Summary Background Inhibition of phosphatidylinositol 3-kinase (PI3K) is a promising approach to overcome resistance to endocrine therapy in breast cancer. Pictilisib is an oral inhibitor of multiple ...PI3K isoforms. The aim of this study is to establish if addition of pictilisib to fulvestrant can improve progression-free survival in oestrogen receptor-positive, endocrine-resistant breast cancer. Methods In this two-part, randomised, double-blind, placebo-controlled, phase 2 study, we recruited postmenopausal women aged 18 years or older with oestrogen receptor-positive, HER2-negative breast cancer resistant to treatment with an aromatase inhibitor in the adjuvant or metastatic setting, from 123 medical centres across 21 countries. Part 1 included patients with or without PIK3CA mutations, whereas part 2 included only patients with PIK3CA mutations. Patients were randomly allocated (1:1 in part 1 and 2:1 in part 2) via a computer-generated hierarchical randomisation algorithm to daily oral pictilisib (340 mg in part 1 and 260 mg in part 2) or placebo starting on day 15 of cycle 1, plus intramuscular fulvestrant 500 mg on day 1 and day 15 of cycle 1 and day 1 of subsequent cycles in both groups. In part 1, we stratified patients by presence or absence of PIK3CA mutation, primary or secondary aromatase inhibitor resistance, and measurable or non-measurable disease. In part 2, we stratified patients by previous aromatase inhibitor treatment for advanced or metastatic disease or relapse during or within 6 months of an aromatase inhibitor treatment in the adjuvant setting and measurable or non-measurable disease. All patients and those administering treatment and assessing outcomes were masked to treatment assignment. The primary endpoint was progression-free survival in the intention-to-treat population for both parts 1 and 2 and also separately in patients with PIK3CA -mutated tumours in part 1. Tumour assessment (physical examination and imaging scans) was investigator-assessed and done at screening and after 8 weeks, 16 weeks, 24 weeks, and 32 weeks of treatment from day 1 of cycle 1 and every 12 weeks thereafter. We assessed safety in as-treated patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov , number NCT01437566. Findings In part 1, between Sept 27, 2011, and Jan 11, 2013, we randomly allocated 168 patients to the pictilisib (89 53%) or placebo (79 47%) group. In part 2, between March 18, 2013, and Jan 2, 2014, we randomly allocated 61 patients to the pictilisib (41 67%) or placebo (20 33%) group. In part 1, we found no difference in median progression-free survival between the pictilisib (6·6 months 95% CI 3·9–9·8) and placebo (5·1 months 3·6–7·3) group (hazard ratio HR 0·74 95% CI 0·52–1·06; p=0·096). We also found no difference when patients were analysed according to presence (pictilisib 6·5 months 95% CI 3·7–9·8 vs placebo 5·1 months 2·6–10·4; HR 0·73 95% CI 0·42–1·28; p=0·268) or absence (5·8 months 3·6–11·1 vs 3·6 months 2·8–7·3; HR 0·72 0·42–1·23; p=0·23) of PIK3CA mutation. In part 2, we also found no difference in progression-free survival between groups (5·4 months 95% CI 3·8–8·3 vs 10·0 months 3·6–13·0; HR 1·07 95% CI 0·53–2·18; p=0·84). In part 1, grade 3 or worse adverse events occurred in 54 (61%) of 89 patients in the pictilisib group and 22 (28%) of 79 in the placebo group. 19 serious adverse events related to pictilisib treatment were reported in 14 (16%) of 89 patients. Only one (1%) of 79 patients reported treatment-related serious adverse events in the placebo group. In part 2, grade 3 or worse adverse events occurred in 15 (36%) of 42 patients in the pictilisib group and seven (37%) of 19 patients in the placebo group. Four serious adverse events related to pictilisib treatment were reported in two (5%) of 42 patients. One treatment-related serious adverse event occurred in one (5%) of 19 patients in the placebo group. Interpretation Although addition of pictilisib to fulvestrant did not significantly improve progression-free survival, dosing of pictilisib was limited by toxicity, potentially limiting its efficacy. For future assessment of PI3K inhibition as an approach to overcome resistance to hormonal therapy, inhibitors with greater selectivity than that of pictilisib might be needed to improve tolerability and potentially increase efficacy. No further investigation of pictilisib in this setting is ongoing. Funding F Hoffmann-La Roche.
2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention Levine, Glenn N., MD, FACC, FAHA; Bates, Eric R., MD, FACC, FAHA; Blankenship, James C., MD, FACC, FSCAI ...
Journal of the American College of Cardiology,
12/2011, Letnik:
58, Številka:
24
Journal Article
Objectives The aim of this study was to ascertain the 1-year incidence of stent thrombosis (ST) and major bleeding (MB) in a large, unselected population treated with sirolimus-eluting stents (SES). ...Background Stent thrombosis and MB are major potential complications of drug-eluting stent implantation. Their relative incidence and predisposing factors among large populations treated worldwide are unclear. Methods The SES were implanted in 15,147 patients who were entered in a multinational registry. We analyzed the incidence of: 1) definite and probable ST as defined by the Academic Research Consortium; and 2) MB, with the STEEPLE (Safety and efficacy of Enoxaparin in PCI) definition, together with their relation to dual antiplatelet therapy (DAPT) and to 1-year clinical outcomes. Results The mean age of the sample was 62 ± 11 years, 30.4% were diabetic, 10% had a Charlson comorbidity index ≥3, and 44% presented with acute coronary syndrome or myocardial infarction. At 1 year, the reported compliance with DAPT as recommended by the European Society of Cardiology guidelines was 86.3%. Adverse event rates were: ST 1.0%, MB 1.0%, mortality 1.7%, myocardial infarction 1.9%, and target lesion revascularization 2.3%. Multivariate analysis identified 9 correlates of ST and 4 correlates of MB. Advanced age and a high Charlson index were associated with an increased risk of both ST and MB. After ST, the 7-day and 1-year all-cause mortality was 30% and 35%, respectively, versus 1.5% and 10% after MB. Only 2 of 13,749 patients (0.015%) experienced both MB and ST during the entire 1-year follow-up period. Conclusions In this worldwide population treated with ≥1 SES, the reported compliance with DAPT was good, and the incidence of ST and MB was low. Stent thrombosis and MB very rarely occurred in the same patient. (The e-SELECT Registry: a Multicenter Post-Market Surveillance; NCT00438919 )
Abstract Ischemic mitral regurgitation (MR) has been associated with worse outcome myocardial infarction. However, severity of MR and its impact on patients with STEMI undergoing primary PCI remains ...unknown. We sought to determine impact of increasing severity of ischemic MR on outcomes in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). All patients presenting with STEMI who underwent primary PCI within 12 hours of symptoms from 1994-2014 were included. Ischemic MR was graded from 0 to 4+ within 3 days of index MI by echocardiography. Overall, 4,005 STEMI patients were included. None, 1+, 2+, 3+ and 4+ MR was present in 3,200 (79.9%), 427 (10.7%), 260 (6.5%), 91 (2.3%) and 27 (0.7%) patients, respectively. On Multivariate logistic regression analysis, more severe MR was associated with older age, female gender, lower body mass index, anemia, inferior STEMI and longer door-to-balloon time (DBT). The 30-day mortality was 6.8, 7.3, 8.8, 19.8 and 26.1%, respectively, with increasing grade of MR. The 1-year mortality rate was 10.8, 12.4, 20.8, 37.4 and 37.1%, while 5-year mortality rates were 16.2, 23.1, 36.5, 53.8 and 63%, respectively (p<0.001 all) for none to 4+ MR. After adjusting for age, gender, co-morbidities, ejection fraction and shock by multivariate analysis, severity of ischemic MR was associated with incremental effect on long-term mortality (HR of 1.42, 1.83, 2.41 and 2.95 for 1+ to 4+ MR respectively, p <0.01 for all). In conclusion, higher grades of MR in patients with STEMI undergoing primary PCI are associated with worse short- and long-term outcomes.
Stent Thrombosis Holmes, David R., MD; Kereiakes, Dean J., MD; Garg, Scot, MD ...
Journal of the American College of Cardiology,
10/2010, Letnik:
56, Številka:
17
Journal Article
Recenzirano
Odprti dostop
Intense investigation continues on the pathobiology of stent thrombosis (ST) because of its morbidity and mortality. Because little advance has been made in outcomes following ST, ongoing research is ...focused on further understanding predictive factors as well as ST frequency and timing in various patient subsets, depending upon whether a drug-eluting stent or bare-metal stent has been implanted. Although the preventive role of antiplatelet therapies remains unchallenged, new data on genomics and variability in response to antiplatelet therapy, as well as the effects of novel therapeutic agents and duration of therapy, have become available. The goal remains identification of patients at particularly increased risk of ST so that optimal prevention strategies can be developed and employed.
Objectives This study sought to compare the 1-year safety and efficacy of Cypher Select or Cypher Select Plus (Cordis Corporation, Bridgewater, New Jersey) sirolimus-eluting stents (SES) with the ...treatment of bare-metal stents (BMS) and drug-eluting stent (DES) in-stent restenosis (ISR) in nonselected, real-world patients. Background There is paucity of consistent data on DES for the treatment of ISR, especially, DES ISR. Methods The e-SELECT (Multicenter Post-Market Surveillance) registry is a Web-based, multicenter and international registry encompassing virtually all subsets of patients and lesions treated with at least 1 SES during the period from 2006 to 2008. We enrolled in this pre-specified subanalysis all patients with at least 1 clinically relevant BMS or DES ISR treated with SES. Primary endpoint was major adverse cardiac events and stent thrombosis rate at 1 year. Results Of 15,147 patients enrolled, 1,590 (10.5%) presented at least 1 ISR (BMS group, n = 1,235, DES group, n = 355). Patients with DES ISR had higher incidence of diabetes (39.4% vs. 26.9%, p < 0.001), renal insufficiency (5.8% vs. 2.3%, p = 0.003), and prior coronary artery bypass graft (20.5% vs. 11.8%, p < 0.001). At 1 year, death (1.4% for BMS vs. 2.1% for DES, p = 0.3) and myocardial infarction (2.4% for BMS and 3.3% for DES, p = 0.3) rates were similar, whereas ischemia-driven target lesion revascularization and definite/probable late stent thrombosis were higher in patients with DES ISR (6.9% vs. 3.1%, p = 0.003, and 1.8% vs. 0.5%, p = 0.04, respectively). Conclusions Use of SES for either BMS or DES ISR treatment is safe and associated with low target lesion revascularization recurrence and no apparent safety concern.
Objectives The study undertook a systematic review to establish and compare the risk of stroke between the 2 widely used approaches (transfemoral TF vs. transapical TA) and valve designs (CoreValve, ...Medtronic, Minneapolis, Minnesota vs. Edwards Valve, Edwards Lifesciences, Irvine, California) for transcatheter aortic valve replacement (TAVR). Background There has been a rapid adoption and expansion in the use of TAVR. The technique is however far from perfect and requires further refinement to alleviate safety concerns that include stroke. Methods All studies reporting on the risk of stroke after TAVR were identified using an electronic search and pooled using established meta-analytical guidelines. Results 25 multicenter registries and 33 single-center studies were included in the analysis. There was no difference in pooled 30-day stroke post-TAVR between the TF and TA approach in multicenter (2.8% 95% confidence interval (CI): 2.4 to 3.4 vs. 2.8% 95% CI: 2.0 to 3.9) and single-center studies (3.8% 95% CI: 3.1 to 4.6 vs. 3.4% 95% CI: 2.5 to 4.5). Similarly, there was no difference in pooled 30-day stroke post TAVR between the CoreValve and Edwards Valve in multicenter (2.4% 95% CI: 1.9 to 3.2 vs. 3.0% 95% CI: 2.4 to 3.7) and single-center studies (3.8% 95% CI: 2.8 to 4.9 vs. 3.2% 95% CI: 2.4 to 4.3). There was a decline in stroke risk with experience and technological advancement. There was no difference in the outcome of 30-day stroke between TAVR and surgical aortic valve replacement. Conclusions Our findings suggest that the risk of 30-day stroke after TAVR is similar between the approaches and valve types. There has been a decline in stroke risk after TAVR with improvements in valve technology, patient selection, and operator experience.
Objectives The aim of this study was to identify the worldwide practice of Cypher Select (Cordis Corporation, Bridgewater, New Jersey) or Cypher Select Plus sirolimus-eluting stent (SES) in patients ...80 years of age (octogenarian) and to identify clinical outcomes in this patient population. Background The use of drug-eluting stents in elderly patients may have different features compared with younger patients. Methods Between 2006 and 2008, 15,147 patients from 320 hospitals in 56 countries were enrolled in a registry. Initial implantation and follow-up outcome information obtained at 1-year follow-up in 675 octogenarian patients were compared with those in 14,472 nonoctogenarian patients. Results Octogenarians had significantly more comorbidities and had higher Charlson comorbidity index scores (1.5 ± 1.6 vs. 1.0 ± 1.3, p < 0.001). Rates of cardiac death (3.3% vs. 0.9%, p < 0.001), myocardial infarction (2.3% vs. 1.9%, p = 0.021), and definite or probable stent thrombosis (2.3% vs. 0.9%, p = 0.0002), and major bleeding (2.0% vs. 0.9%, p = 0.015) were significantly higher in octogenarians at 1 year; however, there was no significant difference in the rate of target lesion revascularization between the 2 groups (3.2% vs. 2.2%, p = 0.12). In octogenarians, a high Charlson comorbidity index was an independent predictor of death and stent thrombosis up to 360 days from the index procedure (hazard ratio: 1.3, 95% confidence interval: 1.1 to 1.5, p < 0.001, and hazard ratio: 1.5, 95% confidence interval: 1.3 to 1.8, p < 0.001, respectively). Conclusions Stenting with SES may be an effective therapeutic option in elderly patients, with acceptable rates of complications and a very low rate of repeat revascularization as demonstrated by this e-SELECT (A Multi-Center Post-Market Surveillance Registry) subgroup analysis.
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