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A Review of Pericarditis
Steven Du
LMPS Resident
January 21st, 2013
1
Objective
• Discuss the etiology, clinical presentation,
and diagnostic evaluation of pericarditis
• Discuss the treatment options and
monitoring for acute pericarditis
2
Our Patient – SF
ID
56 year old female admitted on Jan 10th 2014 to CCU
CC
Pleuritic chest pain 7/10
HPI
New onset of pleuritic chest pain in last 2 days that worsened
when reclined.
Allergies
NKA
Social
Nonsmoker, social EtOH
3
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
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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
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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
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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
8
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
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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
Mayo Clin Proc. 2010 June; 85(6):
572–593.
11
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
Eur Heart J (2009) 30 (5): 532-539.
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Review of Systems
Vitals
BP: 110/75 HR: 105 RR: 19 O2 Sat: 97% RA Temp: 37.5
CNS/HEENT
A/O X3
Respiratory
SOBOE, mild crackles
CVS
Normal 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/GU
Unremarkable
Liver/Endo
Unremarkable
Chemistry
Na 138 K 3.8 Cl 102 HCO3 28, Cr 71, BUN 3
CBC
WBC 12.9, Neutrophils 9.1, Hgb 126, Platelets 333
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PMH and Medications
PMH
MPTA
Ulcerative Colitis
In remission
Asthma
Fluticasone/Salmeterol Inh 500/50 BID
Salbutamol Inh 200 ug q4-6h prn
Depression
Sertraline 25mg QHS
Trazodone 100mg QHS
Insomnia
Zopiclone 22.5mg daily
Pericarditis
ASA 650mg po QID
GI protection
Pantoprazole 40mg daily
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Goals of therapy
•
•
•
•
Symptom management
Reduce recurrence
Reduce complications
Minimize ADR
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Drug Therapy Problems
• Patient is experiencing pericarditis and
would benefit from reassessment of her
drug therapy
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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
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Literature Search
• Searched: Medline, Embase
• Terms: pericarditis, NSAIDs, colchicine,
• Limits: Humans, English, RCT, Metaanalysis, Systematic review
• Results: 4 RCT, 1 meta analysis
19
CORE: Imazio et al. 2005
Trial Design
Open label RCT performed in Italy.
Patients
N=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
20
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. 2005
Trial Design
Open label RCT performed in Italy.
Patients
N=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
22
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
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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
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CORP: Imazio et al. 2011
Trial Design
Double Blind multicenter RCT performed in Italy
Patients
N=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
18 month follow up
Recurrent or incessant pericarditis
Secondary
Remission at 1 week, number of recurrences, time to first
recurrence, hospitalization, tamponade, constrictive
pericarditis
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Safety
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ICAP: Imazio et al. 2013
Trial Design
Double Blind multicenter RCT performed in Italy.
Patients
N=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
18 month follow up
Recurrent or incessant pericarditis
Secondary
Remission at 1 week, number of recurrences, time to first
recurrence, hospitalization, tamponade, constrictive
pericarditis
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Results
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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
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Meta Analysis: Imazio et al. 2012
Patients
N=795
Patients undergoing cardiac surgery (primary prevention)
Patients with pericarditis (secondary prevention
Study Type
5 Randomized controlled trials
Various doses/durations of colchicine versus placebo
Databases
Medline, Embase, Cochrane library
Outcomes
Recurrent pericarditis
Adverse events
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Results: Risk of Pericarditis
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Results: Adverse events
Drug withdrawal:
RR=1.85 (CI 1.04-3.29)
p = 0.04
Primarily due to GI
intolerance
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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.
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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.
40
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!
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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
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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
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 + 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
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”
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Monitoring
Efficacy
Improvement in pleuritic chest
pain and rub
Daily
Normalization in Echocardiogram Repeat in 1 week
Normalization in ECG findings
Repeat in 1 week
Inflammatory biomarkers: CBC,
ESR, CRP
Repeat in 1 week
Safety
N/V/D
Daily
Myopathy
Daily
Serum creatinine
Repeat in 1 week
Liver function tests
Repeat in 1 week
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Questions?
48
References
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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.
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