Numerous patients are treated with the MitraClip, although they do not fulfill the stringent inclusion criteria of the Endovascular Valve Edge-to-Edge Repair Study (EVEREST) trials. The outcome of ...those patients is not well known. Therefore, we compared the long-term outcome after MitraClip treatment between patients who matched (group 1) and did not match (group 2) the EVEREST criteria. One hundred thirty-four consecutive patients were treated from September 2009 to July 2012: 59 patients (44%) in group 1 versus 75 patients (56%) in group 2. Investigated end points were acute procedural success (for group 1 vs 2: 97% vs 95%; p = 0.694), all-cause mortality (28% vs 27%; p = 0.656), reintervention (RI) rate (11% vs 37%; p = 0.010), and improvement in mitral regurgitation (MR) (−1.3 ± 1 vs −1.5 ± 1, p = 0.221) and in New York Heart Association functional class (−0.7 ± 1 vs −0.9 ± 0.8, p = 0.253) during the follow-up of 33 months (27.9 to 38.3). The morphologic extent of a flail leaflet was an independent predictor for RI. In conclusion, although the overall outcome was comparable between both groups, recurrent symptomatic MR with need for RI was higher in group 2, mainly because of complex valve pathologies: especially flail width >15 mm and gap ≥10 mm. Improvements in the interventional strategy are warranted for reducing the need for RI in patients with primary MR.
Midterm outcomes for patients presenting with heart failure and functional mitral regurgitation (MR) treated with Mitraclip remain unclear. Pubmed, Medline, and Google Scholar were systematically ...searched for studies enrolling patients with severe-moderate MR who underwent Mitraclip implantation. All events after at least 6 months were the primary safety end point (including death, rehospitalization for heart failure, and reinterventions), whereas change in the ejection fraction, left ventricular volumes, arterial pulmonary pressure, and left atrial diameters were considered as secondary end points. Meta-regression analysis was performed to evaluate the effect of baseline clinical and echocardiographic parameters on efficacy outcomes: 875 patients were included in 9 studies; 1.48 clips (1.3 to 1.7) for patients were implanted, and after a median follow-up of 9 months (6 to 12), 409 patients (78% 75% to 83%) were in class New York Heart Association I/II and 57 (11% 8% to 14%) still had moderate-to-severe MR. Overall adverse events occurred in 137 (26% 20% to 31%) of the patients and 78 (15% 1% to 17%) of them died; 6-minute walk test improved by 100 m (83 to 111), whereas a significant reduction in left ventricular volumes and systolic pulmonary pressure was reported. At meta-regression analysis, an increase in left ventricle systolic volumes positively affected reduction of volumes after Mitraclip, whereas atrial fibrillation reduced the positive effect of the valve implantation on ejection fraction on end-diastolic and -systolic volumes. In conclusion, Mitraclip represents an efficacious strategy for patients with heart failure and severe MR. It offers a significant improvement in functional class and in cardiac remodeling, in patients with severely dilated hearts as well, although its efficacy remains limited in the presence of atrial fibrillation.
Summary Background Ixekizumab is a humanised monoclonal antibody against the proinflammatory cytokine interleukin 17A. We report two studies of ixekizumab compared with placebo or etanercept to ...assess the safety and efficacy of specifically targeting interleukin 17A in patients with widespread moderate-to-severe psoriasis. Methods In two prospective, double-blind, multicentre, phase 3 studies (UNCOVER-2 and UNCOVER-3), eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic plaque psoriasis at least 6 months before baseline (randomisation), 10% or greater body-surface area involvement at both screening and baseline visits, at least a moderate clinical severity as measured by a static physician global assessment (sPGA) score of 3 or more, and a psoriasis area and severity index (PASI) score of 12. Participants were randomly assigned (1:2:2:2) by computer-generated random sequence with an interactive voice response system to receive subcutaneous placebo, etanercept (50 mg twice weekly), or one injection of 80 mg ixekizumab every 2 weeks, or every 4 weeks after a 160 mg starting dose. Blinding was maintained with a double-dummy design. Coprimary efficacy endpoints were proportions of patients achieving sPGA score 0 or 1 and 75% or greater improvement in PASI at week 12. Analysis was by intention to treat. These trials are registered with ClinicalTrials.gov , numbers NCT01597245 and NCT01646177. Findings Between May 30, 2012, and Dec 30, 2013, 1224 patients in UNCOVER-2 were randomly assigned to receive subcutaneous placebo (n=168), etanercept (n=358), or ixekizumab every 2 weeks (n=351) or every 4 weeks (n=347); between Aug 11, 2012, and Feb 27, 2014, 1346 patients in UNCOVER-3 were randomly assigned to receive placebo (n=193), etanercept (n=382), ixekizumab every 2 weeks (n=385), or ixekizumab every 4 weeks (n=386). At week 12, both primary endpoints were met in both studies. For UNCOVER-2 and UNCOVER-3 respectively, in the ixekizumab every 2 weeks group, PASI 75 was achieved by 315 (response rate 89·7%; effect size 87·4% (97·5% CI 82·9–91·8) vs placebo; 48·1% (41·2–55·0) vs etanercept) and 336 (87·3%; 80·0% (74·4–85·7) vs placebo; 33·9% (27·0–40·7) vs etanercept) patients; in the ixekizumab every 4 weeks group, by 269 (77·5%; 75·1% (69·5–80·8) vs placebo; 35·9% (28·2–43·6) vs etanercept) and 325 (84·2%; 76·9% (71·0–82·8) vs placebo; 30·8% (23·7–37·9) vs etanercept) patients; in the placebo group, by four (2·4%) and 14 (7·3%) patients; and in the etanercept group by 149 (41·6%) and 204 (53·4%) patients (all p<0·0001 vs placebo or etanercept). In the ixekizumab every 2 weeks group, sPGA 0/1 was achieved by 292 (response rate 83·2%; effect size 80·8% (97·5% CI 75·6–86·0) vs placebo; 47·2% (39·9–54·4) vs etanercept) and 310 (80·5%; 73·8% (67·7–79·9) vs placebo; 38·9% (31·7–46·1) vs etanercept) patients; in the ixekizumab every 4 weeks group by 253 (72·9%; 70·5% (64·6–76·5) vs placebo; 36·9% (29·1–44·7) vs etanercept) and 291 (75·4%; 68·7% (62·3–75·0) vs placebo; 33·8% (26·3–41·3) vs etanercept) patients; in the placebo group by four (2·4%) and 13 (6·7%) patients; and in the etanercept group by 129 (36·0%) and 159 (41·6%) patients (all p<0·0001 vs placebo or etanercept). In combined studies, serious adverse events were reported in 14 (1·9%) of 734 patients given ixekizumab every 2 weeks, 14 (1·9%) of 729 given ixekizumab every 4 weeks, seven (1·9%) of 360 given placebo, and 14 (1·9%) of 739 given etanercept; no deaths were noted. Interpretation Both ixekizumab dose regimens had greater efficacy than placebo and etanercept over 12 weeks in two independent studies. These studies show that selectively neutralising interleukin 17A with a high affinity antibody potentially gives patients with psoriasis a new and effective biological therapy option. Funding Eli Lilly and Co.
Background Safety of biologics is important when treating patients with psoriasis. Objective We sought to determine the safety of ixekizumab in psoriasis. Methods Integrated safety data are presented ...from a 12-week induction period, a 12- to 60-week maintenance period, and from all ixekizumab-treated patients from 7 clinical trials. Exposure-adjusted incidence rates (IRs) per 100 patient-years are reported. Results Overall, 4209 patients received ixekizumab (total exposure: 6480 patient-years). During the induction period, the IRs of patients experiencing 1 or more treatment-emergent adverse event (AE) were 251 and 236 among ixekizumab- and etanercept-treated patients, respectively, and for serious AEs was 8.3 in both groups. During maintenance, for ixekizumab, the IRs of treatment-emergent AEs and serious AEs were 100.4 and 7.8, respectively. Among all ixekizumab-treated patients from 7 trials, the IR of Candida infections was 2.5. The IRs of treatment-emergent AEs of special interest (including serious infections, malignancies, major adverse cardiovascular events) were comparable for ixekizumab and etanercept during the induction period. Limitations Additional long-term data are required. Conclusion Ixekizumab had an acceptable safety profile with no unexpected safety findings during ixekizumab maintenance in psoriasis.
Background Patients with moderate to severe plaque psoriasis demonstrated positive responses to ixekizumab, an anti-interleukin-17A monoclonal antibody, in a phase-II, randomized, placebo-controlled ...trial. Objective We sought to evaluate long-term efficacy and safety of ixekizumab. Methods After receiving 10, 25, 75, or 150 mg of ixekizumab or placebo during randomized, placebo-controlled trial, patients with less than 75% improvement from baseline on the Psoriasis Area and Severity Index (PASI) score (PASI75) entered open-label extension (OLE); patients with PASI75 or higher entered a treatment-free period (weeks 20-32), then entered OLE after meeting response criteria. During OLE, patients received 120 mg of subcutaneous ixekizumab every 4 weeks. Results In all, 120 patients entered OLE; 103 completed 52 weeks or more of treatment. Overall, 77% of patients achieved PASI75 at week 52 (nonresponder imputation). Patients who responded to treatment in the randomized, placebo-controlled trial maintained a high-level response by week 52 of OLE (PASI75 = 95%; 90% improvement from baseline on the PASI score = 94%; 100% improvement from baseline on the PASI score = 82%). Irrespective of dose in the randomized, placebo-controlled trial, each group had similar response rates at week 52 of OLE. The exposure-adjusted incidence rate for adverse events was 0.47 and for serious adverse events was 0.06 per patient-year during OLE. Limitations No control group, small sample sizes, and bias toward retention of patients with positive responses limit interpretation. Conclusion A high proportion of patients responded to ixekizumab therapy and maintained clinical responses over 1 year of treatment with no unexpected safety signals.
Background Ticagrelor treatment has the side effect of increased incidence of dyspnea. Adenosine-induced dyspnea is augmented by ticagrelor and can be alleviated with the adenosine antagonist ...theophylline. Caffeine is a closely related xanthine derivative. Objectives The primary objective of the TROCADERO is to evaluate the effect of caffeine versus placebo on ticagrelor-associated dyspnea, measured by the visual analog scale area under the curve in patients with ongoing ticagrelor treatment after an acute coronary syndrome event. Design After a run-in period of 1 to 7 days of absence of caffeine intake, acute coronary syndrome patients with ticagrelor-induced dyspnea (planned inclusion 416) are randomized in a blinded fashion to either caffeine 200 mg twice daily or matching placebo with a treatment duration of 1 week. The primary efficacy end point is change in visual analog scale area under the curve for dyspnea, and the primary safety end point is occurrence of high on-treatment platelet reactivity measured by the VerifyNow P2Y12 assay. Conclusions This trial will determine if adenosine antagonism by caffeine can alleviate ticagrelor-related dyspnea, without impairing the antiplatelet effect of ticagrelor.
The clinical outcome of patients with severe primary and secondary mitral regurgitation (MR) and heart failure or significantly reduced left ventricular ejection fraction (LVEF) who underwent ...percutaneous mitral valve repair (pMVR) is yet not well known. This study compares midterm outcome of patients with severe left ventricular dysfunction (EF ≤30%) versus patients with slightly or moderately reduced or normal LVEF (EF >30%) after pMVR. One hundred thirty-six consecutive patients were enrolled: 42 patients displayed severe left ventricular dysfunction, group 1 (logistic EuroSCORE I 27.7 ± 21.8%; secondary MR in 37 patients), and 94 patients displayed slightly or moderately reduced or normal LVEF, group 2 (logistic EuroSCORE I 17 ± 18.2%; secondary MR in 21 patients). The primary efficacy endpoint was death of any cause, repeat mitral valve intervention, and/or New York Heart Association class ≥III, which was reached in 31% of patients in group 1 versus 40% in group 2 (p = 0.719) at a median follow-up of 371 days. MR, graded by transthoracic echocardiography, was reduced in both groups (p <0.001) and New York Heart Association class improved in each group (p <0.001), with no differences between groups (p >0.05). In conclusion, at midterm follow-up, the pMVR provided significant clinical benefits with comparable results achieved both in patients with significantly reduced and in patients with moderately reduced to normal LVEF. Thus, pMVR represents a feasible and effective treatment in high-risk patients who otherwise have limited therapeutic options and no safe option to reduce MR.
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