A Review of Pericarditis

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

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

3. Our Patient – SF

4. 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

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

6. 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

7. 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

8. 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 j.amjcard.2005.04.055

9. 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

10. 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

11. 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 Mayo Clin Proc. 2010 June; 85(6): 572–593.

12. 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

13. 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 Eur Heart J (2009) 30 (5): 532-539.

14. Review of Systems

15. PMH and Medications

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

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

18. Clinical Question

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

20. CORE: Imazio et al. 2005

21. 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

22. COPE: Imazio et al. 2005

23. Results • Recurrence at 18 months: 32.3%(control) vs. 10.7% (intervention) p = 0.004 • 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

24. 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

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

26. CORP: Imazio et al. 2011

29. Safety

30. ICAP: Imazio et al. 2013

31. Results

33. Safety

34. 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

35. 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

36. Meta Analysis: Imazio et al. 2012

37. Results: Risk of Pericarditis

38. Results: Adverse events Drug withdrawal: RR=1.85 (CI 1.04-3.29) p = 0.04 Primarily due to GI intolerance

39. 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.

40. 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 N Engl J Med 2004; 351:2195.

41. 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, 1.10-8.26 (CORE) • OR: 4.30; 95% CI, 1.21-15.25 (COPE) • Non-randomized data!

42. 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 0.2-0.5mg/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 Circulation. 2008;118:667-671

43. 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 0.2-0.5mg/kg/day x 2-4 weeks • Taper by 5-10mg q1-2 weeks if asymptomatic

44. 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

45. Treatment Summary • Colchicine as adjunct therapy • First episode: 1-2mg x 1 dose + 0.5-1mg daily x 3 months • Patients <70kg or poor tolerance should receive 0.5mg • Recurrent episode:1-2mg x 1 dose + 0.5-1mg 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

46. 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”

47. Monitoring

48. Questions?

49. 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. 2013 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):1987. • 3. 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):409–14. • 4. Imazio M. Colchicine in Addition to Conventional Therapy for Acute Pericarditis: Results of the COlchicine for acute PEricarditis (COPE) Trial. Circulation. 2005 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. 2010 Feb 22;121(7):916–28. • 6. 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. 2008 Aug 5;118(6):667–71. • 7. 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. 2012 Mar 22;98(14):1078–82. • 8. 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. 2013 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. 2004 Apr;25(7):587–610. • 10. Seferović PM, Ristić AD, Maksimović R, Simeunović DS, Milinković I, Seferović Mitrović JP, et al. Pericardial syndromes: an update after the ESC guidelines 2004. Heart Failure Reviews. 2012 Aug 2;18(3):255–66. • 11. 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. 1990 Oct 1;82(4):1117–20. • 12. Lange RA, Hillis LD. Clinical practice. Acute pericarditis. N Engl J Med 2004; 351:2195.