The December journal club reviewed two papers, first up was Imazio’s paper investigating the benefits of treating pericarditis with colchicine. You should definitely know this paper and be implementing it into practice. This is a must read.
The second paper was a retrospective review looking at the presenting symptoms and labwork abnormalities in pediatric myocarditis.
Imazio et al. A Randomized Trial of Colchicine for Acute Pericarditis NEJM 2013
METHODS/SETTING/DESIGN/NUMBER OF PATIENTS INCLUDED
- Multicenter, double-blind randomized trail
- 240 patients, 120 per study group
- Colchicine at a dose of 0.5mg BID for 3 months for pts weighing > 70kg or 0.5 mg once daily for patients weighing <= 70 kg, vs placebo.
- Each participant also took a tapering dose of conventional anti-inflammatory therapy with aspirin, Ibuprofen, or corticosteroid.
- PPIs were also prescribed for GI prophylaxis
- 18 years of age or older
- First episode of pericarditis
- Etiology either idiopathic, viral, after cardiac injury, or associated with connective tissues disease
- Acute pericarditis was diagnosed with 2 of the following:
- Typical chest pain (sharp and pleuritic, improved by sitting up and leaning forward), or pain radiating to trapezius ridge.
- A pericardial friction rub
- Suggestive changes on ECG (widespread ST segment elevation or PR depression)
- New or worsening pericardial effusion
- Tuberculous, neoplastic, or purulent pericarditis
- Evidence of myopericarditis as indicated by elevation in serum troponin levels. This has become controversial with the new use of high sensitivity trops.
- Severe liver disease or current aminotransferase levels of more than 1.5 times the upper limit of the normal range
- Serum creatinine level of more than 221 umol/L
- Skeletal myopathy or a serum CK level above upper limit of the normal range
- Blood dyscrasia
- Inflammatory bowel disease
- Hypersensitivity to Colchicine or CI to it’s use
- Current treatment with Colchicine
- Life expectancy of < 18 months
- Pregnant, lactating women, or women of childbearing potential who were not protected by contraception
- Incessant or recurrent pericarditis
- Symptom persistence at 72 hours
- Remission within 1 week
- Number of recurrences
- The time to the first recurrence
- Disease-related hospitalization
- Cardiac tamponade
- Constrictive pericarditis
- Incessant or recurrent pericarditis occurred in 20 patients (16.7%) in the colchicine group, and 45 patients (37.5%) in the placebo group
- Relative risk reduction in the colchicine group of 0.56; 95% CI
- NNT to prevent on case of incessant or recurrent pericarditis was 4
- Reduced frequency of symptom persistence at 72 hours (19.2% vs 40.0%, P=0.001)
- Reduced number of recurrences per patient (0.21 vs 0.52, P=0.001)
- Reduced rate of hospitalization related to pericarditis (5.0% vs 14.2%, P=0.02)
- Improved rate of remission within 1 week (85% vs 58.3%, P< 0.001)
- Prolonged time to first recurrence (24.7 weeks vs 17.7 weeks, P <0.001)
- No significant difference in the incidence of adverse events (9.2% vs 8.3% for GI side effects)
- Multivariable analysis showed independent risk factors for recurrence were the use of glucocorticoids (OR 4.17,95% CI, 1.28 to 13.53; P=0.02) and CRP elevation at presentation (OR 3.15; 95% CI, 1.05 to 9.49; P=0.04)
- In patients with acute pericarditis, colchicine, when added to conventional anti-inflammatory therapy, significantly reduced the rate of incessant or recurrent pericarditis
Pros: This was a well designed, randomized, double-blind placebo controlled trial that was powered to find a clinically meaningful difference in a patient-centred outcome. The population studied was fairly representative of the patient population we will be seeing in the ED, and the follow-up interval was adequate, with excellent treatment adherence.
Cons: This study was not powered to detect differences in the more rare side effects that can be associated with colchicine, though it is not pragmatic to design such a trial. As there was no pre-planned subgroup analysis of patients who received the weight-adjusted lower dose versus those who received the conventional dose, and there is no evidence to suggest why a cut-off of 70kg was used, it is not accurate to state that low dose and conventional dose colchicine are equally efficacious, though it is biologically plausible and also supported by the results of the CORE and COPE trials.
Discussion Points: In light of the strong methodology of this trial, as well as multiple other favorable trials of colchicine in acute pericarditis (eg. CORP, COPE, recent Cochrane Review), using colchicine in first-episode, uncomplicated pericarditis patients will be considered by most staff. The trial used dosing regimens of 0.5-1.0mg daily based on patient weight; however, in Canada, colchicine is available as 0.6mg tablets, which would result in a 20% higher dose than that in the study. The clinical criteria used to define acute pericarditis in the trial are helpful to making the diagnosis of pericarditis in practice. Surprisingly, there was no increase in adverse GI side effects in the colchicine group.
Freedman et al. Pediatric Myocarditis: Emergency Department Clinical Findings and Diagnostic Evaluation Pediatrics 2007
OVERVIEW: This was a retrospective study aimed at describing the clinical presentations of pediatric patients with myocarditis– a very rare disease. This article was used to discuss how to critically appraise retrospective studies.
METHODS/SETTING/DESIGN/NUMBER OF PATIENTS INCLUDED
- Retrospective chart review looking at patients from May 2000 to May 2006
- Hospital for Sick Children in Toronto
- 31 patients with Myocarditis (16 with biopsy proven/definite myocarditis, and 15 with probable myocarditis)
- Charts were reviewed twice by single investigator, and two investigators independently classified patients exclusively into 1 of 5 presentations
- 5 ED clinical presentations were defined:
- Respiratory (rhinorrhea, cough, shortness of breath)
- Gastrointestinal (nausea, vomiting, diarrhea, or abdominal pain)
- Cardiac (chest pain or palpitations)
- Hypoperfusion (lethargy, lightheadedness, dizziness, syncope, or seizure)
- Kawasaki associated
- CXR defined as abnormal and associated with myocarditis if cardiomegaly, pulmonary vascular congestion, or pleural effusion present
- ECG defined as abnormal and associated with myocarditis if one of the following present: axis deviation, decreased ventricular voltages, ST segment or T wave abnormalities, atrial enlargement, ventricular enlargement, heart block, or an infarction pattern
- Echocardiogram findings defined as consistent with myocarditis included increased ventricular end systolic or diastolic dimension, reduced shortening or ejection fractions, atrioventricular valve regurgitation, and regional wall motion abnormalities
- Lab tests used age appropriate normal values were used (troponins were not used)
- All patients < 18 yrs of age
- Diagnosed at Hospital for Sick Children as having myocarditis between May 2000 and May 2006
- Initial presentation was to an emergency department (either Hospital for Sick Children or transferred from another institution) or if the child underwent autopsy at Hospital for Sick Children and had a diagnosis of myocarditis
- Initial presentation with myocarditis
- Either having definite myocarditis (biopsy proven) or probable myocarditis (diagnosis assigned by pediatric cardiologist on basis of history, physical examination, and investigation results in the absence of an endomyocardial biopsy or in presence of negative biopsy results)
- No ED visit
- Patients who did not meet the definitions of definite or probably myocarditis
- Inadequate documentation of initial presentation
- Discharge diagnosis other than myocarditis
- Relative frequency of ED presenting symptom complexes in children with myocarditis
- Sensitivity of clinical exam findings, laboratory investigations, chest radiographs, ECGs, and echocardiograms in diagnosis myocarditis
- The most common presenting symptoms at the time of ED presentation relate to the respiratory system
- These are age related and patients > 10 years of age present predominantly with chest pain, and < 10 with respiratory symptoms. Overall more presented with respiratory symptoms
- Sensitivity of clinical exam findings: most common physical exam feature was respiratory distress (68%), followed by tachycardia (18%)
- Sensitivity of laboratory investigations: AST level is most sensitive marker for myocarditis with an elevated value in 85% (including 1 child who had normal ECG and CXR
- Sensitivity of CXR: 55% sensitivity with cardiomegaly being most common abnormality (42%), followed by pulmonary venous congestion (32%)
- Sensitivity of ECGs: 93% of cases, with ST or T wave abnormalities being the most common (67%), and Axis deviation second with 37%
- 97% of children with either ECG or CXR done had an abnormality on one test
- Sensitivity of echocardiograms: 87% had abnormalities consistent with myocarditis with myocardial dysfunction detected more frequently among those with definite myocarditis
- Pediatric myocarditis presents primarily with respiratory and cardiac complaints
- Maintain a high index of suspicion for myocarditis even in absence of clinical findings of CHF
- When adequate clinical suspicion exists, screening tests should include CXR and ECGs
- Evidence of elevated liver enzyme levels should raise additional concern regarding myocarditis in the appropriate clinical scenario
Pros: Given how rare the diagnosis of myocarditis is (0.5/10000), the retrospective design of this trial was very appropriate. Moreover, the authors strengthened the quality of their chart review and limited potential bias as best possible by clearly defining variables a priori, drawing on multiple databases for patients to include, describing how missing or conflicting variables were dealt with, and using a third reviewer to clarify discrepancies in coding of the primary outcome.
Cons: Given that the lab tests and other investigations in the study were not necessarily applied to the entire population, a true sensitivity cannot be calculated based on the results.
Discussion Points: This article was used as an example to discuss how retrospective studies can be methodologically strengthened. Troponins were not checked routinely in this patient population. Key clinical take-homes include: the overall very low incidence of myocarditis, the biphasic age distribution, and that young children tend to present with respiratory symptoms, while older children tend to present with cardiac symptoms.
Thanks to Anjali Pandya (PGY-3 FRCPC EM program) and Tasha Haiduk (CCFP-EM resident) as well as Shawn Dowling for the journal club appraisals.