Objectives This study sought to evaluate the safety and efficacy of the CoreValve transcatheter heart valve (THV) for the treatment of severe aortic stenosis in patients at extreme risk for surgery. ...Background Untreated severe aortic stenosis is a progressive disease with a poor prognosis. Transcatheter aortic valve replacement (TAVR) with a self-expanding bioprosthesis is a potentially effective therapy. Methods We performed a prospective, multicenter, nonrandomized investigation evaluating the safety and efficacy of self-expanding TAVR in patients with symptomatic severe aortic stenosis with prohibitive risks for surgery. The primary endpoint was a composite of all-cause mortality or major stroke at 12 months, which was compared with a pre-specified objective performance goal (OPG). Results A total of 41 sites in the United States recruited 506 patients, of whom 489 underwent attempted treatment with the CoreValve THV. The rate of all-cause mortality or major stroke at 12 months was 26.0% (upper 2-sided 95% confidence bound: 29.9%) versus 43.0% with the OPG (p < 0.0001). Individual 30-day and 12-month events included all-cause mortality (8.4% and 24.3%, respectively) and major stroke (2.3% and 4.3%, respectively). Procedural events at 30 days included life-threatening/disabling bleeding (12.7%), major vascular complications (8.2%), and need for permanent pacemaker placement (21.6%). The frequency of moderate or severe paravalvular aortic regurgitation was lower 12 months after self-expanding TAVR (4.2%) than at discharge (10.7%; p = 0.004 for paired analysis). Conclusions TAVR with a self-expanding bioprosthesis was safe and effective in patients with symptomatic severe aortic stenosis at prohibitive risk for surgical valve replacement. (Safety and Efficacy Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902 )
Abstract Background In patients with severe aortic stenosis at increased risk for surgery, self-expanding transcatheter aortic valve replacement (TAVR) is associated with improved 2-year survival ...compared with surgery. Objectives This study sought to determine whether this clinical benefit was sustained over time. Methods Patients with severe aortic stenosis deemed at increased risk for surgery by a multidisciplinary heart team were randomized 1:1 to TAVR or open surgical valve replacement (SAVR). Three-year clinical and echocardiographic outcomes were obtained in those patients with an attempted procedure. Results A total of 797 patients underwent randomization at 45 U.S. centers; 750 patients underwent an attempted procedure. Three-year all-cause mortality or stroke was significantly lower in TAVR patients (37.3% vs. 46.7% in SAVR; p = 0.006). Adverse clinical outcome components were also reduced in TAVR patients compared with SAVR patients, including all-cause mortality (32.9% vs. 39.1%, respectively; p = 0.068), all stroke (12.6% vs. 19.0%, respectively; p = 0.034), and major adverse cardiovascular or cerebrovascular events (40.2% vs. 47.9%, respectively; p = 0.025). At 3 years aortic valve hemodynamics were better with TAVR patients (mean aortic valve gradient 7.62 ± 3.57 mm Hg vs. 11.40 ± 6.81 mm Hg in SAVR; p < 0.001), although moderate or severe residual aortic regurgitation was higher in TAVR patients (6.8% vs. 0.0% in SAVR; p < 0.001). There was no clinical evidence of valve thrombosis in either group. Conclusions Patients with severe aortic stenosis at increased risk for surgery had improved 3-year clinical outcomes after TAVR compared with surgery. Aortic valve hemodynamics were more favorable in TAVR patients without differences in structural valve deterioration. (Safety and Efficacy Study of the Medtronic CoreValve® System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902 )
Abstract Background The U.S. pivotal trial for the self-expanding valve found that among patients with severe aortic stenosis at increased risk for surgery, the 1-year survival rate was 4.9 ...percentage points higher in patients treated with a self-expanding transcatheter aortic valve bioprosthesis than in those treated with a surgical bioprosthesis. Objectives Longer-term clinical outcomes were examined to confirm if this mortality benefit is sustained. Methods Patients with severe aortic stenosis who were at increased surgical risk were recruited. Eligible patients were randomly assigned in a 1:1 ratio to transcatheter aortic valve replacement with the self-expanding transcatheter valve (transcatheter aortic valve replacement TAVR group) or to aortic valve replacement with a surgical bioprosthesis (surgical group). The 2-year clinical and echocardiographic outcomes were evaluated in these patients. Results A total of 797 patients underwent randomization at 45 centers in the United States. The rate of 2-year all-cause mortality was significantly lower in the TAVR group (22.2%) than in the surgical group (28.6%; log-rank test p < 0.05) in the as-treated cohort, with an absolute reduction in risk of 6.5 percentage points. Similar results were found in the intention-to-treat cohort (log-rank test p < 0.05). The rate of 2-year death or major stroke was significantly lower in the TAVR group (24.2%) than in the surgical group (32.5%; log-rank test p = 0.01). Conclusions In patients with severe aortic stenosis who are at increased surgical risk, the higher rate of survival with a self-expanding TAVR compared with surgery was sustained at 2 years. (Safety and Efficacy Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902 )
Summary Background VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 ...antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. Methods In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT01140347. Findings Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0–10·6) versus 7·6 months (6·0–9·3) for the placebo group (HR 0·87 95% CI 0·72–1·05; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 5% of 277 patients treated with ramucirumab vs 11 4% of 276 patients treated with placebo), hypertension (34 12% vs ten 4%), asthenia (14 5% vs five 2%), malignant neoplasm progression (18 6% vs 11 4%), increased aspartate aminotransferase concentration (15 5% vs 23 8%), thrombocytopenia (13 5% vs one <1%), hyperbilirubinaemia (three 1% vs 13 5%), and increased blood bilirubin (five 2% vs 14 5%). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. Interpretation Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable. Funding Eli Lilly and Co.
Abstract Hypertension Canada provides annually-updated, evidence-based guidelines for the diagnosis, assessment, prevention, and treatment of hypertension. This year, we introduce 10 new guidelines. ...Three previous guidelines have been revised and 5 have been removed. Previous age and frailty distinctions have been removed as considerations for when to initiate antihypertensive therapy. In the presence of macrovascular target organ damage, or in those with independent cardiovascular risk factors, antihypertensive therapy should be considered for all individuals with elevated average systolic blood pressure readings ≥140 mmHg. For individuals with diastolic hypertension (with or without systolic hypertension), fixed-dose single pill combinations are now recommended as an initial treatment option. Preference is given to pills containing an angiotensin converting enzyme inhibitor or angiotensin receptor blocker in combination with either a calcium channel blocker or diuretic. Whenever a diuretic is selected as monotherapy, longer-acting agents are preferred. In patients with established ischemic heart disease, caution should be exercised in lowering diastolic pressure ≤60 mmHg, especially in the presence of left ventricular hypertrophy. Following a hemorrhagic stroke, in the first 24 hours, systolic blood pressure lowering to <140 mmHg is not recommended. Finally, guidance is now provided for screening, initial diagnosis, assessment, and treatment of renovascular hypertension arising from fibromuscular dysplasia. The specific evidence and rationale underlying each of these guidelines are discussed.
Abstract Objectives This study evaluated the safety and effectiveness of self-expanding transcatheter aortic valve replacement (TAVR) in patients with surgical valve failure (SVF). Background ...Self-expanding TAVR is superior to medical therapy for patients with severe native aortic valve stenosis at increased surgical risk. Methods The CoreValve U.S. Expanded Use Study was a prospective, nonrandomized study that enrolled 233 patients with symptomatic SVF who were deemed unsuitable for reoperation. Patients were treated with self-expanding TAVR and evaluated for 30-day and 1-year outcomes after the procedure. An independent core laboratory was used to evaluate serial echocardiograms for valve hemodynamics and aortic regurgitation. Results SVF occurred through stenosis (56.4%), regurgitation (22.0%), or a combination (21.6%). A total of 227 patients underwent attempted TAVR and successful TAVR was achieved in 225 (99.1%) patients. Patients were elderly (76.7 ± 10.8 years), had a Society of Thoracic Surgeons Predicted Risk of Mortality score of 9.0 ± 6.7%, and were severely symptomatic (86.8% New York Heart Association functional class III or IV). The all-cause mortality rate was 2.2% at 30 days and 14.6% at 1 year; major stroke rate was 0.4% at 30 days and 1.8% at 1 year. Moderate aortic regurgitation occurred in 3.5% of patients at 30 days and 7.4% of patients at 1 year, with no severe aortic regurgitation. The rate of new permanent pacemaker implantation was 8.1% at 30 days and 11.0% at 1 year. The mean valve gradient was 17.0 ± 8.8 mm Hg at 30 days and 16.6 ± 8.9 mm Hg at 1 year. Factors significantly associated with higher discharge mean aortic gradients were surgical valve size, stenosis as modality of SVF, and presence of surgical valve prosthesis patient mismatch (all p < 0.001). Conclusions Self-expanding TAVR in patients with SVF at increased risk for surgery was associated with a low 1-year mortality and major stroke rate, significantly improved aortic valve hemodynamics, and low rates of moderate and no severe residual aortic regurgitation, with improved quality of life.
Summary Background The safety and short-term efficacy of laparoscopic surgery for rectal cancer after preoperative chemoradiotherapy has not been demonstrated. The aim of the randomised Comparison of ...Open versus laparoscopic surgery for mid and low REctal cancer After Neoadjuvant chemoradiotherapy (COREAN) trial was to compare open surgery with laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy. Methods Between April 4, 2006, and Aug 26, 2009, patients with cT3N0–2 mid or low rectal cancer without distant metastasis after preoperative chemoradiotherapy were enrolled at three tertiary-referral hospitals. Patients were randomised 1:1 to receive either open surgery (n=170) or laparoscopic surgery (n=170), stratified according to sex and preoperative chemotherapy regimen. Short-term outcomes assessed were involvement of the circumferential resection margin, macroscopic quality of the total mesorectal excision specimen, number of harvested lymph nodes, recovery of bowel function, perioperative morbidity, postoperative pain, and quality of life. Analyses were based on the intention-to-treat population. Patients continue to be followed up for the primary outcome (3-year disease-free survival). This study is registered with ClinicalTrials.gov , number NCT00470951. Findings Two patients (1·2%) in the laparoscopic group were converted to open surgery, but were included in the laparoscopic group for analyses. Estimated blood loss was less in the laparoscopic group than in the open group (median 217·5 mL 150·0–400·0 in the open group vs 200·0 mL 100·0–300·0 in the laparoscopic group, p=0·006), although surgery time was longer in the laparoscopic group (mean 244·9 min SD 75·4 vs 197·0 min 62·9, p<0·0001). Involvement of the circumferential resection margin, macroscopic quality of the total mesorectal excision specimen, number of harvested lymph nodes, and perioperative morbidity did not differ between the two groups. The laparoscopic surgery group showed earlier recovery of bowel function than the open surgery group (time to pass first flatus, median 38·5 h 23·0–53·0 vs 60·0 h 43·0–73·0, p<0·0001; time to resume a normal diet, 85·0 h 66·0–95·0 vs 93·0 h 86·0–121·0, p<0·0001; time to first defecation, 96·5 h 70·0–125·0 vs 123 h 94·0–156·0, p<0·0001). The total amount of morphine used was less in the laparoscopic group than in the open group (median 107·2 mg 80·0–150·0 vs 156·9 mg 117·0–185·2, p<0·0001). 3 months after proctectomy or ileostomy takedown, the laparoscopic group showed better physical functioning score than the open group (0·501 n=122 vs −4·970 n=128, p=0·0073), less fatigue (−5·659 n=122 vs 0·098 n=129, p=0·0206), and fewer micturition (−2·583 n=122 vs 4·725 n=129, p=0·0002), gastrointestinal (−0·400 n=122 vs 4·331 n=129, p=0·0102), and defecation problems (0·535 n=103 vs 5·327 n=99, p=0·0184) in repeated measures analysis of covariance, adjusted for baseline values. Interpretation Laparoscopic surgery after preoperative chemoradiotherapy for mid or low rectal cancer is safe and has short-term benefits compared with open surgery; the quality of oncological resection was equivalent. Funding The National Cancer Center, South Korea.
Objectives This study sought to investigate the predictors and outcomes of side branch (SB) occlusion after main vessel (MV) stenting in coronary bifurcation lesions. Background SB occlusion is a ...serious complication that occurs during percutaneous coronary intervention (PCI) for bifurcation lesions. Methods Consecutive patients undergoing PCI using drug-eluting stents for bifurcation lesions with SB ≥2.3 mm were enrolled. We selected patients treated with the 1-stent technique or MV stenting first strategy. SB occlusion after MV stenting was defined as Thrombolysis in Myocardial Infarction flow grade <3. Results SB occlusion occurred in 187 (8.4%) of 2,227 bifurcation lesions. In multivariate analysis, independent predictors of SB occlusion were pre-procedural percent diameter stenosis of the SB ≥50% (odds ratio OR: 2.34; 95% confidence interval CI: 1.59 to 3.43; p < 0.001) and the proximal MV ≥50% (OR: 2.34; 95% CI: 1.57 to 3.50; p < 0.001), SB lesion length (OR: 1.03; 95% CI: 1.003 to 1.06; p = 0.03), and acute coronary syndrome (OR: 1.53; 95% CI: 1.06 to 2.19; p = 0.02). Of 187 occluded SBs, flow was restored spontaneously in 26 (13.9%) and by SB intervention in 103 (55.1%) but not in 58 (31.0%). Jailed wire in the SB was associated with flow recovery (74.8% vs. 57.8%, p = 0.02). Cardiac death or myocardial infarction occurred more frequently in patients with SB occlusion than in those without SB occlusion (adjusted hazard ratio: 2.34; 95% CI: 1.15 to 4.77; p = 0.02). Conclusions Angiographic findings of SB, proximal MV stenosis, and clinical presentation are predictive of SB occlusion after MV stenting. Occlusion of sizable SB is associated with adverse clinical outcomes. (Korean Coronary Bifurcation Stenting Registry II COBIS; NCT01642992 )
Abstract Background The classification of aortic dissection into acute (<14 days from symptom onset) versus chronic (≥14 days) is based on survival estimates of patients treated decades before modern ...diagnostic and treatment modalities were available. A new classification of aortic dissection in the current era may provide clinicians with a more precise method of characterizing the interaction of time, dissection location, and treatment type with survival. Methods We developed separate Kaplan-Meier survival curves for Type A and Type B aortic dissection using data from the International Registry of Aortic Dissection (IRAD). Daily survival was stratified based on type of therapy provided: medical therapy alone (medical), nonsurgical intervention plus medical therapy (endovascular), and open surgery plus medical therapy (surgical). The log-rank statistic was used to compare the survival curves of each management type within Type A and Type B aortic dissection. Results There were 1815 patients included, 67.3% male with mean age 62.0 ± 14.2 years. When survival curves were constructed, 4 distinct time periods were noted: hyperacute (symptom onset to 24 hours), acute (2-7 days), subacute (8-30 days), and chronic (>30 days). Overall survival was progressively lower through the 4 time periods. Conclusions This IRAD classification system can provide clinicians with a more robust method of characterizing survival after aortic dissection over time than previous methods. This system will be useful for treating patients, counseling patients and families, and studying new diagnostic and treatment methods.
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