Impact of vessel size on outcome after implantation of sirolimus-eluting and paclitaxel-eluting stents: a subgroup analysis of the SIRTAX trial

OBJECTIVES: We assessed the impact of vessel size on angiographic and long-term clinical outcome after percutaneous coronary intervention (PCI) with sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) within a randomized trial (SIRTAX [Sirolimus-Eluting Stent Compared With Paclitaxel-Eluting Stent for Coronary Revascularization]). BACKGROUND: Percutaneous coronary intervention in small-vessel disease is associated with an increased risk of major adverse cardiac events (MACE). METHODS: A total of 1,012 patients were randomly assigned to treatment with SES (n = 503) or PES (n = 509). A stratified analysis of angiographic and clinical outcome was performed up to 2 years after PCI according to size of the treated vessel (reference vessel diameter < or =2.75 vs. >2.75 mm). RESULTS: Of 1,012 patients, 370 patients (37%) with 495 lesions underwent stent implantation in small vessels only, 504 patients (50%) with 613 lesions in large vessels only, and 138 patients (14%) with 301 lesions in both small and large vessels (mixed). In patients with small-vessel stents, SES reduced MACE by 55% (10.4% vs. 21.4%; p = 0.004), mainly driven by a 69% reduction of target lesion revascularization (TLR) (6.0% vs. 17.7%; p = 0.001) compared with PES at 2 years. In patients with large- and mixed-vessel stents, rates of MACE (large: 10.4% vs. 13.1%; p = 0.33; mixed: 16.7% vs. 18.0%; p = 0.83) and TLR (large: 6.9% vs. 8.6%; p = 0.47; mixed: 16.7% vs. 15.4%; p = 0.86) were similar for SES and PES. There were no significant differences with respect to death and myocardial infarction between the 3 groups. CONCLUSIONS: Compared with PES, SES more effectively reduced MACE and TLR in small-vessel disease. Differences between SES and PES appear less pronounced in patients with large- and mixed-vessel disease. (The SIRTAX trial; http://clinicaltrials.gov/ct/show/NCT00297661?order=1; NCT00297661).

Impact of local endothelial shear stress on neointima and plaque following stent implantation in patients with ST-elevation myocardial infarction: A subgroup-analysis of the COMFORTABLE AMI-IBIS 4 trial.

BACKGROUND Numerous studies have demonstrated an association between endothelial shear stress (ESS) and neointimal formation after stent implantation. However, the role of ESS on the composition of neointima and underlying plaque remains unclear. METHODS Patients recruited in the Comfortable AMI-IBIS 4 study implanted with bare metal stents (BMS) or biolimus eluting stents (BES) that had biplane coronary angiography at 13month follow-up were included in the analysis. The intravascular ultrasound virtual-histology (IVUS-VH) and the angiographic data were used to reconstruct the luminal surface, and the stent in the stented segments. Blood flow simulation was performed in the stent surface, which was assumed to represent the luminal surface at baseline, to assess the association between ESS and neointima thickness. The predominant ESS was estimated in 3-mm segments and was correlated with the amount of neointima, neointimal tissue composition, and with the changes in the underlying plaque burden and composition. RESULTS Forty three patients (18 implanted with BMS and 25 with BES) were studied. In both stent groups negative correlations were noted between ESS and neointima thickness in BMS (P<0.001) and BES (P=0.002). In BMS there was a negative correlation between predominant ESS and the percentage of the neointimal necrotic core component (P=0.015). In BES group, the limited neointima formation did not allow evaluation of the effect of ESS on its tissue characteristics. ESS did not affect vessel wall remodeling and the plaque burden and composition behind BMS (P>0.10) and BES (P>0.45). CONCLUSIONS ESS determines neointimal formation in both BMS and BES and affects the composition of the neointima in BMS. Conversely, ESS does not impact the plaque behind struts irrespective of stent type throughout 13months of follow-up.

Clinical Outcomes According to Diabetic Status in Patients Treated With Biodegradable Polymer Sirolimus-Eluting Stents Versus Durable Polymer Everolimus-Eluting Stents: Prespecified Subgroup Analysis of the BIOSCIENCE Trial.

BACKGROUND Ultrathin strut biodegradable polymer sirolimus-eluting stents (BP-SES) proved noninferior to durable polymer everolimus-eluting stents (DP-EES) for a composite clinical end point in a population with minimal exclusion criteria. We performed a prespecified subgroup analysis of the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent for Percutaneous Coronary Revascularisation (BIOSCIENCE) trial to compare the performance of BP-SES and DP-EES in patients with diabetes mellitus. METHODS AND RESULTS BIOSCIENCE trial was an investigator-initiated, single-blind, multicentre, randomized, noninferiority trial comparing BP-SES versus DP-EES. The primary end point, target lesion failure, was a composite of cardiac death, target-vessel myocardial infarction, and clinically indicated target lesion revascularization within 12 months. Among a total of 2119 patients enrolled between February 2012 and May 2013, 486 (22.9%) had diabetes mellitus. Overall diabetic patients experienced a significantly higher risk of target lesion failure compared with patients without diabetes mellitus (10.1% versus 5.7%; hazard ratio [HR], 1.80; 95% confidence interval [CI], 1.27-2.56; P=0.001). At 1 year, there were no differences between BP-SES versus DP-EES in terms of the primary end point in both diabetic (10.9% versus 9.3%; HR, 1.19; 95% CI, 0.67-2.10; P=0.56) and nondiabetic patients (5.3% versus 6.0%; HR, 0.88; 95% CI, 0.58-1.33; P=0.55). Similarly, no significant differences in the risk of definite or probable stent thrombosis were recorded according to treatment arm in both study groups (4.0% versus 3.1%; HR, 1.30; 95% CI, 0.49-3.41; P=0.60 for diabetic patients and 2.4% versus 3.4%; HR, 0.70; 95% CI, 0.39-1.25; P=0.23, in nondiabetics). CONCLUSIONS In the prespecified subgroup analysis of the BIOSCIENCE trial, clinical outcomes among diabetic patients treated with BP-SES or DP-EES were comparable at 1 year. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01443104.

The role of adjuvant hormonal treatment after surgery for localized high-risk prostate cancer: results of a matched multiinstitutional analysis

Introduction. To assess the role of adjuvant androgen deprivation therapy (ADT) in high-risk prostate cancer patients (PCa) after surgery. Materials and Methods. The analysis case matched 172 high-risk PCa patients with positive section margins or non-organ confined disease and negative lymph nodes to receive adjuvant ADT (group 1, n = 86) or no adjuvant ADT (group 2, n = 86). Results. Only 11.6% of the patients died, 2.3% PCa related. Estimated 5-10-year clinical progression-free survival was 96.9% (94.3%) for group 1 and 73.7% (67.0%) for group 2, respectively. Subgroup analysis identified men with T2/T3a tumors at low-risk and T3b margins positive disease at higher risk for progression. Conclusion. Patients with T2/T3a tumors are at low-risk for metastatic disease and cancer-related death and do not need adjuvant ADT. We identified men with T3b margin positive disease at highest risk for clinical progression. These patients benefit from immediate adjuvant ADT.

Subgroup analyses in randomised controlled trials: cohort study on trial protocols and journal publications.

OBJECTIVE To investigate the planning of subgroup analyses in protocols of randomised controlled trials and the agreement with corresponding full journal publications. DESIGN Cohort of protocols of randomised controlled trial and subsequent full journal publications. SETTING Six research ethics committees in Switzerland, Germany, and Canada. DATA SOURCES 894 protocols of randomised controlled trial involving patients approved by participating research ethics committees between 2000 and 2003 and 515 subsequent full journal publications. RESULTS Of 894 protocols of randomised controlled trials, 252 (28.2%) included one or more planned subgroup analyses. Of those, 17 (6.7%) provided a clear hypothesis for at least one subgroup analysis, 10 (4.0%) anticipated the direction of a subgroup effect, and 87 (34.5%) planned a statistical test for interaction. Industry sponsored trials more often planned subgroup analyses compared with investigator sponsored trials (195/551 (35.4%) v 57/343 (16.6%), P<0.001). Of 515 identified journal publications, 246 (47.8%) reported at least one subgroup analysis. In 81 (32.9%) of the 246 publications reporting subgroup analyses, authors stated that subgroup analyses were prespecified, but this was not supported by 28 (34.6%) corresponding protocols. In 86 publications, authors claimed a subgroup effect, but only 36 (41.9%) corresponding protocols reported a planned subgroup analysis. CONCLUSIONS Subgroup analyses are insufficiently described in the protocols of randomised controlled trials submitted to research ethics committees, and investigators rarely specify the anticipated direction of subgroup effects. More than one third of statements in publications of randomised controlled trials about subgroup prespecification had no documentation in the corresponding protocols. Definitive judgments regarding credibility of claimed subgroup effects are not possible without access to protocols and analysis plans of randomised controlled trials.

Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial

OBJECTIVE: Dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is superior to ASA alone in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention. We sought to determine whether clopidogrel plus ASA conferred benefit on limb outcomes over ASA alone in patients undergoing below-knee bypass grafting. METHODS: Patients undergoing unilateral, below-knee bypass graft for atherosclerotic peripheral arterial disease (PAD) were enrolled 2 to 4 days after surgery and were randomly assigned to clopidogrel 75 mg/day plus ASA 75 to 100 mg/day or placebo plus ASA 75 to 100 mg/day for 6 to 24 months. The primary efficacy endpoint was a composite of index-graft occlusion or revascularization, above-ankle amputation of the affected limb, or death. The primary safety endpoint was severe bleeding (Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries [GUSTO] classification). RESULTS: In the overall population, the primary endpoint occurred in 149 of 425 patients in the clopidogrel group vs 151 of 426 patients in the placebo (plus ASA) group (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.78-1.23). In a prespecified subgroup analysis, the primary endpoint was significantly reduced by clopidogrel in prosthetic graft patients (HR, 0.65; 95% CI, 0.45-0.95; P = .025) but not in venous graft patients (HR, 1.25; 95% CI, 0.94-1.67, not significant [NS]). A significant statistical interaction between treatment effect and graft type was observed (P(interaction) = .008). Although total bleeds were more frequent with clopidogrel, there was no significant difference between the rates of severe bleeding in the clopidogrel and placebo (plus ASA) groups (2.1% vs 1.2%). CONCLUSION: The combination of clopidogrel plus ASA did not improve limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting. Subgroup analysis suggests that clopidogrel plus ASA confers benefit in patients receiving prosthetic grafts without significantly increasing major bleeding risk.

Cell-based therapy for myocardial repair in patients with acute myocardial infarction: rationale and study design of the SWiss multicenter Intracoronary Stem cells Study in Acute Myocardial Infarction (SWISS-AMI)

Recent studies report that intracoronary administration of autologous bone marrow mononucleated cells (BM-MNCs) may improve remodeling of the left ventricle after acute myocardial infarction (AMI). Subgroup analysis suggest that early treatment between days 4 and 7 after AMI is probably most effective; however, the optimal time point of intracoronary cell administration has never been addressed in clinical trials. Furthermore, reliable clinical predictors are lacking for identifying patients who are thought to have most benefit from cellular therapy.

The influence of the surgeon's and the hospital's caseload on survival and local recurrence after colorectal cancer surgery

BACKGROUND: Past studies have identified surgeon- and institution- related characteristics as prognostic factors in colorectal cancer surgery. The present work assesses the influence of the surgeon's and the hospital's caseload on long-term results of colorectal cancer surgery. METHODS: The data on 2706 patients from 2, randomized, colorectal cancer trials (Swiss Group for Clinical Cancer Research [SAKK] 40/81, SAKK 40/87) investigating adjuvant intraportal and systemic chemotherapy and 1 concurrent registration study (SAKK 40/88) were reviewed. A first analysis included 1809 eligible, nonmetastatic patients from all 3 studies. A subsequent subgroup analysis included 915 eligible patients from both randomized trials. Overall survival (OS), disease-free survival (DFS), and local recurrence (LR) were analyzed in multivariate models taking into account the possible effect of clustering. The main potential covariates were surgeon's annual caseload (>5 operations/year vs < or =5 operations/year), hospital's annual caseload (>26 operations/year vs < or =26 operations/year), tumor site, T stage, and nodal status. RESULTS: Primary analysis of all 3 studies combined found a high surgeon's caseload to be positively associated with OS (P = .025) and marginally with DFS (P = .058). Separate analysis for each trial, however, showed that a high surgeon's caseload was beneficial for outcome in both randomized trials but not in the registration study. A subgroup analysis of 915 patients with 376 rectal and 539 colonic primaries from both randomized trials, therefore, was performed. Neither age, gender, year of operation, adjuvant chemotherapy (intraportal vs systemic vs operation alone), hospital academic status (university vs non-university), training status of the surgeon (certified surgeon vs surgeon-in-training), nor inclusion in 1 of the 2 randomized trials (SAKK 40/81 vs SAKK 40/87) was a significant predictor of outcome. However, both high surgeon's and high hospital's annual caseloads were independent, beneficial prognostic factors for OS (P = .0003, P = .044) and DFS (P = .0008, P = .020), and marginally significant factors for LR (P = .057, P = .055). CONCLUSIONS: High surgeon's and hospital's annual caseloads are strong, independent prognostic factors for extending overall and disease-free survival and reducing the rate of local recurrence in 2 randomized colorectal cancer trials.

Relationship between glomerular filtration rate and the adipokines adiponectin, resistin and leptin in coronary patients with predominantly normal or mildly impaired renal function

BACKGROUND: Due to their molecular weight, it is possible that the adipokines adiponectin, resistin and leptin accumulate when glomerular filtration rate (GFR) is decreased. In reduced renal clearance, altered serum concentrations of these proteins might affect cardiovascular risk. The objective of the study was to investigate the relationship between adipokine concentrations and GFR. METHODS: The association between GFR, as determined by the abbreviated MDRD equation, and the concentrations of the adipokines adiponectin, resistin and leptin was assessed in a cohort of coronary patients (n=538; 363 male, 165 female). After calculation of correlations between GFR and adipokine concentrations, the association was further assessed by analysis of covariance following adjustment for age, gender, BMI, presence of type 2 diabetes, presence of hypertension, history of smoking as well as for serum lipid concentrations. RESULTS: Mean GFR in our study population was 68.74+/-15.27 ml/min/1.73 m(2). 74.3% of the patients had a GFR >60 ml/min/1.73 m(2), 24% of the patients had a GFR between 30 and 60 ml/min/1.73 m(2), and 1.7% of the patients had a GFR <30 ml/min/1.73 m(2). There were significant inverse correlations between adiponectin (r=-0.372; p<0.001), resistin (r=-0.227; p<0.001) and leptin (r=-0.151; p=0.009) concentrations and GFR. After multivariate adjustment, the associations remained significant for adiponectin and resistin. Subgroup analysis in patients with GFR >60 ml/min/1.73 m(2) showed a significant correlation between GFR and adiponectin as well as leptin concentrations. However, after adjustment, these associations no longer were significant. CONCLUSIONS: There is an independent association between GFR and the serum concentrations of adiponectin and resistin. However, this association is not present at GFR >60 ml/min/1.73 m(2). This finding suggests that adipokine concentrations in mildly impaired and normal renal function are influenced by factors other than GFR.

Is pseudophakia a risk factor for neovascular age-related macular degeneration?

PURPOSE: To examine the possible association between pseudophakia and neovascular age-related macular degeneration (AMD). METHODS: Reports of all patients undergoing fluorescein angiography in the authors' department over a 6-year period were retrospectively reviewed. Four hundred ninety-nine patients with recent onset of neovascular AMD in one eye and early age-related maculopathy (ARM) in the fellow eye were included in the study. Lens status (phakic or pseudophakic) in both eyes at the time of onset of neovascular AMD and the time between cataract surgeries (if performed) and onset of neovascular AMD were determined. RESULTS: There was no significant difference in lens status between eyes with neovascular AMD and fellow eyes with early ARM (115/499 [23.0%] vs. 112/499 [22.4%] pseudophakic; P = 0.88, odds ratio 1.035, 95% CI 0.770-1.391). Subgroup analysis revealed no difference between the groups with large drusen, small drusen, or pigmentary changes only (respectively, 20.3% vs. 19.6% pseudophakic, P = 0.92; 20.5% vs. 23.3% pseudophakic, P = 0.84; 33.3% vs. 31.7% pseudophakic, P = 1.0). Pseudophakic eyes with neovascular AMD had not been pseudophakic for a significantly longer period at the time of onset of neovascular AMD than their pseudophakic fellow eyes at the same time point (225.9 +/- 170.4 vs. 209.9 +/- 158.2 weeks, P = 0.27). CONCLUSIONS: The results do not support the hypothesis that pseudophakia is a major risk factor for the development of neovascular AMD.

Drug-eluting or bare-metal stents for large coronary vessel stenting? The BASKET-PROVE (PROspective Validation Examination) trial: study protocol and design

BACKGROUND: Based on a subgroup analysis of 18-month BAsel Stent Kosten Effektivitäts Trial (BASKET) outcome data, we hypothesized that very late (> 12 months) stent thrombosis occurs predominantly after drug-eluting stent implantation in large native coronary vessel stenting. METHODS: To prove or refute this hypothesis, we set up an 11-center 4-country prospective trial of 2260 consecutive patients treated with > or = 3.0-mm stents only, randomized to receive Cypher (Johnson ; Johnson, Miami Lakes, FL), Vision (Abbott Vascular, Abbott Laboratories, IL), or Xience stents (Abbott Vascular). Only patients with left main or bypass graft disease, in-stent restenosis or stent thrombosis, in need of nonheart surgery, at increased bleeding risk, without compliance/consent are excluded. All patients are treated with dual antiplatelet therapy for 12 months. The primary end point will be cardiac death/nonfatal myocardial infarction after 24 months with further follow-up up to 5 years. RESULTS: By June 12, 229 patients (10% of the planned total) were included with a baseline risk similar to that of the same subgroup of BASKET (n = 588). CONCLUSIONS: This study will answer several important questions of contemporary stent use in patients with large native vessel stenting. The 2-year death/myocardial infarction-as well as target vessel revascularization-and bleeding rates in these patients with a first- versus second-generation drug-eluting stent should demonstrate the benefit or harm of these stents compared to cobalt-chromium bare-metal stents in this relevant, low-risk group of everyday patients. In addition, a comparison with similar BASKET patients will allow to estimate the impact of 12- versus 6-month dual antiplatelet therapy on these outcomes.

Development of a screening tool predicting the transition from acute to chronic low back pain for patients in a GP setting: protocol of a multinational prospective cohort study

BACKGROUND: Low back pain (LBP) is by far the most prevalent and costly musculoskeletal problem in our society today. Following the recommendations of the Multinational Musculoskeletal Inception Cohort Study (MMICS) Statement, our study aims to define outcome assessment tools for patients with acute LBP and the time point at which chronic LBP becomes manifest and to identify patient characteristics which increase the risk of chronicity. METHODS: Patients with acute LBP will be recruited from clinics of general practitioners (GPs) in New Zealand (NZ) and Switzerland (CH). They will be assessed by postal survey at baseline and at 3, 6, 12 weeks and 6 months follow-up. Primary outcome will be disability as measured by the Oswestry Disability Index (ODI); key secondary endpoints will be general health as measured by the acute SF-12 and pain as measured on the Visual Analogue Scale (VAS). A subgroup analysis of different assessment instruments and baseline characteristics will be performed using multiple linear regression models. This study aims to examine: 1. Which biomedical, psychological, social, and occupational outcome assessment tools are identifiers for the transition from acute to chronic LBP and at which time point this transition becomes manifest. 2. Which psychosocial and occupational baseline characteristics like work status and period of work absenteeism influence the course from acute to chronic LBP. 3. Differences in outcome assessment tools and baseline characteristics of patients in NZ compared with CH. DISCUSSION: This study will develop a screening tool for patients with acute LBP to be used in GP clinics to access the risk of developing chronic LBP. In addition, biomedical, psychological, social, and occupational patient characteristics which influence the course from acute to chronic LBP will be identified. Furthermore, an appropriate time point for follow-ups will be given to detect this transition. The generalizability of our findings will be enhanced by the international perspective of this study. TRIAL REGISTRATION: [Clinical Trial Registration Number, ACTRN12608000520336].

Thalamic stimulation for tremor. Subtle changes in episodic memory are related to stimulation per se and not to a microthalamotomy effect

The aim of this study was to investigate the impact of unilateral deep brain stimulation (DBS) of the ventrointermediate (Vim) thalamic nucleus on neuropsychological functioning comparing stimulation-on with stimulation-off conditions. Nine patients [five patients with Parkinson's Disease (PD), two patients with essential tremor (ET) and 2 patients with multiple sclerosis (MS)] underwent comprehensive neuropsychological testing for cognitive functions, including general mental impairment, aphasia, agnosia, executive and constructional abilities, learning, memory, cognitive processing speed and attention as well as depression. The neuropsychological assessments were performed at least 6 months postoperatively (mean 9 months). Testing in the stimulation-on and stimulation-off condition was obtained within a period of 3 to 4 weeks. Unilateral DBS resulted in improvement of tremor in all patients. There were no significant differences between the stimulation-on and the stimulation-off condition with the exception of a decrement of word-recall in the short delay free-recall subtest of the Rey Auditory-Verbal Learning Test (RAVLT). Subgroup analysis indicated that the impairment in word-recall was related to left-sided thalamic stimulation. Our study confirms that chronic unilateral DBS is a safe method with regard to cognitive function. The subtle changes in episodic memory are related to stimulation per se and not to a microthalamotomy effect.

Effect of once-yearly zoledronic acid 5 mg on fracture risk and change in femoral neck bone mineral density

Context: In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly - Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg significantly reduced fracture risk. Objective: To identify factors associated with greater efficacy during ZOL 5 mg treatment. Design, Setting and Patients: Subgroup analysis (preplanned and post hoc) of a multicenter, double-blind, placebo-controlled, 36-month trial in 7765 women with postmenopausal osteoporosis. Intervention: Single infusion of ZOL 5 mg or placebo at baseline, 12 and 24 months. Main Outcome Measures: Primary endpoints: new vertebral fracture and hip fracture. Secondary endpoints: non-vertebral fracture, change in femoral neck bone mineral density (BMD). Baseline risk factor subgroups: age, BMD T-score and vertebral fracture status, total hip BMD, race, weight, geographical region, smoking, height loss, history of falls, physical activity, prior bisphosphonates, creatinine clearance, body mass index (BMI), concomitant osteoporosis medications. Results: Greater ZOL induced effects on vertebral fracture risk with younger age (treatment-by-subgroup interaction P=0.05), normal creatinine clearance (P=0.04), and BMI >/=25 kg/m(2) (P=0.02). There were no significant treatment-factor interactions for hip or non-vertebral fracture or for change in BMD. Conclusions: ZOL appeared more effective in preventing vertebral fracture in younger women, overweight/obese women and women with normal renal function. ZOL had similar effects irrespective of fracture risk factors or femoral neck BMD.