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.

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.

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.

Intravenous human immunoglobulins for refractory recurrent pericarditis: a systematic review of all published cases.

AIMS: Refractory recurrent pericarditis is a major clinical challenge after colchicine failure, especially in corticosteroid-dependent patients. Human intravenous immunoglobulins (IVIGs) have been proposed as possible therapeutic options for these cases. The goal of this systematic review is to assess the efficacy and safety of IVIGs in this context. METHODS: Studies reporting the use of IVIG for the treatment of recurrent pericarditis and published up to October 2014 were searched in several databases. All references found, upon initial assessment at title and abstract level for suitability, were consequently retrieved as full reports for further appraisal. RESULTS: Among the 18 citations retrieved, 17 reports (4 case series and 13 single case reports, with an overall population of 30 patients) were included. The mean disease duration was 14 months and the mean number of recurrences before IVIG was 3. Approximately 47% of patients had idiopathic recurrent pericarditis, 10% had an infective cause, and the remainder a systemic inflammatory disease. Nineteen out of the 30 patients (63.3%) were on corticosteroids at IVIG commencement. IVIGs were generally administered at a dose of 400-500 mg/kg/day for 5 consecutive days with repeated cycles according to the clinical response. Complications were uncommon (headache in ~3%) and not life-threatening. After a mean follow-up of approximately 33th months, recurrences occurred in 26.6% of cases after the first IVIG cycle, and 22 of the 30 patients (73.3%) were recurrence-free. Five patients (16.6%) were on corticosteroids at the end of the follow-up. CONCLUSIONS: IVIGs are rapidly acting, well tolerated, and efficacious steroid-sparing agents in refractory pericarditis.

Incidence and prognostic significance of new onset atrial fibrillation/flutter in acute pericarditis.

OBJECTIVE: Data on the incidence of new onset atrial fibrillation and flutter (AF/f) in patients with acute pericarditis are limited. We sought to determine the incidence and prognostic significance of AF/f in this setting. METHODS: Between January 2006 and June 2014, consecutive new cases of acute pericarditis were included in two urban referral centres for pericardial diseases. All new cases of AF/f defined as episodes lasting ≥30 s were recorded. Events considered during follow-up consisted of AF/f and pericarditis recurrence, cardiac tamponade, pericardial constriction and death. RESULTS: 822 consecutive new cases of acute pericarditis (mean age 53±15 years, 444 men) were analysed. AF/f was detected in 35 patients (4.3%, mean age 66.5±11.3 years, 18 men). Patients with AF/f were significantly older (p=0.017) and presented more frequently with pericardial effusion (p<0.001). Arrhythmias developed within 24 h of pericarditis onset in 91.4% of cases, lasted >24 h in 25.7% and spontaneously converted in 74.3% of patients. Underlying structural heart disease was present in 17% of AF/f cases. In a 30-month follow-up, patients with history of AF/f at the initial episode had a higher rate of arrhythmia occurrence (34.3% vs 0.9%, p<0.001), mostly (75%) within 3 months. No other differences were detected in additional clinical events including haemorrhagic complications in patients receiving oral anticoagulation. CONCLUSIONS: The occurrence of AF/f in acute pericarditis identifies a predisposed population to AF/f with a high recurrence risk (about 35%): in these patients, pericarditis may act as an arrhythmic trigger and oral anticoagulation should be seriously considered according to guidelines.

Clinical epidemiology in Italian Registry of Infective Endocarditis (RIEI): Focus on age, intravascular devices and enterococci.

INTRODUCTION: The epidemiology of infective endocarditis (IE) is changing due to a number of factors, including aging and health related comorbidities and medical procedures. The aim of this study is to describe the main clinical, epidemiologic and etiologic changes of IE from a large database in Italy. METHODS: We prospectively collected episodes of IE in 17 Italian centers from July 2007 to December 2010. RESULTS: We enrolled 677 patients with definite IE, of which 24% health-care associated. Patients were male (73%) with a median age of 62 years (IQR: 49-74) and 61% had several comorbidities. One hundred and twenty-eight (19%) patients had prosthetic left side IE, 391 (58%) native left side IE, 94 (14%) device-related IE and 54 (8%) right side IE. A predisposing cardiopathy was present in 50%, while odontoiatric and non odontoiatric procedures were reported in 5% and 21% of patients respectively. Symptoms were usually atypical and precocious. The prevalent etiology was represented by Staphylococcus aureus (27%) followed by coagulase-negative staphylococci (CNS, 21%), Streptococcus viridans (15%) and enterococci (14%). CNS and enterococci were relatively more frequent in patients with intravascular devices and prosthesis and S. viridans in left native valve. Diagnosis was made by transthoracic and transesophageal echocardiography in 62% and 94% of cases, respectively. The in-hospital mortality was 14% and 1-year mortality was 21%. CONCLUSION: The epidemiology is changing in Italy, where IE more often affects older patients with comorbidities and intravascular devices, with an acute onset and including a high frequency of enterococci. There were few preceding odontoiatric procedures.

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.

Patent foramen ovale treatment strategy: an Italian large prospective study.

AIM: There is still controversy regarding the benefit of percutaneous closure of patent foramen ovale (PFO) among patients with cryptogenic stroke. Here we aimed to evaluate the factors associated with treatment choice and predictors of adverse events in patients with cryptogenic stroke or transient ischemic attack (TIA) and PFO. METHODS: Of 418 consecutive patients with PFO and cryptogenic stroke or TIA, 262 underwent percutaneous PFO closure, whereas 156 were medically treated. Multivariable logistic regression models were developed to evaluate factors influencing the treatment strategy and predictors of outcome, a composite of stroke, TIA or all-cause mortality. RESULTS: Patients with large interatrial right-to-left shunt were more likely treated with percutaneous closure [odds ratio (OR) = 4.79, 95% confidence interval (2.73-8.42); P < 0.0001], whereas those with multiple cerebrovascular accident (CVA) risk factors were more likely treated medically [OR = 0.15 (0.03-0.60); P = 0.023]. Age greater than 55 years [OR = 2.70 (1.05-6.88); P = 0.04], previous CVAs [OR = 2.49 (1.03-6.02); P = 0.02] and atrial septal aneurism [ASA, OR = 2.64 (1.09-6.39); P = 0.02], but not percutaneous closure of PFO [OR = 1.10 (0.44-2.74); P = 0.81], were independent predictors of outcome. CONCLUSION: Among patients with cryptogenic stroke and PFO, the presence of large interatrial right-to-left shunt and multiple CVA risk factors influenced the treatment choice. Older age, multiple previous CVAs and ASA, but not PFO closure, independently predicted the composite outcome of cryptogenic stroke, TIA or all-cause mortality.

Colchicine for the prevention of pericarditis: what we know and what we do not know in 2014 - systematic review and meta-analysis.

AIMS: The purpose of this study was to investigate and summarize available evidence on the efficacy and safety of colchicine for pericarditis prevention. Disease recurrence is the major and most common complication of pericarditis and its prevention may reduce morbidity and management costs. Colchicine has been intensively studied in the last decade for pericarditis prevention. METHODS: Controlled clinical studies were searched in several databases and were included provided they focused on the pharmacologic primary or secondary prevention of pericarditis. We performed a meta-analysis including studies of primary outcome, adverse events and drug withdrawal. RESULTS: From the initial sample of 175 citations, seven controlled clinical trials were finally included (1275 patients): five studies were double-blind randomized controlled trials (RCT), and two studies were open-label RCTs. Trials followed patients for a mean of 19 months. Meta-analytic pooling showed that colchicine use was associated with a reduced risk of pericarditis during follow-up [odds ratio (OR) 0.33 (0.25-0.44), P for effect <0.001, P for heterogeneity 0.98, I = 0%] either for primary or secondary prevention without a significant higher risk of adverse events [OR 1.28 (0.84-1.93), P for effect = 0.25, P for heterogeneity = 0.72, I = 0%], and drug withdrawals compared with placebo [OR 1.54 (0.98-2.41), P for effect = 0.06, P for heterogeneity = 0.54, I = 0%]. Gastrointestinal intolerance is the most frequent side-effect (mean incidence 8%), but no severe adverse events were recorded. CONCLUSION: Colchicine is well tolerated and efficacious for the primary and secondary prevention of pericarditis without a significant increase of the risk of side-effects and drug withdrawals.

Prognostic indicators for recurrent thrombotic events in HIV-infected patients with acute coronary syndromes: use of registry data from 12 sites in Europe, South Africa and the United States.

AIMS: Limited data are available on prognostic indicators for HIV patients presenting with ACS. METHODS AND RESULTS: Data on consecutive patients with HIV infection receiving standard highly active antiretroviral therapy (HAART) presenting with ACS between January 2001 and September 2012 were collected. Cardiac death and myocardial infarction (MI) were the primary end-points. 10,050 patients with ACS were screened, and among them a total of 201 patients (179 [89%] males and a median age of 53 [47-62] years) were included, 48% of them admitted for ST-elevation myocardial infarction and 14% having left ventricular systolic dysfunction (LVSD) at discharge. CD4+ counts less than 200 cells/mm(3) were reported in 18 patients (9%), and 136 patients (67%) were treated with nucleoside-reverse transcriptase inhibitors (NRTI). After a median of 24 months (10-41), 30 patients (15%) died, 12 (6%) for cardiac reasons, 20 (10%) suffered a MI, 29 (15%) a subsequent revascularization, and 7 (3%) a stent thrombosis. Other than LVSD (hazard ratio=6.4 [95% confidence interval [CI]: 1.6-26: p=0.009]), the only other independent predictor of cardiac death was not being treated with NRTI (hazard ratio=9.9 [95% CI: 2.1-46: p=0.03); a CD4 cell count <200 cells/mm(3) was the only predictor of MI (hazard ratio=5.9 [95% CI: 1.4-25: p=0.016]). CONCLUSIONS: HIV patients presenting with ACS are at significantly increased risk for cardiac death if not treated with NRTI, and at significantly increased risk of MI if their CD4 cell count is <200 cells/mm(3), suggesting that the stage of HIV disease (and lack of NRTI treatment) may contribute to cardiovascular instability.

[Clinical and economical comparison between in-house (Make) and outsourcing (Buy) management of the cardiac catheterization laboratory from two high-volume diagnostic and interventional centers: immediate and 6-month results]. / Confronto clinico ed economico tra gestione aziendale (Make) ed esternalizzata (Buy) del laboratorio di emodinamica di due centri ad elevato volume di procedure diagnostiche ed interventistiche coronariche: risultati immediati e a 6 mesi.

BACKGROUND: Percutaneous coronary interventions (PCI) are widespread procedures in the Italian Healthcare System, but concerns are raised about their economic sustainability. In the last decade, public hospitals have outsourced the PCI services (building and maintaining the technological instruments and the personnel) "buying" them from private companies (Buy) rather than building and maintaining them through public expenditure (Make). The aim of this study was to compare the economic and clinical impact of these two management solutions (Buy and Make) in two community hospitals located in the Turin metropolitan area (Italy). METHODS: We conducted: 1) a quantitative assessment in order to compare differences in the economic impact between Buy and Make for providing PCI; 2) a qualitative assessment comparing the clinical characteristics of two inpatient populations undergoing PCI and then analyzing the efficacy of the procedure in-hospital and at 6-month follow-up. RESULTS: Between January and June 2010, a total of 332 patients underwent PCI at the "degli Infermi" Hospital in Rivoli and 340 at the "Maria Vittoria" Hospital in Turin (Italy). There were no significant differences between the two populations neither about the clinical characteristics nor in procedural efficacy (either immediate or at follow-up). For 600 units of diagnostic-therapeutic pathway, the net present value at a discount rate of 3.5% of the Make project is higher than that of the Buy by €278.402,25, and is therefore the less convenient of the two solutions. The Buy solution is still the more convenient of the two at volumes <700 units. CONCLUSIONS: Our findings show that the Buy solution, if tailored to the specific local needs, provides access to sophisticated technology without making worse quality of services and may save capital expenditure below 700 PCI/years.

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).

Impact of transcatheter closure of patent foramen ovale in the evolution of migraine and role of residual shunt.

OBJECTIVES: To retrospectively evaluate the impact on daily activities of transcatheter closure of patent foramen ovale (PFO) versus medical therapy in patients with migraine and to analyze the role of the residual shunt after PFO closure. BACKGROUND: While non-controlled observational studies reported an improvement of migraine after PFO closure, a randomized trial has shown no benefit of such an intervention. The role of residual shunt after PFO closure is also poorly known. METHODS: Out of 217 patients with migraine and echocardiographic evidence of PFO, 89 were managed with percutaneous PFO closure (Group A) while 128 were medically treated (Group B). All MIDAS questionnaires were obtained at the first evaluation and repeated at least 6 months after the index evaluation or after the PFO closure. All the patients were also asked to give a subjective estimate of their migraine status. A postprocedural transcranial Doppler study was available in 70 patients in Group A. RESULTS: The mean basal MIDAS score did not differ between the two groups (p = 0.859). After a mean follow-up (FU) of 1399 ± 982 days the MIDAS score decreased significantly in both groups (Group A baseline vs FU, p < 0.001; Group B baseline vs FU, p < 0.001), but no differences were observed between groups (p = 0.204). However a significantly higher number of Group A patients reported a perceived clinical benefit or the disappearance of migraine compared to Group B (p < 0.001). Patients with moderate or severe residual right to left shunt were no more likely to have an higher MIDAS score or to complain of migraine than those with mild or no shunt. CONCLUSIONS: Although the overall evolution of migraine is not significantly different, the abolition of migraine occurs in a larger proportion after PFO closure.

DRainage Or Pericardiocentesis alone for recurrent nonmalignant, nonbacterial pericardial effusions requiring intervention: rationale and design of the DROP trial, a randomized, open-label, multicenter study.

OBJECTIVES: Evidence to support the use of pericardial drainage instead of simple pericardiocentesis for nonmalignant pericardial effusions refractory to medical therapy is based on observational studies and experts' opinions, rather than randomized trials. The aim of the present trial is to fill this knowledge gap and to provide a stronger base of evidence to support a specific interventional treatment in this setting. METHODS: DRainage Or Pericardiocentesis (DROP) alone for recurrent nonmalignant, nonbacterial pericardial effusions requiring intervention is a randomized, open-label and multicenter study. The primary efficacy endpoints are the incidence of recurrent pericardial effusion, and the need for additional pericardiocentesis or cardiac surgery at 12 months. Secondary endpoints are hospital length stay, disease-related admission and overall mortality. Safety and complications rates of each intervention will be also assessed. IMPLICATIONS AND CONCLUSION: The DROP trial will be the first multicenter randomized trial to evaluate the efficacy and safety of pericardiocentesis versus pericardiocentesis and extended pericardial drainage for recurrent nonmalignant, nonbacterial pericardial effusions refractory to medical therapy and requiring interventional treatments (ClinicalTrials.gov Identifier: NCT01665495).

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.).

A clinical and angiographic study of the XIENCE V everolimus-eluting coronary stent system in the treatment of patients with multivessel coronary artery disease: the EXECUTIVE trial (EXecutive RCT: evaluating XIENCE V in a multi vessel disease).

OBJECTIVES: This study sought to investigate the efficacy and performance of the XIENCE V everolimus-eluting stent (EES) (Abbott Vascular, Santa Clara, California) in the treatment of de novo coronary lesions in patients with 2- to 3-vessel multivessel coronary artery disease (MV-CAD). BACKGROUND: Drug-eluting stents (DES) have emerged as an alternative to conventional coronary artery bypass surgery in patients with MV-CAD although first-generation DES yielded inferior efficacy and safety compared with surgery. METHODS: Prospective, randomized (1:1), multicenter feasibility trial was designed to assess angiographic efficacy of EES compared with the TAXUS paclitaxel-eluting stent (PES) in 200 patients, and a prospective, open-label, single-arm, controlled registry was designed to analyze the clinical outcome of EES at 1-year follow-up in 400 MV-CAD patients. For the randomized trial, the primary endpoint was in-stent late loss at 9 months. For the registry, the primary endpoint was a composite of all-cause death, myocardial infarction, and ischemia-driven target vessel revascularization at 12 months. RESULTS: The primary endpoint per single lesion was significantly lower in the EES group compared with the PES group (-0.03 ± 0.49 mm vs. 0.23 ± 0.51 mm, p = 0.001). Similar results were observed when analyzing all lesions (0.05 ± 0.51 mm vs. 0.24 ± 0.50 mm, p < 0.001). Clinical outcome at 1 year yielded a composite of major adverse cardiac events of 9.2% in the single-arm registry, and 11.1% and 16.5% in the EES and PES randomized groups, respectively (p = 0.30). CONCLUSIONS: The EXECUTIVE trial was a randomized pilot trial dedicated to the comparison of the efficacy of 2 different DES among patients with 2- to 3-vessel MV-CAD. The study shows lower in-stent late loss at 9 months with the EES XIENCE V compared with the PES TAXUS Libertè, and a low major adverse cardiac event rate at 1 year in patients with 2-to 3-vessel MV-CAD. (EXECUTIVE [EXecutive RCT: Evaluating XIENCE V in a Multi Vessel Disease]; NCT00531011).

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.

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.