The 2015 ESC Guidelines for the Diagnosis and Management of Pericardial Disease Task Force Report published in the European Heart Journal, August 29, 2015,¹ is a fairly comprehensive document providing practical guidance on the various manifestations of diseases affecting the pericardium.

An attempt to use a best evidence approach is commensurate with other guidelines that have emanated from both sides of the Atlantic. Both strength of recommendation and level of evidence are provided in this document, which is a significant advancement for pericardial disease. The notable components are the trial-based guidance as it relates to therapy based on recent data that really enhances the value of the document. The Europeans have been instrumental in providing this evidence for treatment based on the recent clinical trials starting in 2005 COPE², 2010 COPPS³ study followed by the CORP⁴ study in 2011, the ICAP⁵ in 2013, the CORP-2⁶ and COPPS-2⁷ in 2015.

Definitive care provided early on and the importance of agreeing on the definitions of pericardial disease cannot be underestimated, as commonality of language and semantics for registries for future studies need to be comparable. More importantly, recognition of the various clinical entities based on these definitions will guide appropriate treatment of acute, incessant, recurrent and chronic pericarditis, the current titular segments of import. Missing however, is the category of "relapsing pericarditis" that occurs not infrequently with inflammation after an initial insult followed by quiescent periods at times when medication reduction or tapering is attempted. This may fall under the category of chronic/incessant pericarditis. The use of these clinical entities in categorizing patients with pericarditis and their treatment regimen based on these definitions may still be unclear to the practicing cardiologist.

Diagnosis

The clinical diagnosis coupled with ECG, and chest x-ray (CXR) will suffice in the majority of cases. However, the explicit role of biomarkers in clinical decision making as well as therapeutic decision making is better quantified in this document. A risk score (level 1B evidence) to guide hospital admissions for higher risk patients will better inform the use of resources both in terms of admission but also which diagnostic tests from serologic testing, biomarkers and radiologic imaging have added value. More evidence is required to refine this guidance, but the guideline certainly provides an excellent introduction.

For viral pericarditis a comprehensive work-up of histologic, cytologic, immunologic and molecular investigations of the pericardial fluid is a Class II-A indication, with Level C evidence, mostly because specific etiologic drug therapy is experimental with limited data. Routine vital viral serology is not recommended with a Class III-C indication with the exception of suspected hepatitis C and human immunodeficiency virus (HIV) cases.

Imaging

While multimodality imaging is discussed in detail for diagnosing the more challenging pericardial disease, the inclusion of a comparative table for the various diagnostic tests is extremely helpful. An added advantage is the reference to costs which in the current fiscal environment, especially in the United States, is almost mandatory. More than one imaging modality may be needed to confirm a clinical diagnosis, particularly in the more challenging cases of recurrent pericarditis or pericardial constriction, to facilitate appropriate therapeutic intervention. A proposal for diagnostic work-up adds to the overall pragmatism that these guidelines offer. The value of clinical risk apportionment, in particular, the major risk factors, are helpful to manage patients appropriately with particular regard to hospital admission versus outpatient management, is likely the single factor that will be beneficial in delivering cost effective healthcare. Missing from the guidelines is a discussion of the use of advanced imaging, that is, tissue characterization with CMR in modulating treatment of challenging cases of recurrent pericarditis or transient constriction.

Treatments

The document is complete and spans both developing and developed nations in the etiologies of pericarditis. Tuberculous pericarditis diagnosis and treatment is mentioned. However, multi-drug resistant tuberculosis is notably absent as far as recommendations go. A treatment strategy using aspirin and colchicine gets a Level A recommendation, with ibuprofen and indomethacin mentioned as well. Absent is any guidance regarding long acting non-steroidal anti-inflammatory drugs such as naproxen the nonselective COX inhibitor, diclofenac, naproxen the nonselective COX inhibitor and the selective COX-2 inhibitors. Missing also is a discussion of administering a multidrug regimen, that is, triple drug vs dual drug therapy and slow tapering of these medications. Recommendations regarding restricting physical activity with pericardial inflammation are broad, but certainly needs to be individualized. Admittedly, the taskforce highlights this point. The long-term use of these medications has a definable risk of gastrointestinal side effects, but a paucity of guidance in this regard with prophylactic gastro-protection is noted. Common sense or gastroenterology consultation with endoscopy may be required in some instances. In the United States, colchicine is difficult to obtain in the dose and form recommended by the ESC guidelines, however, colcrys (Takeda Pharmaceuticals U.S.A) has been marketed at a 0.6 mg dose. American physicians are aware of this dose, which is higher than the European dose and cCo-administration of P-gp and/or CYP3A4 inhibitors (e.g.,clarithromycin or cyclosporine) have been demonstrated to alter the concentration of colchicine. The potential for drug-drug interactions must be considered prior to and during therapy.

Immunotherapy with azathioprine, intravenous immunoglobulin and anakinra a recombinant IL-1 beta receptor antagonist is mentioned, but strong evidence is lacking. Anakinra is given a class II-B designation and extant data suggests it is best used in cases of corticosteroid dependency. Other immunosuppressive drugs such as cyclophosphamide, cyclosporine, methotrexate, hydroxychloroquine and, anti-tumor necrosis factor (TNF) agents have sparse clinical trial data but are appropriately given mention for the sake of completion. The use of these medications in steroid dependent, difficult-to-treat pericarditis may have a role, but more data is required. The costs and risks of these medications require a multidisciplinary expertise, including immunology and rheumatology consultations, which may already be the standard of care for those who run a pericardial disease specialty clinic. This multidisciplinary pericardial team and specialty clinic/center may be important in the future management of these complex patients.

IgG related pericardial disease is an aggressive form of pericarditis with chronicity and relapses are common, often warranting steroid based therapy. This entity is absent from the document in its entirety.

For post-viral pericardial inflammation that is acute, a short course of nonsteroidal anti-inflammatory drugs with colchicine is recommended. Appropriately, steroid-based therapy is not recommended (Class III-C).

A laudatory guideline on pericardial disease using available best evidence to guide clinical practice is now at hand. Ensuing iterations will likely incorporate more clinical studies. The current document points out gaps in knowledge and this is likely to drive further clinical studies that could underpin and strengthen evidence-based guidelines for these complex set of pericardial diseases. For this increasingly recognized and complex subspecialty that is diagnosed infrequently, appropriate treatment strategies have been less than organized and hence, ideal outcomes suboptimal in many cases. The strength of these guidelines is a delivery of recent evidence-based treatment strategies based on several clinical trials. The authors further recognize the lack of complete data and supplement the knowledge gaps with expert opinion that has been well categorized into the segments of diagnosis, diagnostic testing, serologicically diagnostic testing, by imaging, by risk stratification for admission versus outpatient therapy, drug therapy guidance and surgical recommendations when appropriate. Finally, the guidelines explicitly mention the absence of evidence and putative direction of research and focus in the "Unmet Needs" section. Due to this knowledge gap in this growing field of pericardiology, these European guidelines may stimulate the ACC/AHA to embark on their own set of guidelines and recommendations on this side of the Atlantic.

References

1. Adler Y, Charron P, Imazio M et al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases: The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC)Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2015. - See more at: http://www.acc.org/latest-in-cardiology/articles/2015/09/09/12/19/transient-constrictive-pericarditis
2. Imazio M, Bobbio M, Cecchi E, et al. Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation 2005;112:2012-6.
3. Imazio M, Trinchero R, Brucato A, et al. COlchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS): a multicentre, randomized, double-blind, placebo-controlled trial. Eur Heart J 2010;31:2749-54
4. Imazio M, Brucato A, Cemin R, et al. Colchicine for recurrent pericarditis (CORP): a randomized trial. Ann Intern Med 2011;155:409-14.
5. Imazio M, Brucato A, Cemin R, et al. A randomized trial of colchicine for acute pericarditis. N Engl J Med 2013;369:1522-8.
6. Imazio M, Belli R, Brucato A, et al. Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): a multicentre, double-blind, placebo-controlled, randomised trial. Lancet 2014;383:2232-7.
7. Imazio M, Brucato A, Ferrazzi P, et al. Colchicine for prevention of postpericardiotomy syndrome and postoperative atrial fibrillation: the COPPS-2 randomized clinical trial. JAMA 2014;312:1016-23

Keywords: Adrenal Cortex Hormones, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Azathioprine, Biomarkers, Clarithromycin, Colchicine, Constriction, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors, Cyclophosphamide, Cyclosporine, Cytochrome P-450 CYP3A, Decision Making, Diagnostic Tests, Routine, Diclofenac, Drug Interactions, Electrocardiography, Endoscopy, Expert Testimony, Gastroenterology, Hepatitis C, Hydroxychloroquine, Ibuprofen, Immunoglobulins, Intravenous, Immunotherapy, Indomethacin, Inflammation, Interleukin 1 Receptor Antagonist Protein, Interleukin-1beta, Methotrexate, Motor Activity, Naproxen, Outpatients, ATP Binding Cassette Transporter, Subfamily B, Member 1, Pericarditis, Pericarditis, Tuberculous, Pericardium, Referral and Consultation, Registries, Rheumatology, Risk Factors, Semantics, Standard of Care, Tuberculosis, Multidrug-Resistant, Tumor Necrosis Factors, X-Rays

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