A randomized trial of colchicine for acute pericarditis.

BACKGROUND: Colchicine is effective for the treatment of recurrent pericarditis. However, conclusive data are lacking regarding the use of colchicine during a first attack of acute pericarditis and in the prevention of recurrent symptoms. METHODS: In a multicenter, double-blind trial, eligible adults with acute pericarditis were randomly assigned to receive either colchicine (at a dose of 0.5 mg twice daily for 3 months for patients weighing >70 kg or 0.5 mg once daily for patients weighing ≤70 kg) or placebo in addition to conventional antiinflammatory therapy with aspirin or ibuprofen. The primary study outcome was incessant or recurrent pericarditis. RESULTS: A total of 240 patients were enrolled, and 120 were randomly assigned to each of the two study groups. The primary outcome 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, 0.56; 95% confidence interval, 0.30 to 0.72; number needed to treat, 4; P<0.001). Colchicine reduced the rate of symptom persistence at 72 hours (19.2% vs. 40.0%, P=0.001), the number of recurrences per patient (0.21 vs. 0.52, P=0.001), and the hospitalization rate (5.0% vs. 14.2%, P=0.02). Colchicine also improved the remission rate at 1 week (85.0% vs. 58.3%, P<0.001). Overall adverse effects and rates of study-drug discontinuation were similar in the two study groups. No serious adverse events were observed. CONCLUSIONS: In patients with acute pericarditis, colchicine, when added to conventional antiinflammatory therapy, significantly reduced the rate of incessant or recurrent pericarditis. (Funded by former Azienda Sanitaria Locale 3 of Turin [now Azienda Sanitaria Locale 2] and Acarpia; ICAP ClinicalTrials.gov number, NCT00128453.).

Effect of Anakinra on Recurrent Pericarditis Among Patients With Colchicine Resistance and Corticosteroid Dependence: The AIRTRIP Randomized Clinical Trial.

Importance: Anakinra, an interleukin 1ß recombinant receptor antagonist, may have potential to treat colchicine-resistant and corticosteroid-dependent recurrent pericarditis. Objective: To determine the efficacy of anakinra for colchicine-resistant and corticosteroid-dependent recurrent pericarditis. Design, Setting, and Participants: The Anakinra-Treatment of Recurrent Idiopathic Pericarditis (AIRTRIP) double-blind, placebo-controlled, randomized withdrawal trial (open label with anakinra followed by a double-blind withdrawal step with anakinra or placebo until recurrent pericarditis occurred) conducted among 21 consecutive patients enrolled at 3 Italian referral centers between June and November 2014 (end of follow-up, October 2015). Included patients had recurrent pericarditis (with ≥3 previous recurrences), elevation of C-reactive protein, colchicine resistance, and corticosteroid dependence. Interventions: Anakinra was administered at 2 mg/kg per day, up to 100 mg, for 2 months, then patients who responded with resolution of pericarditis were randomized to continue anakinra (n = 11) or switch to placebo (n = 10) for 6 months or until a pericarditis recurrence. Main Outcomes and Measures: The primary outcomes were recurrent pericarditis and time to recurrence after randomization. Results: Eleven patients (7 female) randomized to anakinra had a mean age of 46.5 (SD, 16.3) years; 10 patients (7 female) randomized to placebo had a mean age of 44 (SD, 12.5) years. All patients were followed up for 12 months. Median follow-up was 14 (range, 12-17) months. Recurrent pericarditis occurred in 9 of 10 patients (90%; incidence rate, 2.06% of patients per year) assigned to placebo and 2 of 11 patients (18.2%; incidence rate, 0.11% of patients per year) assigned to anakinra, for an incidence rate difference of -1.95% (95% CI, -3.3% to -0.6%). Median flare-free survival (time to flare) was 72 (interquartile range, 64-150) days after randomization in the placebo group and was not reached in the anakinra group (P <.001). During anakinra treatment, 20 of 21 patients (95.2%) experienced transient local skin reactions: 1 (4.8%) herpes zoster, 3 (14.3%) transaminase elevation, and 1 (4.8%) ischemic optic neuropathy. No patient permanently discontinued the active drug. No adverse events occurred during placebo treatment. Conclusion and Relevance: In this preliminary study of patients with recurrent pericarditis with colchicine resistance and corticosteroid dependence, the use of anakinra compared with placebo reduced the risk of recurrence over a median of 14 months. Larger studies are needed to replicate these findings as well as to assess safety and longer-term efficacy. Trial Registration: clinicaltrials.gov Identifier: NCT02219828.

Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): a multicentre, double-blind, placebo-controlled, randomised trial.

BACKGROUND: Colchicine is effective for the treatment of acute pericarditis and first recurrences. However, conclusive data are lacking for the efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis. METHODS: We did this multicentre, double-blind trial at four general hospitals in northern Italy. Adult patients with multiple recurrences of pericarditis (≥two) were randomly assigned (1:1) to placebo or colchicine (0·5 mg twice daily for 6 months for patients weighing more than 70 kg or 0·5 mg once daily for patients weighing 70 kg or less) in addition to conventional anti-inflammatory treatment with aspirin, ibuprofen, or indometacin. Permuted block randomisation (size four) was done with a central computer-based automated sequence. Patients and all investigators were masked to treatment allocation. The primary outcome was recurrent pericarditis in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00235079. FINDINGS: 240 patients were enrolled and 120 were assigned to each group. The proportion of patients who had recurrent pericarditis was 26 (21·6%) of 120 in the colchicine group and 51 (42·5%) of 120 in the placebo group (relative risk 0·49; 95% CI 0·24-0·65; p=0·0009; number needed to treat 5). Adverse effects and discontinuation of study drug occurred in much the same proportions in each group. The most common adverse events were gastrointestinal intolerance (nine patients in the colchicine group vs nine in the placebo group) and hepatotoxicity (three vs one). No serious adverse events were reported. INTERPRETATION: Colchicine added to conventional anti-inflammatory treatment significantly reduced the rate of subsequent recurrences of pericarditis in patients with multiple recurrences. Taken together with results from other randomised controlled trials, these findings suggest that colchicine should be probably regarded as a first-line treatment for either acute or recurrent pericarditis in the absence of contraindications or specific indications. FUNDING: Azienda Sanitaria 3 of Torino (now ASLTO2).

Good prognosis for pericarditis with and without myocardial involvement: results from a multicenter, prospective cohort study.

BACKGROUND: The natural history of myopericarditis/perimyocarditis is poorly known, and recently published studies have presented contrasting data on their outcomes. The aim of the present article is to assess the prognosis of myopericarditis/perimyocarditis in a multicenter, prospective cohort study. METHODS AND RESULTS: A total of 486 patients (median age, 39 years; range, 18-83 years; 300 men) with acute pericarditis or a myopericardial inflammatory syndrome (myopericarditis/perimyocarditis; 85% idiopathic, 11% connective tissue disease or inflammatory bowel disease, 5% infective) were prospectively evaluated from January 2007 to December 2011. The diagnosis of acute pericarditis was based on the presence of 2 of 4 clinical criteria (chest pain, pericardial rubs, widespread ST-segment elevation or PR depression, and new or worsening pericardial effusion). Myopericardial inflammatory involvement was suspected with atypical ECG changes for pericarditis, arrhythmias, and cardiac troponin elevation or new or worsening ventricular dysfunction on echocardiography and confirmed by cardiac magnetic resonance. After a median follow-up of 36 months, normalization of left ventricular function was achieved in >90% of patients with myopericarditis/perimyocarditis. No deaths were recorded, as well as evolution to heart failure or symptomatic left ventricular dysfunction. Recurrences (mainly as recurrent pericarditis) were the most common complication during follow-up and were recorded more frequently in patients with acute pericarditis (32%) than in those with myopericarditis (11%) or perimyocarditis (12%; P<0.001). Troponin elevation was not associated with an increase in complications. CONCLUSIONS: The outcome of myopericardial inflammatory syndromes is good. Unlike acute coronary syndromes, troponin elevation is not a negative prognostic marker in this setting.

Percutaneous implantation of a second device in patients with residual right-to-left shunt after patent foramen ovale closure.

INTRODUCTION: The management of patients with residual right-to-left shunt (rRLS) after percutaneous patent foramen ovale (PFO) closure is debated. The aim of this study was to define the incidence of moderate-to-large rRLS and to report the feasibility, safety and long-term clinical outcome of transcatheter closure of rRLS. METHODS AND RESULTS: From June 2000 to March 2013, 322 subjects underwent percutaneous PFO closure. In 39 patients (12.1%) with moderate-to-large rRLS on transcranial Doppler (TCD) and/or transesophageal echocardiogram a second cardiac catheterization was performed with the aim of completing the closure. A second closure device was implanted in 21 patients (53.8%). In the remaining 18 (46.2%), a second device was not delivered for the following reasons: in 13 (72.2%) no residual passage could be crossed, in 5 (27.8%) the residual shunt was deemed to be negligible. No complications occurred. After the second procedure, complete closure was proved by TCD in 16/21 (76.2%) subjects. One patient received a third device. During follow-up (41 ± 19 months), no cerebrovascular ischemic accidents occurred. CONCLUSION: A second percutaneous PFO occlusion device can be safely implanted in patients with significant rRLS. However, a moderate-to-large rRLS on TCD and/or TEE may not necessarily represent a significant risk of further paradoxical embolization.

Colchicine for prevention of postpericardiotomy syndrome and postoperative atrial fibrillation: the COPPS-2 randomized clinical trial.

IMPORTANCE: Postpericardiotomy syndrome, postoperative atrial fibrillation (AF), and postoperative effusions may be responsible for increased morbidity and health care costs after cardiac surgery. Postoperative use of colchicine prevented these complications in a single trial. OBJECTIVE: To determine the efficacy and safety of perioperative use of oral colchicine in reducing postpericardiotomy syndrome, postoperative AF, and postoperative pericardial or pleural effusions. DESIGN, SETTING, AND PARTICIPANTS: Investigator-initiated, double-blind, placebo-controlled, randomized clinical trial among 360 consecutive candidates for cardiac surgery enrolled in 11 Italian centers between March 2012 and March 2014. At enrollment, mean age of the trial participants was 67.5 years (SD, 10.6 years), 69% were men, and 36% had planned valvular surgery. Main exclusion criteria were absence of sinus rhythm at enrollment, cardiac transplantation, and contraindications to colchicine. INTERVENTIONS: Patients were randomized to receive placebo (n=180) or colchicine (0.5 mg twice daily in patients ≥70 kg or 0.5 mg once daily in patients <70 kg; n=180) starting between 48 and 72 hours before surgery and continued for 1 month after surgery. MAIN OUTCOMES AND MEASURES: Occurrence of postpericardiotomy syndrome within 3 months; main secondary study end points were postoperative AF and pericardial or pleural effusion. RESULTS: The primary end point of postpericardiotomy syndrome occurred in 35 patients (19.4%) assigned to colchicine and in 53 (29.4%) assigned to placebo (absolute difference, 10.0%; 95% CI, 1.1%-18.7%; number needed to treat = 10). There were no significant differences between the colchicine and placebo groups for the secondary end points of postoperative AF (colchicine, 61 patients [33.9%]; placebo, 75 patients [41.7%]; absolute difference, 7.8%; 95% CI, -2.2% to 17.6%) or postoperative pericardial/pleural effusion (colchicine, 103 patients [57.2%]; placebo, 106 patients [58.9%]; absolute difference, 1.7%; 95% CI, -8.5% to 11.7%), although there was a reduction in postoperative AF in the prespecified on-treatment analysis (placebo, 61/148 patients [41.2%]; colchicine, 38/141 patients [27.0%]; absolute difference, 14.2%; 95% CI, 3.3%-24.7%). Adverse events occurred in 21 patients (11.7%) in the placebo group vs 36 (20.0%) in the colchicine group (absolute difference, 8.3%; 95% CI; 0.76%-15.9%; number needed to harm = 12), but discontinuation rates were similar. No serious adverse events were observed. CONCLUSIONS AND RELEVANCE: Among patients undergoing cardiac surgery, perioperative use of colchicine compared with placebo reduced the incidence of postpericardiotomy syndrome but not of postoperative AF or postoperative pericardial/pleural effusion. The increased risk of gastrointestinal adverse effects reduced the potential benefits of colchicine in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01552187.

Capmatinib plus nazartinib in patients with EGFR-mutated non-small cell lung cancer.

PURPOSE: This phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: In phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200-400 mg bid plus nazartinib 50-150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1-3 prior lines; EGFRL858R/ex19del; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0-2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFRL858R/ex19del; T790M-; any MET); group 4 (with food; 0-2 prior lines; EGFRL858R/ex19del; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1-3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients. RESULTS: The RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET- (n = 42), T790M+ (n = 29), and T790M- (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %). CONCLUSION: Capmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02335944.

Rationale and design of the COlchicine for Prevention of the Post-pericardiotomy Syndrome and Post-operative Atrial Fibrillation (COPPS-2 trial): a randomized, placebo-controlled, multicenter study on the use of colchicine for the primary prevention of the postpericardiotomy syndrome, postoperative effusions, and postoperative atrial fibrillation.

BACKGROUND: The efficacy and safety of colchicine for the primary prevention of the postpericardiotomy syndrome (PPS), postoperative effusions, and postoperative atrial fibrillation (POAF) remain uncertain. Although preliminary data from a single trial of colchicine given for 1 month postoperatively (COPPS trial) were promising, the results have not been confirmed in a large, multicenter trial. Moreover, in the COPPS trial, colchicine was given 3 days postoperatively. METHODS: The COPPS-2 study is a multicenter, double-blind, placebo-controlled randomized trial. Forty-eight to 72 hours before planned cardiac surgery, 360 patients, 180 in each treatment arm, will be randomized to receive placebo or colchicine without a loading dose (0.5 mg twice a day for 1 month in patients weighing ≥70 kg and 0.5 mg once for patients weighing <70 kg or intolerant to the highest dose). The primary efficacy end point is the incidence of PPS, postoperative effusions, and POAF at 3 months after surgery. Secondary end points are the incidence of cardiac tamponade or need for pericardiocentesis or thoracentesis, PPS recurrence, disease-related admissions, stroke, and overall mortality. CONCLUSIONS: The COPPS-2 trial will evaluate the use of colchicine for the primary prevention of PPS, postoperative effusions, and POAF, potentially providing stronger evidence to support the use of preoperative colchicine without a loading dose to prevent several postoperative complications. ClinicalTrials.gov Identifier: NCT01552187.

The diagnostic utility of transthoracic echocardiography for the diagnosis of infective endocarditis in the real world of the Italian Registry on Infective Endocarditis.

BACKGROUND: The choice of the imaging modality (transthoracic [TTE] vs. transesophageal echocardiography [TEE]) for the diagnosis of infective endocarditis (IE) depends on different variables. Aim of the present study is to provide updated data on the diagnostic sensitivity and the clinical usefulness of TTE vs. TEE from the Italian Registry on IE (RIEI). METHODS: The RIEI has enrolled consecutive cases of IE in every participating centre, evaluating diagnostic and therapeutic data from a real world practice perspective. RESULTS: From July 2007 to October 2010, 658 consecutive cases with definite IE according to Duke criteria have been enrolled in the RIEI (483 males). The following diagnostic echocardiographic exams were performed: 616 TTE (94%) and 476 TEE (72%). A positive TTE was recorded in 399 cases (65%), an uncertain TTE in 108 cases (17%), and a negative TTE in 109 cases (18%). For TEE, a positive study was reported in 451 cases (95%), uncertain in 13 cases (2.7%), and negative in 12 cases (2.5%) (P < 0.001). This difference is not evident in patients with tricuspid valve IE or i.v. drug addiction, and in Streptococcus bovis or Streptococcus viridans IE. TTE was significantly more performed before the admission and earlier than TEE during admission (P = 0.000). TTE was mainly responsible for the initial diagnosis in 59%. TEE contributed to changing the therapeutic approach in 42%. CONCLUSIONS: In the real world, TTE is performed earlier and more commonly, and it is the major echocardiographic tool for the initial diagnosis. TEE confirms its superior diagnostic sensitivity in most cases, although it is relatively underused.

Risk of constrictive pericarditis after acute pericarditis.

BACKGROUND: Constrictive pericarditis (CP) is considered a rare, dreaded possible complication of acute pericarditis. Nevertheless, there is a lack of prospective studies that have evaluated the specific risk according to different etiologies. The aim of this study is to evaluate the risk of CP after acute pericarditis in a prospective cohort study with long-term follow-up. METHODS AND RESULTS: From January 2000 to December 2008, 500 consecutive cases with a first episode of acute pericarditis (age, 51±16 years; 270 men) were prospectively studied to evaluate the evolution toward CP. Etiologies were viral/idiopathic in 416 cases (83.2%), connective tissue disease/pericardial injury syndromes in 36 cases (7.2%), neoplastic pericarditis in 25 cases (5.0%), tuberculosis in 20 cases (4.0%), and purulent in 3 cases (0.6%). During a median follow-up of 72 months (range, 24 to 120 months), CP developed in 9 of 500 patients (1.8%): 2 of 416 patients with idiopathic/viral pericarditis (0.48%) versus 7 of 84 patients with a nonviral/nonidiopathic etiology (8.3%). The incidence rate of CP was 0.76 cases per 1000 person-years for idiopathic/viral pericarditis, 4.40 cases per 1000 person-years for connective tissue disease/pericardial injury syndrome, 6.33 cases per 1000 person-years for neoplastic pericarditis, 31.65 cases for 1000 person-years for tuberculous pericarditis, and 52.74 cases per 1000 person-years for purulent pericarditis. CONCLUSIONS: CP is a relatively rare complication of viral or idiopathic acute pericarditis (<0.5%) but, in contrast, is relatively frequent for specific etiologies, especially bacterial.

Colchicine reduces postoperative atrial fibrillation: results of the Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) atrial fibrillation substudy.

BACKGROUND: Inflammation and pericarditis may be contributing factors for postoperative atrial fibrillation (POAF), and both are potentially affected by antiinflammatory drugs and colchicine, which has been shown to be safe and efficacious for the prevention of pericarditis and the postpericardiotomy syndrome (PPS). The aim of the Colchicine for the Prevention of the Post-Pericardiotomy Syndrome (COPPS) POAF substudy was to test the efficacy and safety of colchicine for the prevention of POAF after cardiac surgery. METHODS AND RESULTS: The COPPS POAF substudy included 336 patients (mean age, 65.7±12.3 years; 69% male) of the COPPS trial, a multicenter, double-blind, randomized trial. Substudy patients were in sinus rhythm before starting the intervention (placebo/colchicine 1.0 mg twice daily starting on postoperative day 3 followed by a maintenance dose of 0.5 mg twice daily for 1 month in patients ≥70 kg, halved doses for patients <70 kg or intolerant to the highest dose). The substudy primary end point was the incidence of POAF on intervention at 1 month. Despite well-balanced baseline characteristics, patients on colchicine had a reduced incidence of POAF (12.0% versus 22.0%, respectively; P=0.021; relative risk reduction, 45%; number needed to treat, 11) with a shorter in-hospital stay (9.4±3.7 versus 10.3±4.3 days; P=0.040) and rehabilitation stay (12.1±6.1 versus 13.9±6.5 days; P=0.009). Side effects were similar in the study groups. CONCLUSION: Colchicine seems safe and efficacious in the reduction of POAF with the potentiality of halving the complication and reducing the hospital stay.

Colchicine for recurrent pericarditis (CORP): a randomized trial.

BACKGROUND: Recurrence is the most common complication of pericarditis, affecting 10% to 50% of patients. OBJECTIVE: To evaluate the efficacy and safety of colchicine for the secondary prevention of recurrent pericarditis. DESIGN: Prospective, randomized, double-blind, placebo-controlled multicenter trial. (ClinicalTrials.gov registration number: NCT00128414) SETTING: 4 general hospitals in urban areas of Italy. PATIENTS: 120 patients with a first recurrence of pericarditis. INTERVENTION: In addition to conventional treatment, patients were randomly assigned to receive either placebo or colchicine, 1.0 to 2.0 mg on the first day followed by a maintenance dose of 0.5 to 1.0 mg/d, for 6 months. MEASUREMENTS: The primary study end point was the recurrence rate at 18 months. Secondary end points were symptom persistence at 72 hours, remission rate at 1 week, number of recurrences, time to first recurrence, disease-related hospitalization, cardiac tamponade, and rate of constrictive pericarditis. RESULTS: At 18 months, the recurrence rate was 24% in the colchicine group and 55% in the placebo group (absolute risk reduction, 0.31 [95% CI, 0.13 to 0.46]; relative risk reduction, 0.56 [CI, 0.27 to 0.73]; number needed to treat, 3 [CI, 2 to 7]). Colchicine reduced the persistence of symptoms at 72 hours (absolute risk reduction, 0.30 [CI, 0.13 to 0.45]; relative risk reduction, 0.56 [CI, 0.27 to 0.74]) and mean number of recurrences, increased the remission rate at 1 week, and prolonged the time to subsequent recurrence. The study groups had similar rates of side effects and drug withdrawal. LIMITATION: Multiple recurrences and neoplastic or bacterial causes were excluded. CONCLUSION: Colchicine is safe and effective for secondary prevention of recurrent pericarditis.

Nazartinib for treatment-naive EGFR-mutant non-small cell lung cancer: Results of a phase 2, single-arm, open-label study.

INTRODUCTION: Nazartinib, a novel third-generation EGFR-tyrosine kinase inhibitor, previously demonstrated antitumor activity and manageable safety in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) who received ≤ 3 prior lines of systemic therapy. Herein, we report phase 2 efficacy and safety of first-line nazartinib. METHODS: This single-arm, open-label, global study enrolled treatment-naive adult patients with stage IIIB/IV NSCLC harboring EGFR-activating mutations (eg, L858R and/or ex19del). Patients with neurologically stable and controlled brain metastases were also eligible. Patients received oral nazartinib 150 mg once daily. The primary endpoint was Blinded Independent Review Committee (BIRC)-assessed overall response rate (ORR) per RECIST v1.1. RESULTS: Forty-five patients received ≥ 1 dose of nazartinib. The median follow-up time from enrollment to data cutoff (November 1, 2019) was 30 months (range: 25-34). The BIRC-assessed ORR was 69% (95% CI, 53-82). The median progression-free survival (PFS) was 18 months (95% CI, 15-not estimable [NE]). The median overall survival was NE. In patients with baseline brain metastases (n = 18), the ORR and median PFS (95% CIs) were 67% (41-87) and 17 months (11-21). Seventeen of 18 patients had brain metastases as non-target lesions; the CNS lesions were absent/normalized in 9 of 17 (53%). Only 2 of 27 patients without baseline brain metastases developed new brain metastases postbaseline. Most frequent adverse events (≥ 25%, any grade, all-causality) were diarrhea (47%), maculopapular rash (38%), pyrexia (29%), cough, and stomatitis (27% each). CONCLUSIONS: First-line nazartinib demonstrated promising efficacy, including clinically meaningful antitumor activity in the brain, and manageable safety in patients with EGFR-mutant NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02108964.

Colchicine prevents early postoperative pericardial and pleural effusions.

BACKGROUND: No preventive pharmacologic strategies have been proven efficacious for the prevention of postoperative effusions after cardiac surgery. Colchicine is safe and efficacious for the prevention of pericarditis. On this basis, we realized a substudy of the COPPS trial to assess the efficacy and safety of colchicine for the prevention of postoperative pericardial and pleural effusions. METHODS: The COPPS is a multicenter, double-blind, randomized trial, where 360 consecutive patients (mean age 65.7 ± 12.3 years, 66% men), 180 in each treatment arm, were randomized on the third postoperative day to receive placebo or colchicine for 1 month (1.0 mg twice daily for the first day, followed by a maintenance dose of 0.5 mg twice daily in patients ≥70 kg, and halved doses for patients <70 kg). The incidence of postoperative effusions was evaluated in each study group. RESULTS: Despite similar baseline features, colchicine significantly reduced the incidence of postoperative pericardial (12.8% vs 22.8%, P = .019, relative risk reduction 43.9%, no. of patients needed to treat 10) and pleural effusions (12.2% vs 25.6%, P = .002, relative risk reduction 52.3%, no. of patients needed to treat 8). The rate of side effects (only gastrointestinal intolerance) and drug withdrawal was similar in the study groups with a trend toward an increased rate of both events for colchicine. In multivariable analysis, female gender (hazard ratio 1.76, 95% CI 1.03-3.03, P = .040) and pleura incision (hazard ratio 2.58, 95% CI 1.53-4.53, P < .001) were risk factors for postoperative effusions. CONCLUSIONS: Colchicine is safe and efficacious for the primary prevention of postoperative effusions after cardiac surgery.

Early angio-guided complete revascularization versus culprit vessel PCI followed by ischemia-guided staged PCI in STEMI patients with multivessel disease.

BACKGROUND: Optimal management of multivessel disease (MVD) in ST-segment elevation myocardial infarction (STEMI) patients treated by primary percutaneous coronary intervention (PCI) is still unclear. OBJECTIVES: To compare short- and long-term clinical outcomes of early-staged, angio-guided approach and delayed, ischemia-guided treatment of non-infarct-related arteries (IRAs). METHODS: Consecutive patients with STEMI and MVD treated with primary PCI in 6 tertiary care centers were retrospectively selected and analyzed. Major adverse cardiac events (MACE) were defined as the composite end-point of death, MI, and repeat revascularization. All the events were adjudicated according to the Academic Research Consortium (ARC) definitions. RESULTS: In the time period 2004-2008, 800 primary PCIs in STEMI patients with MVD were performed. Four hundred and seventeen were addressed to early-staged, angio-guided PCI of non-IRAs (CR group) and 383 to an incomplete revascularization (IncR group). During the hospital stay, no difference in terms of death and repeat revascularization was found between groups but the incidence of periprocedural MI/reinfarction and MACE was significantly higher in the CR group (13.9% vs. 3.1%, P = 0.01 and 14.1% vs. 9.1%, P = 0.017, respectively). At a mean follow-up of 642 ± 545 days, no difference in terms of death and MI was found between the CR and IncR group. The MACE-free survival was significantly higher in the IncR group (73.8% vs. 57%, log rank 0.05), mainly driven by the lower incidence of re-PCI. CONCLUSIONS: Early complete revascularization based only on angiographic findings in patients with STEMI and MVD is associated with an excess of periprocedural/re-MI and with a significantly higher incidence of MACE at follow-up.

Corticosteroids for recurrent pericarditis: high versus low doses: a nonrandomized observation.

BACKGROUND: Corticosteroid use is widespread in recurrent pericarditis, even if rarely indicated, and high doses (eg, prednisone 1.0 to 1.5 mg . kg(-1) . d(-1)) are generally recommended, although only weak evidence supports their use with possible severe side effects. The aim of this work was to compare side effects, recurrences and other complications, and hospitalizations of a low- versus high-dose regimen of prednisone for recurrent pericarditis. METHODS AND RESULTS: A retrospective review of all cases of recurrent pericarditis treated with corticosteroids according to different regimens from January 1996 to June 2004 was performed in 2 Italian referral centers. One hundred patients with recurrent pericarditis (mean age, 50.1+/-15.8 years; 57 females) were included in the study; 49 patients (mean age, 47.5+/-16.0; 25 females) were treated with low doses of prednisone (0.2 to 0.5 mg . kg(-1) . d(-1)), and 51 patients (mean age, 52.6+/-15.3; 32 females) were treated with prednisone 1.0 mg . kg(-1) . d(-1). Baseline demographic and clinical characteristics were well balanced across the groups. Each initial dose was maintained for 4 weeks and then slowly tapered. After adjustment for potential confounders (age, female gender, nonidiopathic origin), only high doses of prednisone were associated with severe side effects, recurrences, and hospitalizations (hazard ratio, 3.61; 95% confidence interval, 1.96 to 6.63; P<0.001). CONCLUSIONS: Use of higher doses of prednisone (1.0 mg . kg(-1) . d(-1)) for recurrent pericarditis is associated with more side effects, recurrences, and hospitalizations. Lower doses of prednisone should be considered when corticosteroids are needed to treat pericarditis.

Indicators of poor prognosis of acute pericarditis.

BACKGROUND: The clinical search for indicators of poor prognosis of acute pericarditis may be useful for clinical triage of patients at high risk of specific causal conditions or complications. The aim of the present article is to assess the relationship between clinical features at presentation and specific causes or complications. METHODS AND RESULTS: A total of 453 patients aged 17 to 90 years (mean age 52+/-18 years, 245 men) with acute pericarditis (post-myocardial infarction pericarditis was excluded) were prospectively evaluated from January 1996 to August 2004. A specific cause was found in 76 of 453 patients (16.8%): autoimmune in 33 patients (7.3%), neoplastic in 23 patients (5.1%), tuberculous in 17 patients (3.8%), and purulent in 3 patients (0.7%). In multivariable analysis, women (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.03 to 2.70; P=0.036) and patients with fever >38 degrees C (HR 3.56, 95% CI 1.82 to 6.95; P<0.001), subacute course (HR 3.97, 95% CI 1.66 to 9.50; P=0.002), large effusion or tamponade (HR 2.15, 95% CI 1.09 to 4.23; P=0.026), and failure of aspirin or of nonsteroidal anti-inflammatory drugs (HR 2.50, 95% CI 1.28 to 4.91; P=0.008) were at increased risk of specific causal conditions. After a mean follow-up of 31 months, complications were detected in 95 patients (21.0%): recurrences in 83 patients (18.3%), tamponade in 14 patients (3.1%), and constriction in 7 patients (1.5%). In multivariable analysis, women (HR 1.65, 95% CI 1.08 to 2.52; P=0.020) and patients with large effusion or tamponade (HR 2.51, 95% CI 1.37 to 4.61; P=0.003) and failure of aspirin or of nonsteroidal anti-inflammatory drugs (HR 5.50, 95% CI 3.56 to 8.51; P<0.001) were at increased risk of complications. CONCLUSIONS: Specific clinical features (fever >38 degrees C, subacute course, large effusion or tamponade, and aspirin or NSAID failure) may be useful to identify higher risk of specific causal conditions and complications.

Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial.

BACKGROUND: Colchicine is effective and safe for the treatment and prevention of recurrent pericarditis and might ultimately serve as the initial mode of treatment, especially in idiopathic cases. The aim of this work was to verify the safety and efficacy of colchicine as an adjunct to conventional therapy for the treatment of the first episode of acute pericarditis. METHODS AND RESULTS: A prospective, randomized, open-label design was used. A total of 120 patients (mean age 56.9+/-18.8 years, 54 males) with a first episode of acute pericarditis (idiopathic, viral, postpericardiotomy syndromes, and connective tissue diseases) were randomly assigned to conventional treatment with aspirin (group I) or conventional treatment plus colchicine 1.0 to 2.0 mg for the first day and then 0.5 to 1.0 mg/d for 3 months (group II). Corticosteroid therapy was restricted to patients with aspirin contraindications or intolerance. The primary end point was recurrence rate. During the 2873 patient-month follow-up, colchicine significantly reduced the recurrence rate (recurrence rates at 18 months were, respectively, 10.7% versus 32.3%; P=0.004; number needed to treat=5) and symptom persistence at 72 hours (respectively, 11.7% versus 36.7%; P=0.003). After multivariate analysis, corticosteroid use (OR 4.30, 95% CI 1.21 to 15.25; P=0.024) was an independent risk factor for recurrences. Colchicine was discontinued in 5 cases (8.3%) because of diarrhea. No serious adverse effects were observed. CONCLUSIONS: Colchicine plus conventional therapy led to a clinically important and statistically significant benefit over conventional treatment, decreasing the recurrence rate in patients with a first episode of acute pericarditis. Corticosteroid therapy given in the index attack can favor the occurrence of recurrences.

Colchicine as first-choice therapy for recurrent pericarditis: results of the CORE (COlchicine for REcurrent pericarditis) trial.

BACKGROUND: Colchicine seems to be a good drug for treating recurrences of pericarditis after conventional treatment failure, but no clinical trial has tested the effects of colchicine as first-line drug for the treatment of the first recurrence of pericarditis. METHODS: A prospective, randomized, open-label design was used to investigate the safety and efficacy of colchicine therapy as adjunct to conventional therapy for the first episode of recurrent pericarditis. Eighty-four consecutive patients with a first episode of recurrent pericarditis were randomly assigned to receive conventional treatment with aspirin alone or conventional treatment plus colchicine (1.0-2.0 mg the first day and then 0.5-1.0 mg/d for 6 months). When aspirin was contraindicated, prednisone (1.0-1.5 mg/kg daily) was given for 1 month and then was gradually tapered. The primary end point was the recurrence rate. Intention-to-treat analyses were performed by treatment group. RESULTS: During 1682 patient-months (mean follow-up, 20 months), treatment with colchicine significantly decreased the recurrence rate (actuarial rates at 18 months were 24.0% vs 50.6%; P = .02; number needed to treat = 4.0; 95% confidence interval 2.5-7.1) and symptom persistence at 72 hours (10% vs 31%; P = .03). In multivariate analysis, previous corticosteroid use was an independent risk factor for further recurrences (odds ratio, 2.89; 95% confidence interval, 1.10-8.26; P = .04). No serious adverse effects were observed. CONCLUSION: Colchicine therapy led to a clinically important and statistically significant benefit over conventional treatment, decreasing the recurrence rate in patients with a first episode of recurrent pericarditis.