13

pericarditis following cardiac procedures, as they

are often underdiagnosed or misdiagnosed. Antiinflammatory prophylaxis, such as colchicine, can be

considered to prevent post–cardiac injury pericarditis,

although data supporting this approach are limited.

Traditionally, for patients deemed to be nonresponders

to first-line dual therapy (experiencing recurrence or

intolerance to treatment with first-line agents), corticosteroids were added to the treatment regimen. Low to

moderate doses of corticosteroids (eg, prednisone 0.2-0.5

mg/kg/day) are initiated and maintained until clinical

remission, followed by a slow tapering over months

(Table 5).22 Corticosteroids are prescribed with caution

because of the plethora of known side effects, such as

weight gain, hypertension, hyperglycemia, osteoporosis,

increased risk of infections, gastrointestinal ulcers, and

risk of adrenal suppression. Pharmacological prophylaxis

for pneumocystis pneumonia and osteoporosis should be

considered for patients requiring glucocorticoid doses

equivalent to >20 mg of prednisone for 1 month or longer.

Anti–interleukin-1 (anti–IL-1) agents have been demonstrated in several recent phase 3 randomized clinical trials

to have strong efficacy in pericarditis patients with

elevated CRP (>1 mg/dL or >10 mg/L) to achieving clinical

remission, improve symptoms, reduce recurrences, and

normalize inflammatory markers while maintaining good

safety profile.1,24-26 As a result, there has been a recent

paradigm shift in managing patients with the inflammatory

phenotype (fever and/or elevation of CRP and/or CMR imaging evidence of pericardial inflammation) who meet the

TABLE 6 Common Therapeutic Options for Acute Pericarditis and Recurrent Pericarditis

Therapy Dosing Duration* Tapering Monitoring† LOE‡

Aspirin§,k 500-1,000 mg 3 times daily wks (acute) to mo (recurrent) Weekly Needed A

Ibuprofen§,k 600-800 mg 3 times daily wks (acute) to mo (recurrent) Weekly Needed A

Indomethacink 25-50 mg 3 times daily wks (acute) to mo (recurrent) Weekly Needed B

Colchicine§,¶ 0.6 mg twice daily or 0.6 mg once daily

(<70 kg, severe renal/hepatic impairment)

3 mo (acute),

6-12 mo (recurrent)

May be considered Needed A

Prednisone# 0.2-0.5 mg/kg/d wks to mo Several mo Needed B

Anti–IL-1 agents**

Anakinra 1-2 mg/kg/d up to 100 mg/d in adults >12 mo Needed Needed A

Rilonacept 320 mg once followed by 160 mg weekly >12 mo Stopping vs tapering under

investigation

Needed A

Goflikicept (Not yet available

in United States)

80 mg every 2 wks >12 mo (under investigation) Unknown Needed B

Azathioprine Starting with 1 mg/kg per d then gradually

increased to 2-3 mg/kg/d

Several mo Several mo Needed C

IVIG 400 to 500 mg/kg IV daily for 5 d 5 d Not required Needed C

Radical pericardiectomy High-volume pericardial surgical centers Not applicable Not applicable Needed C

Adapted with permission from Klein et al.1

*Therapy duration at initial dosing; duration of therapy is until clinical remission (typically longer times for recurrent cases).

†Monitoring is mandatory for all medications and may include assessment of blood count, renal function, creatine kinase, liver enzymes, lipid profile, and echocardiography, along with

C-reactive protein and sedimentation rate to monitor pericarditis response to therapy or diagnose recurrence.

‡A ¼ Data derived from multiple randomized clinical trials or meta-analyses. B ¼ Data derived from a single randomized clinical trial or large nonrandomized studies (in this review, a

study with $100 patients is considered "large"). C ¼ Consensus of opinion of experts and/or small studies, retrospective studies, and registries.

§Ibuprofen and aspirin are common first-level treatments for the first episode of pericarditis (acute pericarditis) associated with colchicine for 3 months (usually longer times for

recurrent cases). Aspirin often considered when patients are already on or have another indication to be on aspirin. Aspirin can be given as 325-650 mg 3 times daily.

kIn patients with a relative contraindication to NSAIDs (such as heart failure, chronic kidney disease, peptic ulcer disease, bleeding diathesis or cancer-related hypercoagulability, or

when coprescribing with diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcineurin inhibitors or anticoagulants), NSAIDs should be prescribed at

the lowest effective dose and for the shortest duration possible, and alternatives should be considered (such as high-dose aspirin in those without elevated bleeding risk).

¶Dose reductions (0.3-0.6 mg daily) should be considered when coprescribing colchicine with potent inhibitors of P-glycoprotein (P-gp) and/or cytochrome P450 3A4 (CYP3A4) to

improve tolerability and reduce the risk of toxicity. Of note, dose reduction for drug–drug interactions was not evaluated in colchicine pericarditis clinical trials. Adjusting concomitant

medications (via therapeutic substitutions that avoid P-gp or CYP3A4 interactions) can also be considered to maximize the tolerated dose of colchicine prescribed. #

Increased risk of recurrence if used in first episode pericarditis.

**Before starting anti-IL-1 agents, patients should be screened to be negative for hepatitis, human immunodeficiency virus, and tuberculosis.

IL-1 ¼ interleukin-1; IV ¼ intravenous; IVIG ¼ intravenous immunoglobulin; LOE ¼ Level of Evidence; NSAID ¼ nonsteroidal anti-inflammatory drug.

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aforementioned indications for corticosteroids or have

become steroid-dependent, for the initiation of novel

therapies targeted at the autoinflammatory process. These

agents should be considered the preferred option over

corticosteroids in this setting (Figure 8). Typically, other

anti-inflammatories may be sequentially weaned off once

established on anti-IL-1 agents (such as prednisone, then

NSAID, then colchicine), although colchicine may sometimes be continued, with some limited evidence for additive or synergistic benefits, further reducing recurrence

compared with using an anti–IL-1 agent alone, particularly

with anakinra.27,28 The optimal treatment duration with

anti–IL-1 therapies remains uncertain, as recurrence rates

are very low while on treatment, and many patients

(w50%-75%) have recurrence upon discontinuation. A

recently published long-term extension of the RHAPSODY

(Rilonacept in Acute Pericarditis Study) trial25 supports

prolonged therapy beyond 18 months to achieve a better

and prolonged control of the disease,29 and further

research is necessary to determine the optimal treatment

duration and stopping or weaning method for each anti–IL1 agent. In contrast, low-dose corticosteroids are typically

utilized for patients lacking evidence of the inflammatory

phenotype, as autoimmune mechanisms are presumed to

play a more significant role in these patients (Table 5 and

Figure 8).1

Azathioprine and intravenous immunoglobulins may

also be considered for patients who fail corticosteroids

and anti–IL-1 agents.30 Radical pericardiectomy on cardiopulmonary bypass can be considered as a last resort or

alternative option at high-volume experienced pericardial

surgical centers, especially when patients fail to respond

to the aforementioned pharmacotherapies, have contraindications to conventional therapy, or desire pregnancy.

In this setting, anti-inflammatory medications, including

corticosteroids and/or anti–IL-1 agents, may be continued

until surgery to dampen inflammation as much as

possible, and may be continued for 3 to 6 months as

indicated for ongoing symptoms of pericardial inflammation or active inflammation noted on the pericardial

pathology. Novel risk scores including machine learning

models have been developed to help with risk prognostication of recurrent pericarditis flares to guide

management.31

FIGURE 8 Proposed Schematic Algorithm for Treatment of Recurrent Pericarditis

Initial Treatment: NSAID or aspirin plus colchicine

Response?

Tapering Inflammatory Phenotype

Refractory cases

Yes No

Add corticosteroid†

Consider anti-IL-1 agent*

Consider radical pericardiectomy

(at high volume surgical centers)

Yes No

Add anti-IL-1 agent*

• Rilonacept

• Anakinra

• Goflikicept

Consider corticosteroid†

*Anti–IL-1 agent: rilonacept $12 months, anakinra and goflikicept $12 months, can be years or long-term. †Corticosteroids: start at moderate dose, slow

taper over months. Adapted with permission from Klein AL, et al.1 IL-1 ¼ interleukin-1; NSAID ¼ nonsteroidal anti-inflammatory drug.

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4.3. Complications of Pericarditis

4.3.1. Pericardial Effusion

Pericardial effusion is defined by the accumulation of >50

mL of fluid in the pericardial space and can be a result of

numerous pathologies.3,7 Approximately one-half of

pericardial effusions are idiopathic, and in North America

and Western Europe, postviral infection is the most

common identifiable cause, whereas tuberculosis is the

most common cause in places where it is endemic

(Table 2).30,32 Malignancies are also an important cause of

pericardial effusion and can present as an inflammatory

effusion with negative cytology for cancer.33,34

The objectives of imaging pericardial effusions are to

support diagnosis, evaluate the size and location of the

effusion, assess its hemodynamic impact, and inform

decisions regarding drainage, if indicated (Tables 7

and 8).1 TTE is the first-line imaging investigation

because it is readily available and accurately achieves

these objectives). The size of a pericardial effusion is

determined by measuring the greatest diameter perpendicular to the epicardium and parietal pericardium at

end-diastole or -systole adjacent to ventricles and

atria, respectively, with the following categories: trivial

(<1.0 cm and not visualized throughout cardiac cycle),

small (<1.0 cm), moderate (1.0-1.9 cm), large (2.0-2.5 cm),

and very large (>2.5 cm) (Figure 9).3 Common mimickers

of a pericardial effusion echocardiography are a left

pleural effusion, which is posterior to the descending

thoracic aorta on a parasternal long-axis view, and an

epicardial fat pad, which has a heterogenous echodensity,

moves with the myocardium, and is often located anterior

to the right ventricle.

CCT is a second-line investigation, and potential advantages include further delineation of the size and

extent of a pericardial effusion, characterizing pericardial

fluid based on Hounsfield units, informing secondary

causes such as malignancy, and guiding drainage (Tables 7

to 9).1,35 CMR imaging is also a second-line investigation

that has the additional advantage of assessing for pericardial inflammation and constriction (Tables 7 to 9).19

4.3.2. Cardiac Tamponade and Pericardiocentesis

The hemodynamic consequences of a pericardial effusion

are more closely related to the rapidity of fluid accumulation within the pericardium, not the absolute fluid volume because pericardial compliance can increase when

TABLE 7 Multimodality Imaging Protocols for Pericardial Effusions

Echocardiography CCT CMR

2D with respirometer

n Size and characterize PEff in multiple projection

off-axis views

n Right ventricle diastolic chamber collapse with CTP

n Respirophasic septal shift and IVC dilatation with CTP,

ECP, and TCP

n Identify pocket with clear path of vital structures for

pericardiocentesis

Noncontrast ECG-gated (single phase)

n Distinguish mimickers

n Detect pericardial calcification or hemorrhage

Cine white-blood imaging  tagging

n Detect and size PEff

n Distinguish mimickers

n Evaluate for ECP and TCP (freebreathing sequence)

n Assess pericardial thickness and

identify adhesions (tagging)

M-mode with respirometer

n Higher sensitivity for diastolic chamber collapse with CTP

n Higher sensitivity for respirophasic septal shift with CTP,

ECP, and TCP

Arterial ECG-gated (single or multiphase)

n Detect, size, and characterize content of PEff

n Identify secondary causes and mimickers

n Evaluate pericardial thickness

T1W BB ( T1 mapping)

n Detect and characterize PEff

n Identify secondary causes and

mimickers

Doppler with respirometer

n Respirophasic changes in atrioventricular and hepatic vein

velocities with CTP, ECP, and TCP

 delayed ECG-gated (single phase)

n Detect pericardial inflammation

n Evaluate for acute bleeding with contrast

extravasation into pericardium

T2-STIR

n Detect and characterize PEff

n Evaluate for pericardial edema

n Evaluate for myocardial edema

 3D echocardiography

n  incremental value in PEff sizing and spatial relationship

with surrounding structures

n  improved visualization of pericardial adhesions/strands in

complex PEff

LGE

n Ascertain for pericardial thickening

and inflammation

n Evaluate for pericardial malignancies

Adapted with permission from Klein et al.1

2D ¼ 2-dimensional; 3D ¼ 3-dimensional; BB ¼ black-blood; CCT ¼ cardiac computed tomography; CMR ¼ cardiac magnetic resonance; CTP ¼ cardiac tamponade; ECG ¼ electrocardiogram; ECP ¼ effusive constrictive pericarditis; IVC ¼ inferior vena cava; LGE ¼ late gadolinium enhancement; PEff ¼ pericardial effusion; STIR ¼ short tau inversion recovery;

T1W ¼ T1-weighted; T2W ¼ T2-weighted; TCP ¼ transient constrictive pericarditis.

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