Pharmacotherapy Update of Acute Idiopathic Pericarditis Nicholas C. Schwier,1,2,* James C. Coons,3 and Shivdev K. Rao4 1
Department of Pharmacy: Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, Oklahoma City, Oklahoma; 2PGY-2 Cardiology Pharmacy Resident, University of Pittsburgh Medical Center, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; 3University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; 4UPMC Heart and Vascular Institute, Pittsburgh, Pennsylvania
Idiopathic (viral) pericarditis is the most common form of pericardial disease in the Western world. Despite the combination of colchicine and nonsteroidal antiinflammatory drugs (NSAIDs) plus aspirin (ASA), considered first-line therapy, the incidence of recurrent pericarditis is ~20–30%. In addition, secondary recurrence without optimal first-line therapy is ~50%. This is due to the many clinical challenges, such as inappropriate NSAID/ASA duration of therapy, the use of corticosteroid therapy, contraindications or intolerances to therapy, adverse effects, and issues related to adherence. This review describes contemporary pharmacotherapeutic management of idiopathic (viral) pericarditis, with a particular emphasis on the role of colchicine. Emerging therapies and management strategies, such as high-sensitivity C-reactive protein–guided therapy and novel immunotherapies, are also reviewed. Ultimately, understanding appropriate treatment will assist the clinician in helping decrease the risk of recurrent, incessant, and refractory pericarditis. KEY WORDS colchicine, NSAIDs (Non-Steroidal Anti-Inflammatory Drugs), ASA (Aspirin), hs-CRP (high sensitivity C-reactive protein), recurrence, corticosteroids, immunotherapy. (Pharmacotherapy 2015;35(1):99–111) doi: 10.1002/phar.1527 Pericarditis is an inflammatory disorder affecting the pericardium, which is the membranous sac that encapsulates the heart. In 2003, pericarditis was diagnosed in ~0.1% of hospitalized patients in the United States, and in 5% of patients who presented to the emergency department with noncardiac chest pain. However, the disorder may be underreported, especially in the United States.1, 2 In fact, most of the publications regarding the treatment of acute pericarditis include data from Italy, with 27.7 cases per 100,000 persons per year.3 The lack of recent epidemiological literature may coincide with the relatively limited amount of published clinical literature surrounding pericarditis in general. Despite the lack of drug therapy advances in the
*Address for correspondence: Nicholas C. Schwier, Assistant Professor, Department of Pharmacy: Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, 1110 N. Stonewall Avenue, CPB 214, Oklahoma City, OK 73117; e-mail: [email protected]. Ó 2015 Pharmacotherapy Publications, Inc.
treatment of idiopathic (viral) pericarditis, the clinician needs a thorough understanding of treatment because complications such as recurrence can occur in ~50% of patients.4 This review provides a comprehensive overview of the disease in general, as well as a focused summary of the pharmacotherapy surrounding acute idiopathic (viral) pericarditis. Physiology of the Pericardium The pericardium consists of two layers of tissue: the visceral and parietal layers. The visceral layer is composed of a single layer of mesothelial cells that adhere to the myocardium. The parietal layer is fibrous, less than 2 mm thick, and is composed primarily of collagen and, to a lesser extent, elastin.5 These two layers of the pericardium are separated by the pericardial cavity or space, which usually contains 15–50 ml of serous fluid.6 The pericardium attaches to the sternum, the diaphragm, and the anterior mediastinum where it serves to anchor the heart.
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Due to the nature of its location, the pericardium also functions as a barrier to infection. Because the pericardium is richly innervated, pericardial inflammation, also known as pericarditis, may produce severe pain and trigger vagally mediated reflexes.5 In addition, the pericardium secretes prostaglandins that modulate cardiac reflexes and coronary tone.7 As a result of its relatively inelastic physical properties, the pericardium limits acute cardiac dilatation and enhances mechanical interactions of the atria and ventricles, ultimately preventing the heart from overfilling.8 The pericardium also provides mechanical protection for the heart and lubrication to reduce friction between the heart and surrounding structures.1 Etiology The primary etiology in Western developed countries is idiopathic (viral) pericarditis, which represents ~65–85% of cases.9–11 The most common viral causes are influenza, Coxsackie, Epstein-Barr, and human herpes virus 6. The most common bacterial cause of pericarditis is tuberculosis (TB), which occurs in ~4–5% of people with pericarditis. Although noninfectious causes such as autoimmune, pericardial traumatic injury, neoplastic, metabolic, and druginduced pericarditis comprise ~30% of acute pericarditis,12 this review focuses on the use of pharmacotherapy to treat idiopathic (viral) pericarditis. Clinical Presentation and Diagnosis The diagnosis of pericarditis should take into account the patient’s symptoms, electrocardiographic data, and imaging data. Moreover, the diagnosis should meet at least two of the following criteria: typical chest pain, pericardial friction rub, suggestive electrocardiogram (ECG), and/or new or worsening pericardial effusions.13 Because idiopathic (viral) is the most common cause of pericarditis, many patients may present with signs and symptoms of systemic infection such as fever and leukocytosis. Viral etiologies may be preceded by flulike respiratory or gastrointestinal symptoms. Notably, there is an important distinction between cardiac tamponade and pericarditis. Cardiac tamponade is a life-threatening slow or rapid compression of the heart caused by the pericardial accumulation of fluid, pus, blood, clots, or gas. It may result in the manifestation of effusion, trauma, or rupture of the heart. Critical
tamponade is a form of cardiogenic shock, and the differential diagnosis may initially be unclear because most signs and symptoms are equally nonspecific. However, four landmark signs and symptoms distinguish pericarditis from tamponade: tachycardia (heart rate more than 90 bpm), pericardial rub, jugular venous distention, and pulsus paradoxus. Pulsus paradoxus is traditionally defined as an inspiratory systolic fall in arterial blood pressure of 10 mm Hg or more during normal breathing.2 Because prompt evaluation and diagnosis is imperative, recognizing the difference between tamponade and pericarditis has significant implications for appropriate treatment and patient outcomes. Although chest pain associated with pericarditis can mimic that of a pulmonary embolism or myocardial ischemia, it does have some key differentiating characteristics.6 The chest pain of acute pericarditis is usually sudden in onset, retrosternal, pleuritic, and exacerbated by inspiration. Patients describe amelioration of pain when they lean forward or are in the upright position because the positional change reduces pressure on the parietal pericardium, particularly with inspiration, and may also allow for the inhibition of diaphragmatic movement upward.14 Similar to myocardial ischemia, chest pain secondary to pericarditis can radiate to the neck, arms, left shoulder, but also to one or both trapezius muscle ridges. This is thought to be caused by nociception of the phrenic nerve that traverses the pericardium and also innervates these muscles.1 The art of auscultation can also aid the clinician in diagnosis. Specifically, one may listen for a pericardial friction rub, thought to be generated by friction of the two inflamed layers of the pericardium. The rub tends to vary in intensity over time, and thus patients should be examined repeatedly, throughout the course of their treatment, until the rub is inaudible. An audible friction rub, which is likely to be present in 85% of patients at some time during the course of their disease, is highly specific for pericarditis. A pericardial friction rub is usually a high-pitched, scratchy, or squeaky sound heard best at the left sternal border. The sound of the rub has been likened to footsteps on fresh fallen snow.11 Typical ECG manifestations are found in up to 60% of patients with pericarditis.1 Classic lead involvements include lateral leads I and II, the augmented lead aVR, and precordial leads V3–V6. The ECG evolution of acute pericarditis presents in four stages. Stage I is observed in
ACUTE IDIOPATHIC PERICARDITIS UPDATE Schwier et al ~80% of patients and presents within the first hours to days with concave ST segment elevations and with reciprocal depressions in aVR, frequently in V1, and occasionally in V2. PR segment deviations are a common manifestation, and most patients present with depression of the PR segment in other limb leads and in the left chest leads, primarily V5 and V6 and reciprocal elevation of the PR segment in lead aVR. ST and PR segments normalize at stage II over several days to a week or can evolve to T-wave inversions (stage III). If the patient’s pericarditis resolves, stage IV manifests as normal cardioelectrical activity seen on the ECG.1, 15 A mildly elevated cardiac troponin is detectable in 32– 49% of patients. Troponin concentrations can range from more than 1.5 ng/ml to a mean concentration of 21.4 ng/ml, and they can be detectable for 6 days to 2 weeks following the onset of symptoms. Troponin spikes have been associated with ST elevation, male gender, younger age, and pericardial effusions at presentation.16 Unlike myocardial infarction, however, troponin elevation is not associated with a poor prognosis.15, 16 Patients with acute pericarditis also commonly present with evidence of systemic inflammation, including an elevated erythrocyte sedimentation rate (ESR), rheumatoid factor, antinuclear antibody (ANA), and increased C-reactive protein (CRP). Although the most common etiology of pericarditis is viral (idiopathic), viral cultures and antibody titers have not shown clinical utility.11 A low-grade fever is common, but a temperature higher than 38°C (100.4°F) suggests the possibility of purulent bacterial pericarditis and is an indicator of a poor prognosis. Similarly, a mild leukocytosis is common, whereas a marked leukocytosis may be associated with bacterial pericarditis.6 The use of routine testing for inflammatory markers such as ESR, CRP, and ANA to aid in the diagnosis of pericarditis has historically been regarded as clinically irrelevant. Nevertheless, recent data support the use of high-sensitivity CRP (hs-CRP) in facilitating the diagnosis, treatment, and prognosis of pericarditis.17 Diagnostic imaging can also be a useful tool for the clinician. Although chest radiography is usually unremarkable in patients with acute pericarditis, patients with a significant pericardial effusion may exhibit an enlarged cardiac silhouette (“water bottle heart”) with clear lung fields.2 With this in mind, acute pericarditis should be considered in the evaluation of a
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patient with new and otherwise unexplained cardiomegaly. Cardiac computed tomography (CT) and cardiac magnetic resonance imaging (CMR) are two imaging technologies used to measure pericardial thickness.1 Cardiac CT can show increased pericardial thickness in patients with acute pericarditis, but these findings are not diagnostic for pericarditis. The most sensitive method for the diagnosis of acute pericarditis is delayed enhancement of the pericardium on CMR. In cases where the diagnosis of acute pericarditis remains uncertain, CMR may be useful.6 A transthoracic echocardiogram is recommended to detect a pericardial effusion, to ascertain its hemodynamic relevance, and to check for concomitant heart disease. Despite pericardial effusions being reported in up to 60% of patients with pericarditis, echocardiograms are nonspecific. Echocardiography is commonly normal in patients with acute pericarditis, unless there is an associated pericardial effusion. A standard definition of effusion size has been published. Specifically, a small effusion is defined as an echo-free space less than 10 mm, a moderate effusion as an echo-free pericardial space of 10–20 mm, and a severe effusion as an echo-free space more than 20 mm.18 Diagnostically, the clinician should be diligent in recognizing and ruling out life-threatening causes of chest pain before making the diagnosis of acute pericarditis and take into account the patient’s history as well as results from all diagnostic tools. Clinical Significance Despite recent evidence from multiple trials demonstrating the importance of using appropriate medical therapy, problems of underutilization, subtherapeutic dosing, and insufficient treatment courses of antiinflammatory agents often influence clinical outcomes.12 Inappropriate treatment increases the risk for decreased quality of life and long-term sequela such as incessant pericarditis (discontinuation or attempts to wean from antiinflammatory treatment resulting in relapse within 6 wks),19 recurrent pericarditis (recurrence after a symptomfree interval of 6 wks, which occurs in 20–30% of patients treated),20 refractory pericarditis (those cases that require unacceptably high long-term doses of corticosteroids for control (e.g., prednisone more than 25 mg/day),13 glucocorticoid dependence, and, rarely, constrictive pericarditis and cardiac tamponade.
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Pharmacotherapy In 2004, the European Society of Cardiology (ESC) issued treatment guidelines for pericarditis that provide pharmacotherapy recommendations based largely on a single randomized trial and nonrandomized data.15 Since the ESC guidelines were published, the results of several major landmark trials have been reported (Table 1). Data from these trials have greatly expanded the pharmacotherapeutic evidence surrounding the treatment of idiopathic (viral) pericarditis. The following sections are organized by drug therapy and review pertinent pharmacology, pharmacokinetics, pharmacodynamics, and clinical pearls regarding the treatment of acute idiopathic (viral) pericarditis. NSAID and ASA Therapy Before 2005, nonsteroidal antiinflammatory drugs (NSAIDs) or aspirin (ASA) were considered the mainstay of treatment for pericarditis. The 2004 ESC guidelines recommended these agents as first-line therapy with the suggested treatment duration for “days or weeks.”15 Based on recent landmark trials (Table 1), NSAID/ASA therapy should be used as first-line therapy in combination with colchicine based on the reduction in recurrence rates compared with NSAID/ ASA monotherapy.4, 17, 21–24 It is important to note that the goal of using NSAID/ASA is relief of pain and the resolution of inflammation. However, NSAID/ASA therapy does not alter the natural history of pericarditis. The choice of NSAID-type or ASA therapy should be guided by patient-specific factors such as cost, dosage form, route of administration, comorbid conditions, and tolerability. Patients should be asked about which medication(s) they have tolerated in the past and what has or has not worked for them. This is an important consideration for the clinician because there have been no studies to date comparing the safety or efficacy among different NSAIDs for treating idiopathic pericarditis. Table 2 summarizes the results of studies in patients with pericarditis who have been treated with various NSAIDs and ASA, along with their usual doses. It should be noted that higher doses of NSAIDs/ASA should be used (outlined in Table 2) to achieve antiinflammatory effects. These doses are generally higher than what is normally used, and so the potential for adverse effects such as headache and central nervous system effects may determine NSAID selection.
These adverse effects are more common with indomethacin but are relatively uncommon with ibuprofen.27 Other considerations may include route of administration. Indomethacin can be given intravenously or rectally if the patient cannot tolerate capsules. Ibuprofen is available over the counter as a liquid formulation that can be given instead of a tablet. ASA is available as a tablet or suppository form and is the agent of choice in patients with ischemic heart disease (IHD), when the patient is already on ASA or needs antiplatelet treatment; the doses of ASA used in treating pericarditis are similar to those given to patients following a myocardial infarction.28 NSAIDs such as indomethacin or ibuprofen should be avoided in patients with IHD due to the potential for coronary vasoconstriction and scar formation interference after a coronary event.29 Ketorolac tromethamine is another option for the acute management of pain due to pericarditis.26 Although ketorolac can be administered orally at 10 mg/day every 4–6 hours (not to exceed 40 mg/day), it carries a black box warning that it is to be used only as an extension of parenteral therapy and should not exceed 5 days of therapy based on lack of benefit and increased potential for adverse effects such as gastrointestinal (GI) bleeding. NSAIDs in general are not recommended in patients with advanced renal disease, but ketorolac has specific dosage adjustments in patients with renal dysfunction.25 Appropriate use of NSAIDs or ASA therapy involves administering the drugs at least every 8 hours and maintaining an attack dose until symptoms resolve (usually in 1 wk) and normalization of hs-CRP. At the point of symptom resolution and normalization of hs-CRP, the dose of the agent may be tapered accordingly. If patients are not responding to NSAID therapy after 1 week, etiology other than idiopathic/viral should be explored. After 1 week of the attack dose, tapering should be utilized over 1 month, rather than simply discontinuing use of the agent, to avoid risk of recurrences.30 Colchicine The use of colchicine dates back to the first century A.D. and was eventually extracted and isolated from the meadow saffron plant in 1820 by two French chemists.31 Currently, colchicine is approved by the Food and Drug Administration (FDA) only for the treatment and prophylaxis of gout flares and for the treatment of familial Mediterranean fever, making its use for
Safety and efficacy of colchicine added to ASA for first episode of acute pericarditis Safety and efficacy of colchicine added to ASA for the secondary prevention of recurrence after first recurrence of pericarditis Safety and efficacy of colchicine added to ASA for the secondary prevention of recurrence after first recurrence of pericarditis Safety and efficacy of colchicine to treat a first attack of acute pericarditis and prevent recurrences Safety and efficacy of colchicine for treatment of multiple recurrences of pericarditis Frequency of hs-CRP elevation in acute pericarditis, its time course of normalization, and place for diagnosis, therapy, and prognosis
Aim
Group2: ASA/ NSAID + colchicine
Group 2: Colchicine + ASA/ IBU
Group 2: Colchicine + ASA/ IBU
Group 2: ASA + colchicine
Group 2: ASA + colchicine
ASA, indomethacin, or ibuprofen every 8 hrs with an attack dose for 7 days with gradual taper over 3–4 wks Colchicine (added at discretion of physician) for 3 mo with no attack dose
Group 1: Placebo + ASA/NSAID
Group 1: Placebo + ASA/IBU
Group 1: Placebo + ASA/IBU
Group 1: ASA
Group 1: ASA
Intervention
Recurrence
Incessant or recurrent pericarditis
Recurrence
Recurrence
Recurrence
Primary end point(s)
Group2: 21.6%
Group 2: 16.7%
Group 2: 24%
Group 2: 24%
NSAID/ASA attack dose should be continued until hs-CRP normalization instead of an empirical therapy length Persistently elevated hs-CRP may identify patients at higher risk of recurrence
Group 1: 42.5% p=0.0009
Group 1: 37.5% p
Department of Pharmacy: Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, Oklahoma City, Oklahoma; 2PGY-2 Cardiology Pharmacy Resident, University of Pittsburgh Medical Center, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; 3University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; 4UPMC Heart and Vascular Institute, Pittsburgh, Pennsylvania
Idiopathic (viral) pericarditis is the most common form of pericardial disease in the Western world. Despite the combination of colchicine and nonsteroidal antiinflammatory drugs (NSAIDs) plus aspirin (ASA), considered first-line therapy, the incidence of recurrent pericarditis is ~20–30%. In addition, secondary recurrence without optimal first-line therapy is ~50%. This is due to the many clinical challenges, such as inappropriate NSAID/ASA duration of therapy, the use of corticosteroid therapy, contraindications or intolerances to therapy, adverse effects, and issues related to adherence. This review describes contemporary pharmacotherapeutic management of idiopathic (viral) pericarditis, with a particular emphasis on the role of colchicine. Emerging therapies and management strategies, such as high-sensitivity C-reactive protein–guided therapy and novel immunotherapies, are also reviewed. Ultimately, understanding appropriate treatment will assist the clinician in helping decrease the risk of recurrent, incessant, and refractory pericarditis. KEY WORDS colchicine, NSAIDs (Non-Steroidal Anti-Inflammatory Drugs), ASA (Aspirin), hs-CRP (high sensitivity C-reactive protein), recurrence, corticosteroids, immunotherapy. (Pharmacotherapy 2015;35(1):99–111) doi: 10.1002/phar.1527 Pericarditis is an inflammatory disorder affecting the pericardium, which is the membranous sac that encapsulates the heart. In 2003, pericarditis was diagnosed in ~0.1% of hospitalized patients in the United States, and in 5% of patients who presented to the emergency department with noncardiac chest pain. However, the disorder may be underreported, especially in the United States.1, 2 In fact, most of the publications regarding the treatment of acute pericarditis include data from Italy, with 27.7 cases per 100,000 persons per year.3 The lack of recent epidemiological literature may coincide with the relatively limited amount of published clinical literature surrounding pericarditis in general. Despite the lack of drug therapy advances in the
*Address for correspondence: Nicholas C. Schwier, Assistant Professor, Department of Pharmacy: Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, 1110 N. Stonewall Avenue, CPB 214, Oklahoma City, OK 73117; e-mail: [email protected]. Ó 2015 Pharmacotherapy Publications, Inc.
treatment of idiopathic (viral) pericarditis, the clinician needs a thorough understanding of treatment because complications such as recurrence can occur in ~50% of patients.4 This review provides a comprehensive overview of the disease in general, as well as a focused summary of the pharmacotherapy surrounding acute idiopathic (viral) pericarditis. Physiology of the Pericardium The pericardium consists of two layers of tissue: the visceral and parietal layers. The visceral layer is composed of a single layer of mesothelial cells that adhere to the myocardium. The parietal layer is fibrous, less than 2 mm thick, and is composed primarily of collagen and, to a lesser extent, elastin.5 These two layers of the pericardium are separated by the pericardial cavity or space, which usually contains 15–50 ml of serous fluid.6 The pericardium attaches to the sternum, the diaphragm, and the anterior mediastinum where it serves to anchor the heart.
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Due to the nature of its location, the pericardium also functions as a barrier to infection. Because the pericardium is richly innervated, pericardial inflammation, also known as pericarditis, may produce severe pain and trigger vagally mediated reflexes.5 In addition, the pericardium secretes prostaglandins that modulate cardiac reflexes and coronary tone.7 As a result of its relatively inelastic physical properties, the pericardium limits acute cardiac dilatation and enhances mechanical interactions of the atria and ventricles, ultimately preventing the heart from overfilling.8 The pericardium also provides mechanical protection for the heart and lubrication to reduce friction between the heart and surrounding structures.1 Etiology The primary etiology in Western developed countries is idiopathic (viral) pericarditis, which represents ~65–85% of cases.9–11 The most common viral causes are influenza, Coxsackie, Epstein-Barr, and human herpes virus 6. The most common bacterial cause of pericarditis is tuberculosis (TB), which occurs in ~4–5% of people with pericarditis. Although noninfectious causes such as autoimmune, pericardial traumatic injury, neoplastic, metabolic, and druginduced pericarditis comprise ~30% of acute pericarditis,12 this review focuses on the use of pharmacotherapy to treat idiopathic (viral) pericarditis. Clinical Presentation and Diagnosis The diagnosis of pericarditis should take into account the patient’s symptoms, electrocardiographic data, and imaging data. Moreover, the diagnosis should meet at least two of the following criteria: typical chest pain, pericardial friction rub, suggestive electrocardiogram (ECG), and/or new or worsening pericardial effusions.13 Because idiopathic (viral) is the most common cause of pericarditis, many patients may present with signs and symptoms of systemic infection such as fever and leukocytosis. Viral etiologies may be preceded by flulike respiratory or gastrointestinal symptoms. Notably, there is an important distinction between cardiac tamponade and pericarditis. Cardiac tamponade is a life-threatening slow or rapid compression of the heart caused by the pericardial accumulation of fluid, pus, blood, clots, or gas. It may result in the manifestation of effusion, trauma, or rupture of the heart. Critical
tamponade is a form of cardiogenic shock, and the differential diagnosis may initially be unclear because most signs and symptoms are equally nonspecific. However, four landmark signs and symptoms distinguish pericarditis from tamponade: tachycardia (heart rate more than 90 bpm), pericardial rub, jugular venous distention, and pulsus paradoxus. Pulsus paradoxus is traditionally defined as an inspiratory systolic fall in arterial blood pressure of 10 mm Hg or more during normal breathing.2 Because prompt evaluation and diagnosis is imperative, recognizing the difference between tamponade and pericarditis has significant implications for appropriate treatment and patient outcomes. Although chest pain associated with pericarditis can mimic that of a pulmonary embolism or myocardial ischemia, it does have some key differentiating characteristics.6 The chest pain of acute pericarditis is usually sudden in onset, retrosternal, pleuritic, and exacerbated by inspiration. Patients describe amelioration of pain when they lean forward or are in the upright position because the positional change reduces pressure on the parietal pericardium, particularly with inspiration, and may also allow for the inhibition of diaphragmatic movement upward.14 Similar to myocardial ischemia, chest pain secondary to pericarditis can radiate to the neck, arms, left shoulder, but also to one or both trapezius muscle ridges. This is thought to be caused by nociception of the phrenic nerve that traverses the pericardium and also innervates these muscles.1 The art of auscultation can also aid the clinician in diagnosis. Specifically, one may listen for a pericardial friction rub, thought to be generated by friction of the two inflamed layers of the pericardium. The rub tends to vary in intensity over time, and thus patients should be examined repeatedly, throughout the course of their treatment, until the rub is inaudible. An audible friction rub, which is likely to be present in 85% of patients at some time during the course of their disease, is highly specific for pericarditis. A pericardial friction rub is usually a high-pitched, scratchy, or squeaky sound heard best at the left sternal border. The sound of the rub has been likened to footsteps on fresh fallen snow.11 Typical ECG manifestations are found in up to 60% of patients with pericarditis.1 Classic lead involvements include lateral leads I and II, the augmented lead aVR, and precordial leads V3–V6. The ECG evolution of acute pericarditis presents in four stages. Stage I is observed in
ACUTE IDIOPATHIC PERICARDITIS UPDATE Schwier et al ~80% of patients and presents within the first hours to days with concave ST segment elevations and with reciprocal depressions in aVR, frequently in V1, and occasionally in V2. PR segment deviations are a common manifestation, and most patients present with depression of the PR segment in other limb leads and in the left chest leads, primarily V5 and V6 and reciprocal elevation of the PR segment in lead aVR. ST and PR segments normalize at stage II over several days to a week or can evolve to T-wave inversions (stage III). If the patient’s pericarditis resolves, stage IV manifests as normal cardioelectrical activity seen on the ECG.1, 15 A mildly elevated cardiac troponin is detectable in 32– 49% of patients. Troponin concentrations can range from more than 1.5 ng/ml to a mean concentration of 21.4 ng/ml, and they can be detectable for 6 days to 2 weeks following the onset of symptoms. Troponin spikes have been associated with ST elevation, male gender, younger age, and pericardial effusions at presentation.16 Unlike myocardial infarction, however, troponin elevation is not associated with a poor prognosis.15, 16 Patients with acute pericarditis also commonly present with evidence of systemic inflammation, including an elevated erythrocyte sedimentation rate (ESR), rheumatoid factor, antinuclear antibody (ANA), and increased C-reactive protein (CRP). Although the most common etiology of pericarditis is viral (idiopathic), viral cultures and antibody titers have not shown clinical utility.11 A low-grade fever is common, but a temperature higher than 38°C (100.4°F) suggests the possibility of purulent bacterial pericarditis and is an indicator of a poor prognosis. Similarly, a mild leukocytosis is common, whereas a marked leukocytosis may be associated with bacterial pericarditis.6 The use of routine testing for inflammatory markers such as ESR, CRP, and ANA to aid in the diagnosis of pericarditis has historically been regarded as clinically irrelevant. Nevertheless, recent data support the use of high-sensitivity CRP (hs-CRP) in facilitating the diagnosis, treatment, and prognosis of pericarditis.17 Diagnostic imaging can also be a useful tool for the clinician. Although chest radiography is usually unremarkable in patients with acute pericarditis, patients with a significant pericardial effusion may exhibit an enlarged cardiac silhouette (“water bottle heart”) with clear lung fields.2 With this in mind, acute pericarditis should be considered in the evaluation of a
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patient with new and otherwise unexplained cardiomegaly. Cardiac computed tomography (CT) and cardiac magnetic resonance imaging (CMR) are two imaging technologies used to measure pericardial thickness.1 Cardiac CT can show increased pericardial thickness in patients with acute pericarditis, but these findings are not diagnostic for pericarditis. The most sensitive method for the diagnosis of acute pericarditis is delayed enhancement of the pericardium on CMR. In cases where the diagnosis of acute pericarditis remains uncertain, CMR may be useful.6 A transthoracic echocardiogram is recommended to detect a pericardial effusion, to ascertain its hemodynamic relevance, and to check for concomitant heart disease. Despite pericardial effusions being reported in up to 60% of patients with pericarditis, echocardiograms are nonspecific. Echocardiography is commonly normal in patients with acute pericarditis, unless there is an associated pericardial effusion. A standard definition of effusion size has been published. Specifically, a small effusion is defined as an echo-free space less than 10 mm, a moderate effusion as an echo-free pericardial space of 10–20 mm, and a severe effusion as an echo-free space more than 20 mm.18 Diagnostically, the clinician should be diligent in recognizing and ruling out life-threatening causes of chest pain before making the diagnosis of acute pericarditis and take into account the patient’s history as well as results from all diagnostic tools. Clinical Significance Despite recent evidence from multiple trials demonstrating the importance of using appropriate medical therapy, problems of underutilization, subtherapeutic dosing, and insufficient treatment courses of antiinflammatory agents often influence clinical outcomes.12 Inappropriate treatment increases the risk for decreased quality of life and long-term sequela such as incessant pericarditis (discontinuation or attempts to wean from antiinflammatory treatment resulting in relapse within 6 wks),19 recurrent pericarditis (recurrence after a symptomfree interval of 6 wks, which occurs in 20–30% of patients treated),20 refractory pericarditis (those cases that require unacceptably high long-term doses of corticosteroids for control (e.g., prednisone more than 25 mg/day),13 glucocorticoid dependence, and, rarely, constrictive pericarditis and cardiac tamponade.
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PHARMACOTHERAPY Volume 35, Number 1, 2015
Pharmacotherapy In 2004, the European Society of Cardiology (ESC) issued treatment guidelines for pericarditis that provide pharmacotherapy recommendations based largely on a single randomized trial and nonrandomized data.15 Since the ESC guidelines were published, the results of several major landmark trials have been reported (Table 1). Data from these trials have greatly expanded the pharmacotherapeutic evidence surrounding the treatment of idiopathic (viral) pericarditis. The following sections are organized by drug therapy and review pertinent pharmacology, pharmacokinetics, pharmacodynamics, and clinical pearls regarding the treatment of acute idiopathic (viral) pericarditis. NSAID and ASA Therapy Before 2005, nonsteroidal antiinflammatory drugs (NSAIDs) or aspirin (ASA) were considered the mainstay of treatment for pericarditis. The 2004 ESC guidelines recommended these agents as first-line therapy with the suggested treatment duration for “days or weeks.”15 Based on recent landmark trials (Table 1), NSAID/ASA therapy should be used as first-line therapy in combination with colchicine based on the reduction in recurrence rates compared with NSAID/ ASA monotherapy.4, 17, 21–24 It is important to note that the goal of using NSAID/ASA is relief of pain and the resolution of inflammation. However, NSAID/ASA therapy does not alter the natural history of pericarditis. The choice of NSAID-type or ASA therapy should be guided by patient-specific factors such as cost, dosage form, route of administration, comorbid conditions, and tolerability. Patients should be asked about which medication(s) they have tolerated in the past and what has or has not worked for them. This is an important consideration for the clinician because there have been no studies to date comparing the safety or efficacy among different NSAIDs for treating idiopathic pericarditis. Table 2 summarizes the results of studies in patients with pericarditis who have been treated with various NSAIDs and ASA, along with their usual doses. It should be noted that higher doses of NSAIDs/ASA should be used (outlined in Table 2) to achieve antiinflammatory effects. These doses are generally higher than what is normally used, and so the potential for adverse effects such as headache and central nervous system effects may determine NSAID selection.
These adverse effects are more common with indomethacin but are relatively uncommon with ibuprofen.27 Other considerations may include route of administration. Indomethacin can be given intravenously or rectally if the patient cannot tolerate capsules. Ibuprofen is available over the counter as a liquid formulation that can be given instead of a tablet. ASA is available as a tablet or suppository form and is the agent of choice in patients with ischemic heart disease (IHD), when the patient is already on ASA or needs antiplatelet treatment; the doses of ASA used in treating pericarditis are similar to those given to patients following a myocardial infarction.28 NSAIDs such as indomethacin or ibuprofen should be avoided in patients with IHD due to the potential for coronary vasoconstriction and scar formation interference after a coronary event.29 Ketorolac tromethamine is another option for the acute management of pain due to pericarditis.26 Although ketorolac can be administered orally at 10 mg/day every 4–6 hours (not to exceed 40 mg/day), it carries a black box warning that it is to be used only as an extension of parenteral therapy and should not exceed 5 days of therapy based on lack of benefit and increased potential for adverse effects such as gastrointestinal (GI) bleeding. NSAIDs in general are not recommended in patients with advanced renal disease, but ketorolac has specific dosage adjustments in patients with renal dysfunction.25 Appropriate use of NSAIDs or ASA therapy involves administering the drugs at least every 8 hours and maintaining an attack dose until symptoms resolve (usually in 1 wk) and normalization of hs-CRP. At the point of symptom resolution and normalization of hs-CRP, the dose of the agent may be tapered accordingly. If patients are not responding to NSAID therapy after 1 week, etiology other than idiopathic/viral should be explored. After 1 week of the attack dose, tapering should be utilized over 1 month, rather than simply discontinuing use of the agent, to avoid risk of recurrences.30 Colchicine The use of colchicine dates back to the first century A.D. and was eventually extracted and isolated from the meadow saffron plant in 1820 by two French chemists.31 Currently, colchicine is approved by the Food and Drug Administration (FDA) only for the treatment and prophylaxis of gout flares and for the treatment of familial Mediterranean fever, making its use for
Safety and efficacy of colchicine added to ASA for first episode of acute pericarditis Safety and efficacy of colchicine added to ASA for the secondary prevention of recurrence after first recurrence of pericarditis Safety and efficacy of colchicine added to ASA for the secondary prevention of recurrence after first recurrence of pericarditis Safety and efficacy of colchicine to treat a first attack of acute pericarditis and prevent recurrences Safety and efficacy of colchicine for treatment of multiple recurrences of pericarditis Frequency of hs-CRP elevation in acute pericarditis, its time course of normalization, and place for diagnosis, therapy, and prognosis
Aim
Group2: ASA/ NSAID + colchicine
Group 2: Colchicine + ASA/ IBU
Group 2: Colchicine + ASA/ IBU
Group 2: ASA + colchicine
Group 2: ASA + colchicine
ASA, indomethacin, or ibuprofen every 8 hrs with an attack dose for 7 days with gradual taper over 3–4 wks Colchicine (added at discretion of physician) for 3 mo with no attack dose
Group 1: Placebo + ASA/NSAID
Group 1: Placebo + ASA/IBU
Group 1: Placebo + ASA/IBU
Group 1: ASA
Group 1: ASA
Intervention
Recurrence
Incessant or recurrent pericarditis
Recurrence
Recurrence
Recurrence
Primary end point(s)
Group2: 21.6%
Group 2: 16.7%
Group 2: 24%
Group 2: 24%
NSAID/ASA attack dose should be continued until hs-CRP normalization instead of an empirical therapy length Persistently elevated hs-CRP may identify patients at higher risk of recurrence
Group 1: 42.5% p=0.0009
Group 1: 37.5% p
