and 0.5 – 1mg daily for 6 months Placebo Both arms received ASA 800mg q8h x 7-10 days + taper x 3-4 weeks or prednisone 1.0 to 1.5 mg/kg per day for 4 weeks + taper if ASA contraindicated. Both arms get PPI Outcomes Primary Secondary Recurrent or incessant pericarditis at 18 month follow up Remission at 72hrs, number of recurrences, time to first recurrence, hospitalization, tamponade, constrictive pericarditis, adverse effects

Results Recurrence rate at 18 months: 50.6% (control) vs. 24%(Intervention) (p=0.02) Symptom persistence at 72 hours: 31%(control) vs 10%(intervention) (p=0.03) No difference in minor or major adverse effects 21

COPE: Imazio et al Trial DesignOpen label RCT performed in Italy. PatientsN=120 Adults with first episode of pericarditis of idiopathic, viral, or autoimmune etiology Exclusion: tuberculosis, neoplastic, or purulent pericarditis, severe renal or hepatic dysfunction Intervention Comparator Colchicine 1-2mg stat and 0.5 – 1mg daily for 3 months Placebo Both arms received ASA 800mg q8h x 7-10 days + taper x 3-4 weeks or prednisone 1.0 to 1.5 mg/kg per day for 4 weeks + taper if ASA contraindicated Outcomes Primary Secondary Recurrent or incessant pericarditis at 18 month follow up Remission at 72hrs, number of recurrences, time to first recurrence, hospitalization, tamponade, constrictive pericarditis

Results Recurrence at 18 months: 32.3%(control) vs. 10.7% (intervention) p = Symptom persistence at 72hr: 36.7%(control) vs. 11.7%(intervention) p=0.003 No difference in minor or major adverse effects ITT analysis with minimal loss to follow up 23

Results Corticosteroid use found to be an independent risk factor for recurrence in both trials on logistic regression –Issues: patients were not randomized between corticosteroid vs. ASA –Potential etiology: promotes viral replication Age, gender, presence of pericardial effusion or tamponade not significant risk factors

Limitations Open label. Subjective symptom reporting. Vague definition of “major adverse effect” Potentially underpowered to find serious adverse effects 25

CORP: Imazio et al Trial DesignDouble Blind multicenter RCT performed in Italy PatientsN=120 (Mean age 47) Adults with first recurrent episode of pericarditis of idiopathic, viral, or autoimmune etiology Exclusion: tuberculosis, neoplastic, or purulent pericarditis, severe renal or hepatic dysfunction. Intervention Comparator Colchicine 1-2mg stat and 0.5 – 1mg daily for 6 months Placebo Both arms received ASA 800mg or Ibuprofen 600mg q8h x 7-10 days + taper x 3-4 weeks or prednisone 0.2 to 0.5 mg/kg per day for 4 weeks + taper if ASA contraindicated. Both arms get PPI Outcomes Primary Secondary 18 month follow up Recurrent or incessant pericarditis Remission at 1 week, number of recurrences, time to first recurrence, hospitalization, tamponade, constrictive pericarditis

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Safety 29

ICAP: Imazio et al Trial DesignDouble Blind multicenter RCT performed in Italy. PatientsN=240 (Mean age 52) Adults with first episode of pericarditis of idiopathic, viral, or autoimmune etiology Exclusion: tuberculosis, neoplastic, or purulent pericarditis, severe renal or hepatic dysfunction, myocarditis Intervention Comparator Colchicine 0.5 – 1mg daily for 3 months Placebo Both arms received ASA 800mg or Ibuprofen 600mg q8h x 7-10 days + taper x 3-4 weeks or prednisone 0.2 to 0.5 mg/kg per day for 4 weeks + taper if ASA contraindicated. Both arms get PPI Outcomes Primary Secondary 18 month follow up Recurrent or incessant pericarditis Remission at 1 week, number of recurrences, time to first recurrence, hospitalization, tamponade, constrictive pericarditis

Results 31

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Safety 33

Conclusions Colchicine had a significant benefit on symptom persistence at 72 hours as well as recurrence No significant difference in safety outcomes, similar discontinuation compared to placebo No significant difference found in complications 34

Limitations Did not assess acute effect on pain Strict exclusion criteria Potentially underpowered for detection of serious adverse events and complications All studies performed by one group in Italy 35

Meta Analysis: Imazio et al PatientsN=795 Patients undergoing cardiac surgery (primary prevention) Patients with pericarditis (secondary prevention Study Type5 Randomized controlled trials Various doses/durations of colchicine versus placebo DatabasesMedline, Embase, Cochrane library OutcomesRecurrent pericarditis Adverse events

Results: Risk of Pericarditis 37

Results: Adverse events 38 Drug withdrawal: RR=1.85 (CI ) p = 0.04 Primarily due to GI intolerance

Recommendation Patient would benefit from colchicine therapy for prevention of recurrence and higher likelyhood of remission at 72hrs Fits study criteria well Colchicine 1mg right away, then 0.5mg daily x 3 months. 39

Treatment Summary NSAIDs –ASA 800mg q8h x 7-10 days (preferred following MI) Taper by 800mg weekly over 3-4 weeks when patient symptom free –Ibuprofen 600mg q8h x 7-10 days Taper by 600mg weekly over 3-4 weeks when patient symptom free –Indomethacin 50mg q8h x 7-14 days Taper by 25-50mg q2-3 days No head to head or placebo controlled trials Routine GI protection with PPI 40 N Engl J Med 2004; 351:2195.

Treatment Summary: Corticosteroids Second line for patients with symptoms refractory to NSAIDS or contraindication to NSAIDs. Use for known autoimmune or connective tissue etiology e.g. SLE or vasculitis Associated with increased rate of recurrence from multivariate regression –OR: 2.89; 95% CI, (CORE) –OR: 4.30; 95% CI, (COPE) –Non-randomized data! 41

Treatment Summary: Corticosteroids Corticosteroid dosing –ESC Guideline recommends 1mg/kg/day for 2-4 weeks and tapering over 3 months –Retrospective study compared prednisone 1mg/kg/day to mg/kg/day Patients with recurrent pericarditis who are intolerant to or failed on NSAIDs Baseline characteristics: more females and older in high dose group Higher recurrence rate in 1mg/kg/day group after adjustment for confounders Did not report on treatment success of index event 42 Circulation. 2008;118:

Treatment Summary: Corticosteroids Unfortunately potential bias from retrospective nature Guideline recommendation is no more evidence based – based on one prospective cohort of 12 Recommend dose as used in CORP/ICAP –Prednisone mg/kg/day x 2-4 weeks –Taper by 5-10mg q1-2 weeks if asymptomatic 43

Treatment Summary Colchicine as adjunct therapy –Reduces recurrence in patients with first episode (NNT = 4) or recurrent pericarditis (NNT= 3) –Reduces symptom persistence at 72 hours –No significant difference in safety outcomes, more discontinuation compared to placebo 44

Treatment Summary Colchicine as adjunct therapy –First episode: 1-2mg x 1 dose mg daily x 3 months Patients <70kg or poor tolerance should receive 0.5mg –Recurrent episode:1-2mg x 1 dose mg daily x 6 months –Adverse effects: NVD, bone marrow suppression, hepatotoxicity, myalgia, renal insufficiency –Drug interactions: CYP3A4 substrate, P-glycoprotein substrate Statins, Macrolide antibiotics, cyclosporine, verapamil, amiodarone 45

Impact on practice Strong evidence to use colchicine adjunctively for first episode and recurrent pericarditis patients who fit study criteria No recent guidelines to reflect new evidence Uptodate: “we recommend that colchicine be added to NSAIDs in the management of a first episode of acute pericarditis” 46

Monitoring 47 Efficacy Improvement in pleuritic chest pain and rub Daily Normalization in EchocardiogramRepeat in 1 week Normalization in ECG findingsRepeat in 1 week Inflammatory biomarkers: CBC, ESR, CRP Repeat in 1 week Safety N/V/DDaily MyopathyDaily Serum creatinineRepeat in 1 week Liver function testsRepeat in 1 week

Questions? 48

References 1. Imazio M, Brucato A, Cemin R, Ferrua S, Maggiolini S, Beqaraj F, et al. A Randomized Trial of Colchicine for Acute Pericarditis. New England Journal of Medicine Oct 17;369(16):1522–8. 2. Imazio M, Bobbio M, Cecchi E, Demarie D, Pomari F, Moratti M, et al. Colchicine as first-choice therapy for recurrent pericarditis: results of the CORE (COlchicine for REcurrent pericarditis) trial. Archives of internal medicine. 2005;165(17): Imazio M, Brucato A, Cemin R, Ferrua S, Belli R, Maestroni S, et al. Colchicine for recurrent pericarditis (CORP) a randomized trial. Annals of internal medicine. 2011;155(7):409– Imazio M. Colchicine in Addition to Conventional Therapy for Acute Pericarditis: Results of the COlchicine for acute PEricarditis (COPE) Trial. Circulation Sep 27;112(13):2012–6. 5. Imazio M, Spodick DH, Brucato A, Trinchero R, Adler Y. Controversial Issues in the Management of Pericardial Diseases. Circulation Feb 22;121(7):916– Imazio M, Brucato A, Cumetti D, Brambilla G, Demichelis B, Ferro S, et al. Corticosteroids for Recurrent Pericarditis: High Versus Low Doses: A Nonrandomized Observation. Circulation Aug 5;118(6):667– Imazio M, Brucato A, Forno D, Ferro S, Belli R, Trinchero R, et al. Efficacy and safety of colchicine for pericarditis prevention. Systematic review and meta-analysis. Heart Mar 22;98(14):1078– Imazio M, Brucato A, Barbieri A, Ferroni F, Maestroni S, Ligabue G, et al. Good Prognosis for Pericarditis With and Without Myocardial Involvement: Results From a Multicenter, Prospective Cohort Study. Circulation May 24;128(1):42–9. 9. Maisch B, Seferovic PM, Ristic AD, et al. Guidelines on the Diagnosis and Management of Pericardial Diseases Executive SummaryThe Task Force on the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology. European Heart Journal Apr;25(7):587– Seferović PM, Ristić AD, Maksimović R, Simeunović DS, Milinković I, Seferović Mitrović JP, et al. Pericardial syndromes: an update after the ESC guidelines Heart Failure Reviews Aug 2;18(3):255– Guindo J, Rodriguez de la Serna A, Ramio J, de Miguel Diaz MA, Subirana MT, Perez Ayuso MJ, et al. Recurrent pericarditis. Relief with colchicine. Circulation Oct 1;82(4):1117– Lange RA, Hillis LD. Clinical practice. Acute pericarditis. N Engl J Med 2004; 351: