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CME: Cardiology

Managing acute and recurrent idiopathic pericarditis

Schwier, Nicholas C. PharmD, BCPS-AQ Cardiology; Cornelio, Cyrille K. PharmD; Epperson, Taylor M. PharmD

Author Information
Journal of the American Academy of Physician Assistants: January 2020 - Volume 33 - Issue 1 - p 16-22
doi: 10.1097/01.JAA.0000615468.46936.6d
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Abstract

Figure
Figure
Box 1
Box 1

Pericarditis is the most common form of pericardial disease and affects patients of all ages. Despite its low incidence, pericarditis is associated with significant morbidity and mortality as well as high healthcare costs.1 Patients may need interventions such as pericardiocentesis, pericardiectomy, pericardial window, or pericardiotomy. Complications include a high risk of recurrence within 18 months, chronic pericarditis, constrictive pericarditis, and cardiac tamponade.1

In the United States, the most common causes of pericarditis are viral or idiopathic.2 Although these causes are different, the literature uses the term viral or idiopathic because the onset of signs and/or symptoms of pericarditis often occurs after the viral prodrome has subsided or the virus has cleared the patient's system.

The first guidelines for the management of pericarditis were published by the European Society of Cardiology (ESC) in 2004; the most recent update was in 2015 and focused on the diagnosis and management of patients with idiopathic pericarditis.2-7 This article reviews the 2015 ESC guidelines as well as important aspects of diagnosis and management for patients with acute or recurrent idiopathic pericarditis.

DIAGNOSIS

Because of the symptomatology associated with pericarditis, namely positional chest pain upon inspiration, patients typically present to the ED. However, patients also can present with pericarditis to a variety of intensive care and general medicine departments of the hospital. Clinicians also may encounter patients with pericarditis in outpatient environments, mostly in cardiology clinics.8 Consequently, clinicians should be knowledgeable of the diagnosis of pericarditis. The 2015 ESC guidelines provide diagnostic criteria, and consider pericarditis a clinical diagnosis that can be made if a patient has two of the four criteria in Table 1.2,9

TABLE 1
TABLE 1:
Clinical diagnosis of pericarditis2,9
Box 2
Box 2

In addition to the diagnostic criteria, objective signs of inflammation such as fever, and leukocytosis, the inflammatory markers high-sensitivity C-reactive protein (hs-CRP) and antinuclear antibodies (ANA) may help clinicians determine whether the patient's pericarditis is caused by inflammation or a virus.2 After making the diagnosis, clinicians should determine whether the pericarditis is acute, recurrent, incessant, chronic, or constrictive.

  • Acute pericarditis (Figure 1) is a first episode of pericarditis, usually manifested by the clinical diagnostic criteria in Table 1.2
  • Recurrent pericarditis is diagnosed after a documented first episode of acute pericarditis, a symptom-free interval of more than 6 weeks, and evidence of successive recurrence of pericarditis, using the same diagnostic criteria for acute pericarditis.2
  • Incessant pericarditis is defined as persistent symptoms of pericarditis without a precise remission after the acute episode. Signs and symptoms usually persist for more than 6 weeks but less than 3 months without remission. This type of pericarditis usually is secondary to medication nonadherence.2
FIGURE 1
FIGURE 1:
Anatomy of the pericardium

Both recurrent and incessant disease are complications that can be prevented if patients adhere to appropriately prescribed pharmacotherapy. More than 30% of patients inappropriately treated for acute pericarditis develop incessant or recurrent disease within 18 months of the initial episode; more than 50% of patients who present with a first recurrence and are not started on appropriate pharmacotherapy develop incessant or recurrent disease within 18 months.4,5,7

  • Chronic pericarditis generally describes signs and symptoms of pericarditis (especially pericardial effusions) that last more than 3 months.
  • Constrictive pericarditis results from a chronic inflammatory state that leads to scarring and inelasticity of the pericardium, eventually causing impaired ventricular diastolic filling.

Cardiac tamponade can be associated with acute or recurrent pericarditis, and also is associated with increased mortality and poor prognosis in patients with pericarditis. Constrictive pericarditis and cardiac tamponade rarely are associated with idiopathic pericarditis and are more commonly encountered in patients with identifiable causes of pericarditis.1

Because viral pericarditis is more commonly encountered in clinical practice in the United States, clinicians should be able to identify patients with suspected viral pericarditis. These patients often present with a history of a self-limiting viral prodrome that precedes typical signs and symptoms of pericarditis by a few weeks.2 Patients may complain of symptoms similar to upper respiratory tract infections or gastroenteritis.10 The most common viruses associated with pericarditis include enteroviruses such as Coxsackie, adenoviruses, and parvovirus, and herpes viruses such as Epstein-Barr and cytomegalovirus (CMV).2 Rare infectious causes of pericarditis include bacterial infections, most commonly due to Mycobacterium tuberculosis, fungal, or parasitic infections.1 Noninfectious causes of pericarditis include thyroid dysfunction (such as myxedema and thyrotoxicosis), uremia secondary to nonadherence to hemodialysis, autoimmune disease, malignancy, traumatic or iatrogenic causes such as postmyocardial infarction syndrome, certain drugs, amyloidosis, aortic dissection, pulmonary arterial hypertension, chronic heart failure, and congenital heart diseases.1

PHARMACOTHERAPY

Management of pericarditis in the United States is largely based on recommendations from the 2015 ESC guidelines; however, none of the drugs used to treat idiopathic pericarditis are FDA-approved for this indication. The following sections will provide more specific pharmacotherapy recommendations, using both primary literature and the ESC guidelines in order to provide a more tailored approach to treatment of idiopathic pericarditis in the United States. Treatment dosing and duration, tapering, adverse reactions, and clinical pearls for each agent are summarized in Table 2.

TABLE 2
TABLE 2:
Pharmacotherapy of acute and recurrent idiopathic (viral) pericarditis2-7,13-20,22,25

Colchicine

This drug is recommended as part of first-line treatment for acute and recurrent idiopathic pericarditis in conjunction with aspirin/NSAID therapy.2 Colchicine inhibits microtubule assembly during cellular mitosis, which can subsequently impair leukocyte motility, reducing inflammation in the pericardium.11 When used in combination with aspirin/NSAID therapy in patients diagnosed with acute or recurrent idiopathic pericarditis, colchicine reduces rates of recurrence within 18 months. The three-drug combination also has been shown to increase the symptom-free interval and significantly provide symptomatic improvement within 72 hours of initiating treatment. The combination also decreases incessance, prolongs time to subsequent recurrence, reduces pericarditis-related hospitalization rates, and improves remission rates at 1 week, especially in patients with multiple recurrences.3-7 Landmark studies have used 0.5 mg and 1 mg colchicine formulations in patients with acute and recurrent idiopathic pericarditis. In the United States, however, only 0.6 mg capsules and scored tablets are available. A 0.6 mg/5 mL oral solution has recently been approved by the FDA, although it is not indicated for treating pericarditis. However, it has not been studied in idiopathic pericarditis and has a maximum daily dose of 1.2 mg.12 Because colchicine has a narrow therapeutic index, be aware of the differing dosages and formulations when following recommendations from the 2015 ESC guidelines.13 High (attack) doses of colchicine can be used to achieve symptom control faster due to colchicine's wide volume of distribution. Colchicine dosing in patients with pericarditis is weight-based to mitigate potential adverse reactions. For patients weighing less than 70 kg, a one-time attack dose of 1.2 to 1.8 mg is followed by a maintenance dose of 0.6 mg daily. In patients weighing 70 kg and greater, the one-time dose of 1.2 to 1.8 mg is followed by a maintenance dose of 0.6 mg twice daily; for complete dosing recommendations, see Table 2.

Colchicine is metabolized hepatically via cytochrome P450 3A4 and is eliminated primarily via the kidneys and P-glycoprotein. Thus, excretion and metabolism are impaired in patients with renal and hepatic impairment, respectively.14 Dose adjustment is recommended for patients with renal or hepatic impairment and pericarditis, but no specific recommendations exist.14 Colchicine is contraindicated in patients with renal or hepatic impairment who also are taking strong CYP 3A4 inhibitors (such as amiodarone, azoles, macrolide antibiotics, non-dihydropyridine calcium channel blockers, and protease inhibitors) or P-glycoprotein inhibitors such as amiodarone, azoles, statins, and protease inhibitors. Monitoring for gastrointestinal (GI) symptoms is essential, as dose-dependent adverse reactions are common (diarrhea, vomiting, nausea, and anorexia), especially diarrhea.14 If a patient is unable to tolerate colchicine because of GI symptoms, doses should be reduced, typically by 50%, until the maximum tolerated dose is achieved.13 For a complete list of potential common adverse reactions, see Table 2.

Aspirin or NSAIDs

This therapy plays an important role in controlling chest pain from pericarditis.2 Aspirin and NSAIDs exert their anti-inflammatory and analgesic effects by inhibiting cyclooxygenase enzymes, which prevents production of proinflammatory prostaglandin and subsequently reduces nociception.15 Aspirin and NSAIDs do not affect the natural progression of pericarditis; monotherapy with aspirin or NSAIDs can increase a patient's risk of recurrence.16 Thus, colchicine coadministration is recommended to further reduce recurrence rates and symptoms in acute and recurrent idiopathic pericarditis. Higher initial attack doses of aspirin/NSAIDs for 1 to 2 weeks are necessary for optimal efficacy and treatment duration before tapering is guided by symptom and inflammatory marker resolution.2 Aspirin/NSAIDs can reduce levels of hs-CRP, a potentially important prognostic biomarker in patients with idiopathic pericarditis, and should be monitored weekly for treatment response to high-dose aspirin/NSAIDs. After 1 week of therapy, persistently elevated levels of hs-CRP are independently associated with increased risk of recurrence.2,16 Therefore, prolonged treatment (3 to 4 weeks) and tapering of aspirin/NSAIDs is recommended.2 Failure to elicit a response after 1 week indicates poor prognosis and warrants further workup of other potential causes.2

Common adverse reactions to aspirin and NSAIDs are GI-related, including bleeding and ulceration; high doses and prolonged durations further increase the risk. Prescribe gastroprotection with proton pump inhibitors or histamine2 receptor antagonists for the duration of aspirin/NSAID therapy.2

Although aspirin and ibuprofen are the most commonly studied anti-inflammatories, indomethacin and ketorolac also have been used. However, indomethacin can cause a higher incidence of neurologic adverse reactions, such as headache and dizziness, compared with ibuprofen.15 Consider parenteral ketorolac in the initial phase of idiopathic pericarditis for patients who are unable to take oral medications.17 However, parenteral ketorolac can only be used for a maximum of 5 days because of a black box warning for GI ulceration and bleeding.18 An oral formulation also is available, but is intended only as a continuation of parenteral therapy for up to 5 days.18

Because no evidence suggests that superior efficacy or safety between aspirin or NSAIDs, or even among NSAIDs alone, the choice of agent depends on patient-specific factors such as comorbidities, dosage form, adverse reactions, and access to care.2 Aspirin is preferred for patients who already have or are at risk for cardiovascular disease; NSAIDs should generally be avoided in patients with higher cardiovascular risk or cardiovascular disease.15 NSAIDs are not preferred in patients with renal impairment because of the risk of potentiating acute kidney injury (AKI).

Corticosteroids

By suppressing leukocyte migration, corticosteroids provide potent anti-inflammatory effects.19 However, they are not recommended as first-line agents for patients with acute or recurrent idiopathic pericarditis, because corticosteroid use in landmark trials has been associated with increased rates of recurrence.2,3 Consider corticosteroids when combination therapy with aspirin/NSAIDs plus colchicine fails (due to patient intolerance of the drug or disease persistence), or in patients with contraindications to combination therapy, but only when infectious causes of pericarditis have been ruled out.2 Pay careful attention to dosing in patients with recurrent pericarditis; relatively higher doses of prednisone (1 mg/kg/day) were associated with higher rates of recurrence, hospitalizations, and adverse reactions, compared with lower doses (0.25 to 0.5 mg/kg/day).20 Avoid prednisone doses greater than 50 mg; if doses greater than 50 mg are necessary, taper the dosage to 25 mg/day within the first days of therapy. Initiation of slow corticosteroid tapering is recommended only upon symptom resolution and normalization of hs-CRP (tapering recommendations are included in Table 2). Monitor patients closely at baseline and periodically during treatment—corticosteroids are associated with many adverse reactions, including fluid retention, hypertension, psychiatric disturbances (insomnia, mood changes) and hyperglycemia with short-term use, and infection risk, impaired wound healing, osteoporosis risk, and growth suppression in children with long-term use.19 Because of the risk of peptic ulcer disease with long-term corticosteroid use, prescribe GI prophylaxis for patients receiving corticosteroid treatment for idiopathic pericarditis, especially if they also are taking aspirin/NSAIDs and colchicine.19 All patients receiving glucocorticoids should also take calcium (1,200 to 1,500 mg/day) and vitamin D (800 to 1000 international units/day) supplementation. Bisphosphonate therapy is recommended for all men age 50 years and older, and for postmenopausal women starting long-term glucocorticoid treatment (5 mg/day or more of prednisone or equivalent).2 No specific dosage adjustments are given for patients with renal or hepatic impairment. However, prednisone is hepatically metabolized to the active metabolite prednisolone, so patients with severe hepatic impairment should be encouraged to use prednisolone.21

Immunotherapies

Despite appropriate first-line treatment with combination therapy, patients with recurrent pericarditis may develop pericardial fluid interleukins and ANA, as well as anticardiac antibodies. These developments suggest that autoimmunity may play a role in the pathogenesis of idiopathic pericarditis, and that immunotherapy agents such as anakinra, azathioprine, and immunoglobulin (Ig) may be beneficial in treating recurrent pericarditis.22,23

Anakinra is an injectable biologic agent that binds to the interleukin-1 (IL-1) receptor, antagonizing the inflammatory effects from increased cytokine IL-1 production that occurs in patients with recurrent idiopathic pericarditis.22 This drug can be considered in patients with three or more recurrences who are colchicine-resistant and corticosteroid-dependent, to reduce recurrence rates and prolong time to recurrence.22,24 However, data on anakinra in idiopathic pericarditis are limited and further studies are needed. Infection risk is a main concern with anakinra and patients should be tested for tuberculosis (TB) and treated (if indicated) before starting anakinra. Monitor the patient's neutrophil counts at baseline and routinely during treatment; neutropenia has been associated with anakinra use.22 Anakinra may be tapered over 10 to 12 months after hs-CRP normalization and a symptom-free interval of at least 3 to 6 months.22

Other immunotherapies associated with preventing recurrences in patients with idiopathic pericarditis include azathioprine and parenteral immunoglobulin.22,25,26 Ultimately, immunotherapies are considered to be third-line for the management of recurrent pericarditis episodes that have failed to respond to aspirin/NSAIDs, colchicine, and corticosteroids.2

LIFESTYLE CHANGES AND SURGICAL INTERVENTIONS

Patients with pericarditis should restrict their physical activity until symptoms resolve and their hs-CRP level normalizes. During the acute phase of pericarditis, athletes in particular should avoid all strenuous activity and competitive sports. Usually, athletes are advised to restrict physical activity for 3 months, and nonathletes are advised to restrict activity for a shorter period, typically until disease remission.2 Periodically reassess athletes and clear them for return to athletic activity when their symptoms resolve and their hs-CRP, ECG manifestations, and echocardiographic features have normalized.27

Surgical procedures have varying roles and effects on the management of acute and recurrent idiopathic pericarditis. In patients with features of cardiac tamponade, and those presenting with symptomatic moderate to large pericardial effusions, and patients whose pericardial effusions are unresponsive to medical therapy, echocardiographic or fluoroscopy-guided pericardiocentesis should be performed.2

A pericardial window involves a surgical removal of small portion of the pericardial sac that lets the pericardial effusion drain, and may prevent a large pericardial effusion from causing cardiac tamponade. Pericardial window placement usually is palliative, and is especially useful in patients considered too high-risk for pericardiectomy or who have a reduced life expectancy.

Pericardiotomy involves using a balloon to create a pleuropericardial communication that lets pericardial fluid drain into the pleural space. This procedure typically is used in patients for whom pericardiocentesis is contraindicated. Pericardiotomy is used in large effusions that do not resolve or in patients with recurrent tamponade.2

Pericardiectomy usually is reserved for patients with constrictive pericarditis.2 This procedure also can be useful in patients with multiple episodes of recurrent idiopathic pericarditis who do not respond to or cannot tolerate pharmacotherapy, and in patients who are corticosteroid-dependent. Pericardiectomy requires general anesthesia and thoracotomy or sternotomy. Therefore, it should only be used after pharmacotherapy has been tried and after other surgical procedures have been considered.2

CONCLUSION

Patients diagnosed with acute or recurrent idiopathic pericarditis may suffer significant morbidity due to disease burden or adverse drug reactions. Acute idiopathic pericarditis usually is treated with combination therapy, consisting of colchicine and aspirin/NSAIDs. Corticosteroids are reserved for patients who cannot take aspirin/NSAIDs and/or colchicine, or who present with contraindications. Corticosteroids also can be used with combination therapy in patients with recurrent idiopathic pericarditis. If combination therapy with corticosteroids fails, immunotherapies can be considered as third-line pharmacotherapy. Avoiding physical activity and surgical procedures also can be useful in select patient populations.

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Keywords:

idiopathic; viral; pericarditis; acute; recurrent; pharmacotherapy

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