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N Engl J Med 2024;391:1673-1684Background: Non-ST elevation myocardial infarction (NSTEMI) is the most common acute coronary syndrome subtype in adults over 75 years old. However, these patients were underrepresented in landmark NSTEMI trials. Older adults with multiple comorbidities face an increased risk of mortality. While NSTEMI contributes to this risk, they also have competing risks such as advanced age, frailty, and chronic kidney disease. The presence of competing risks means that aggressively managing one condition may have a smaller impact on overall mortality compared to a younger, otherwise healthy adult with myocardial infarction, whose primary risk of death stems from the myocardial infarction itself. Additionally, comorbid conditions like advanced kidney disease and diffuse atherosclerosis can increase the risks associated with revascularization.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.A patient-level meta-analysis of smaller trials, including 1,479 patients, found that in elderly patients with NSTEMI, an invasive strategy reduced myocardial infarction and urgent revascularization but not mortality.The Older Patients with Non–ST-Segment Elevation Myocardial Infarction Randomized Interventional Treatment (SENRIOR-RITA) trial sought to assess invasive vs conservative management of elderly patients with NSTEMI, in a more pragmatic design.Patients: Eligible patients had to have type I NSTEMI and be 75 years or older.Patients were excluded if they had cardiogenic shock or life expectancy less than 1 year.Baseline characteristics: The trial randomized 1,518 patients from hospitals across England and Scotland – 753 randomized to invasive strategy and 765 to conservative strategy.The average age of patients was 82 years and 55% were men. Approximately 65% had hypertension, 31% had diabetes, 31% had hyperlipidemia, 31% had prior myocardial infarction, 15% had prior stroke or TIA, 21% had kidney disease, 15% had chronic obstructive pulmonary disease, and 5% were current smokers.The average Charlson comorbidity index was 5.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo invasive or conservative strategy.In the invasive strategy, patients underwent coronary angiogram, and revascularization was performed as appropriate. In the conservative arm, patients were treated (unless contraindicated) with aspirin, a P2Y12 receptor antagonist, statin, beta-blocker and an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. Patients in the conservative arm were allowed to have a coronary angiogram if they had worsening clinical status.Endpoints: The primary end point was a composite of cardiovascular death or nonfatal myocardial infarction. Secondary outcomes included all-cause death, subsequent coronary revascularization, hospitalization for heart failure, stroke and bleeding.Analysis was performed based on the intention-to-treat principle. The trial aimed to detect a hazard ratio of 0.78, assuming a 20% risk of the primary outcome in the conservative arm. A sample size of 1,668 patients with at least 688 primary outcome events would provide 90% power at 5% alpha, while 520 events would provide 80% power.Results: Among the patient randomized to the invasive arm, 90% underwent coronary angiography and 50% underwent revascularization. The medium number of days from admission to coronary angiography was 5. Among patients randomized to the conservative arm, 5.6% underwent coronary angiography within 7 days. The median follow-up time was 4.1 years.The primary outcome was not significantly different between both groups (25.6% with invasive vs 26.3% with conservative, HR: 0.94, 95%: 0.77 - 1.14; p= 0.53).There was also no difference in all-cause death (36.1% vs 32.3%), cardiovascular death (15.8% vs 14.2%), stroke (4.2% vs 5.2%), hospitalization for heart failure (10.9% vs 10.7%), or major bleeding (8.2% vs 6.4%) “incidence for invasive mentioned first”. Future coronary revascularization was more frequent in the conservative arm (13.7% vs 3.9%). Non-fatal myocardial infarction was significantly lower with an invasive strategy (11.7% vs 15.0%).Procedural related complications occurred in less than 1% of the patients.There were no significant subgroup interactions for the primary outcome.Conclusion: In older patients with NSTEMI, an invasive strategy compared to conservative strategy, did not reduce the primary composite endpoint of cardiovascular death or nonfatal myocardial infarction, over a median of 4.1 years.The trial enrolled fewer patients than planned, and the lower-than-expected event rate reduced its statistical power. Additionally, the median 5-day delay before coronary angiography may have biased the results toward the conservative strategy.Despite its limitations, this trial demonstrates that a conservative approach is a reasonable option for selected older patients with NSTEMI. It also highlights that, although enrolling older patients with comorbidities in trials is challenging, it is feasible, and greater effort is needed to include more of this population in future trials.Finally, in this trial of patients with myocardial infarction, about one-third died over a median of 4.1 years, with less than half of these deaths attributed to cardiovascular disease. Even if an invasive strategy had reduced cardiovascular mortality, its impact on all-cause mortality would have been less significant. This concept extends beyond this trial; when interventions are applied to older patients with multiple competing risks, their overall benefit diminishes.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

N Engl J Med 2008;358:557-567Background: ST-segment elevation myocardial infarction (STEMI) is caused by disruption of an atherosclerotic plaque, leading to intraluminal thrombosis that partially or completely blocks the coronary artery. Opening the blocked artery using percutaneous coronary intervention (PCI) restores blood flow and is the standard of therapy for these patients. In many patients, spontaneous embolization or embolization caused by thrombus fragmentation during PCI can lead to small thrombi migrating distally and obstructing the coronary microcirculation. This is associated with increased infarct size, reduction in left ventricular recovery and increased risk of mortality.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Several devices designed to retrieve intracoronary thrombus have been developed and have demonstrated improved coronary reperfusion in small studies. The Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction Study (TAPAS) sought to compare the efficacy of thrombus aspiration versus conventional PCI in patients with STEMI.Patients: Eligible patients were recruited from a single center in Netherlands. Patients had STEMI with symptoms lasting more than 30 minutes but less than 12 hours. The EKG criteria were ST-segment elevation of >1mm in at least two leads.Patients were excluded if they had rescue PCI after thrombolysis or if life expectancy was less than 6 months.Baseline characteristics: The trial randomized 1,071 patients – 535 randomized to thrombus aspiration and 536 randomized to conventional PCI.The average age of patients was 63 years and 70% were men. Approximately 35% had hypertension, 12% had diabetes, 25% had hyperlipidemia, 10% had prior myocardial infarction, and 47% were current smokers.Infarct-related vessel was the left anterior descending artery in 43% of the patients, the left circumflex artery in 17% and the right coronary artery in 38%.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo thrombus aspiration during PCI or conventional PCI. All placed stents were bare-metal stents.Before PCI, patients received 500 mg of aspirin, 600mg of clopidogrel and 5000 IU of heparin. Patients also received the glycoprotein IIb/IIIa inhibitor abciximab, if not contraindicated, and additional heparin during the procedure.Endpoints: The primary end point was the postprocedural frequency of a myocardial blush grade of 0 or 1. Secondary end points included complete resolution of ST-segment elevation and the absence of persistent ST-segment deviation. Clinical endpoints were also assessed as part of the secondary endpoints and included target-vessel revascularization, reinfarction or death, at 30 days.A 12-lead EKG was obtained at presentation and again at 30 to 60 minutes after PCI, and the ST-segments on the postprocedural EKG were compared with those at presentation.Not to readers: Myocardial blush is a qualitative angiographic method used to assess microvascular perfusion during coronary angiography. It evaluates how well contrast dye penetrates the myocardium. The grading of myocardial blush was: 0: no myocardial blush, 1: minimal myocardial blush or contrast density, 2: moderate myocardial blush or contrast density but less than that obtained during angiography of a contralateral or ipsilateral non–infarct-related coronary artery, and 3: normal myocardial blush or contrast density, similar to that obtained during angiography of a contralateral or ipsilateral non–infarct-related coronary artery. Persistent myocardial blush suggests leakage of contrast medium into the extravascular space and was given a grade of 0.Analysis was performed based on the intention-to-treat principle. To achieve 80% power with a two-sided alpha of 0.05, a total of 1,080 patients would be needed to detect a 25% reduction in the primary endpoint with thrombus aspiration compared to conventional PCI. This calculation assumed a 30% rate of myocardial blush grade 0 or 1 in the conventional PCI group.Results: Among the 1,161 patients screened for inclusion, 1,071 (92.2%) were randomized. Approximately, 94% of the patients in both groups underwent PCI. Among patients who underwent PCI in the thrombus aspiration group, 89% underwent thrombectomy. Among the patients who underwent thrombus aspiration, histopathological examination showed atherothrombotic material in 331 (72.9%) patients.The primary outcome of myocardial blush grade 0 or 1 was significantly lower in the thrombus aspiration group (17.1% vs 26.3%, RR: 0.65, 95% CI: 0.51 - 0.83; p

N Engl J Med 2003;349:733-742Background: In patients with ST elevation myocardial infarction, treatment with balloon angioplasty improved outcomes compared to fibrinolysis, as seen in the Primary Angioplasty in Myocardial Infarction Study Group trial. Other trials showed similar findings. However, these trials were relatively small in size and mainly conducted at hospitals with high experience in angioplasty.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.At the time this trial was conducted, limited number of hospitals offered angioplasty. Transporting patients with ST-elevation myocardial infarction to these centers posed a significant challenge, and sometimes resulting in delays in treatment.The DANAMI-2 investigators sought to conduct a community-wide trial comparing on-site fibrinolysis vs transferring the patients for primary angioplasty.Patients: Eligible patients had ST-segment elevation myocardial infarction with symptoms lasting for at least 30 minutes but less than 12 hours. The EKG criteria were cumulative ST-segment elevation of at least 4 mm in at least two contiguous leads.Exclusion criteria were many and included contraindication to fibrinolysis, left bundle branch block, acute myocardial infarction and fibrinolytic treatment within the previous 30 days, pulseless femoral arteries, renal failure defined as creatinine > 2.83 mg/dL, life expectancy less than 12 months due to non-cardiac disease, and more. Patients were also excluded if they were high risk for transportation because of cardiogenic shock, persistent life-threatening arrhythmias, or a need for mechanical ventilation.Baseline characteristics: The trial randomized 1,572 patients – 790 randomized to angioplasty and 782 to fibrinolysis. A total of 1129 patients were randomized at referral hospitals, and 443 patients were randomized at invasive-treatment centers.The average age of patients was 63 years and 73% were men. Approximately 20% had hypertension, 7% had diabetes, 11% had prior myocardial infarction, and 58% were current smokers.Among patients who underwent angiography and data were available, 53% had single vessel disease, 25% had two vessel disease and 14% had three vessel disease. Approximately 3% had left main involvement.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo fibrinolysis or angioplasty. Patients were recruited from 24 referral hospitals without angioplasty facilities and 5 invasive-treatment hospitals with angioplasty facilities. For patients recruited from referral hospitals, transfer to angioplasty center had to be completed within 3 hours. A physician accompanied the patient. The participating hospitals served 62% of the Danish populationPatients assigned to fibrinolysis received 300 mg of aspirin orally, beta-blocker intravenously, tissue plasminogen activator (alteplase, given as a 15-mg bolus and an infusion of 0.75 mg/kg over 30 minutes, followed by an infusion of 0.5 mg/kg for 60 minutes), and an intravenous bolus of unfractionated heparin (5000 U), followed by a 48-hour infusion of unfractionated heparin.Patients assigned to angioplasty received 300 mg of aspirin intravenously, beta-blocker intravenously, and 10,000 U of unfractionated heparin bolus, with additional heparin during the angioplasty procedure to achieve an activated clotting time of 350 to 450 seconds.Angioplasty was only performed for target-vessel related infarct.Endpoints: The primary end point was a composite of death from any cause, clinical reinfarction or disabling stroke, at 30 days. Procedure-related reinfarction was not counted in the primary end point.The trial was designed with two parallel sub-studies: One involving patients randomized at referral hospitals and the other involving patients randomized at invasive-treatment centers.Analysis was performed based on the intention-to-treat principle. Sample size calculations assumed that the combined primary endpoint would occur within 30 days in 16% of patients assigned to fibrinolysis, 10% of those assigned to angioplasty at referral hospitals, and 9% of those assigned to angioplasty at invasive-treatment centers. Based on these assumptions, 1100 patients were needed to be enrolled at referral hospitals and 800 patients at invasive-treatment centers.Results: Among the 4,278 patients screened for inclusion, 1,572 (36.7%) were randomized. The study was stopped early after the third interim analysis demonstrated superiority of angioplasty in the referral-hospital sub-study. The median time from the onset of symptoms to randomization was 135 minutes. The median distance patients were transported from a referral hospital to an invasive-treatment center was 50 km. The time from randomization at the referral hospital to arrival in the catheterization laboratory was under 2 hours in 96% of the patients. There were no deaths during transportation.Among the patients randomized to fibrinolysis, 99% received the assigned treatment. Among the patients randomized to angioplasty, 98% underwent angiography. Angioplasty was attempted in 89.4% of the patients, and among them, stents were implanted in 90.4%.Angioplasty reduced the primary composite endpoint among all patients (8.0% vs 13.7%; p

THE LANCET 2011;377:1409-1420Background: When patients undergo coronary angiography, a hollow tube called a sheath is inserted into an artery. The primary function for the sheath is to provide a stable entry point into the artery, allowing for the safe navigation of instruments to the coronary arteries. Traditionally these sheaths were inserted into the femoral artery. One of the common complications associated with this approach is bleeding which is associated with worse outcomes. An alternative approach is inserting the sheath into the radial artery which is more superficial and more readily compressible compared to the femoral artery.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Small randomized trials suggested that a radial artery access is associated with less bleeding with possible reduction in death and myocardial infarctions but also a signal of increased percutaneous coronary intervention (PCI) failure.The RIVAL trial sought to assess if radial artery access is superior to femoral artery access in patients with acute coronary syndrome (ACS) undergoing coronary angiography.Patients: Patients had acute coronary syndrome and an invasive strategy was planned. Dual circulation of the hand, as assessed by an Allen's test, had to be intact.Patients were excluded if they had cardiogenic shock, severe peripheral vascular disease precluding a femoral approach, active bleeding or high bleeding risk, or prior coronary artery bypass grafting (CABG) with the use of more than one internal mammary artery graft.Baseline characteristics: The trial randomized 7,021 patients in 32 countries – 3,507 randomized to radial access and 3,514 to femoral access.The average age of patients was 62 years and 73% were men. Approximately 60% had hypertension, 21% had diabetes, 18% had prior myocardial infarction, 2% had prior CABG, 2% had peripheral vascular disease, and 31% were current smokers.The diagnosis at admission was unstable angina in 45% of the patients, NSTEMI in 27% and STEMI in 28%.The use of antiplatelet and anti-thrombotic drugs was not significantly different between both groups.Procedures: The RIVAL trial initially enrolled patients within the CURRENT-OASIS 7 trial which was a trial of antiplatelets therapy in ACS. After the conclusion of the CURRENT-OASIS 7 trial, RIVAL enrolled additional patients.Patients were assigned in a 1:1 ratio to undergo femoral or radial artery access. The use of anti-thrombotic regimen at the time of PCI as well as femoral artery closure devices was at the discretion of the treating physician.Endpoints: The primary outcome was a composite of all-cause death, myocardial infarction, stroke, or non-CABG related major bleeding, within 30 days. Secondary outcomes included the components of the primary outcome as well as major vascular access site complications and PCI procedural success.The components of the primary outcome were adjudicated by a central committee blinded to the treatment assignment. Major vascular access site complications and PCI procedural success were reported by the investigators.Analysis was performed based on the intention-to-treat principle. Due to low event rate, the sample size was increased from 4,000 to 7,000. This new sample size would provide 80% power to detect 25% relative risk reduction in the primary endpoint assuming 6% event rate in the femoral access arm.The study had six prespecified subgroup analysis: Age (< 75 vs older), sex, body mass index, STEMI vs no STEMI, operator's annual radial PCI volume and center's median operator's radial PCI volume.Results: Among the 7,021 randomized patients, 99.8% underwent coronary angiography. The rate of crossover was 7.6% in the radial group and 2.0% in the femoral group. Most of the crossover in the radial group was due to failure of the coronary angiogram using the radial approach. There was no significant difference in the number of PCI catheters used between both groups. Fluoroscopy time was higher in the radial group (7.8 minutes vs 6.5 minutes; p< 0.001).The primary composite outcome at 30-days was not significantly different between both groups (3.7% with radial vs 4.0% with femoral, HR: 0.92, 95% CI: 0.72 – 1.71; p= 0.50). All of the components of the primary outcome were not significantly different between both groups: 1.3% vs 1.5% for death, 1.7% vs 1.9% for myocardial infarction, 0.6% vs 0.4% for stroke, and 0.7% vs 0.9% for non-CABG related major bleeding.PCI procedural success was 95% in both groups. Major vascular complications were lower using the radial approach (1.4% vs 3.7%; p< 0.001). Major vascular complications were defined as pseudoaneurysms needing closure, large hematoma, arteriovenous fistula, or an ischemic limb needing surgery.There were no significant subgroup interactions based on age, sex, body mass index or operator's radial PCI volume. There was significant interaction based on STEMI vs no STEMI (p for interaction= 0.025) and center's radial PCI volume (p for interaction 0.021), such as patients with STEMI and patients in centers with the highest tertile for PCI volume had reduction in the primary outcome with radial access.Significantly more patients in the radial group said to prefer radial approach if they need a future coronary angiography (90.2% vs 50.7%; p< 0.001).Conclusion: In patients with acute coronary syndrome undergoing coronary angiography, a radial approach compared to femoral approach, did not improve the primary composite outcome of all-cause death, myocardial infarction, stroke, or non-CABG related major bleeding, at 30 days. A radial approach reduced major vascular complications with a number needed to treat of approximately 43 patients. A radial artery approach was more commonly preferred by patients for future coronary angiography.One of the limitations of this trial is that the outcome of major vascular complications is subject to bias as it was reported by the investigators rather than centrally adjudicated.Given that this trial compares two approaches with similar costs, the observed reduction in vascular complications justifies an increased adoption of the radial approach. The safety of the radial approach has likely improved over the years as centers and operators have gained more experience. Moreover, patients have shown a clear preference for the radial approach, which is an important win as well.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

N Engl J Med 2009;360:2503-2515Background: Type 2 diabetes increases the risk of cardiovascular events and death. Previous trials comparing revascularization versus medical therapy included patients with diabetes, however, a large-scale trial specifically focusing on patients with type 2 diabetes was lacking.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial sought to assess the optimal treatment strategy for patients with type 2 diabetes and stable coronary artery disease.Patients: Eligible patients had type 2 diabetes and stable coronary artery disease. Coronary artery disease was defined as a stenosis in a major coronary artery of 50% or more and a positive stress test or 70% or more and classic angina. Patients had to be candidates for percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) without further specification.Patients were excluded if they had left main disease, prior PCI or CABG within 12 months, class III or IV heart failure, hepatic dysfunction, creatinine> 2 mg/dL or glycated hemoglobin> 13%.Baseline characteristics: The trial randomized 2,368 patients – 1,176 randomized to the revascularization arm and 1,192 to the medical therapy arm. Among the 1,176 patients in the revascularization arm, 32% were planned to undergo CABG and 68% planned to undergo PCI.The average age of patients was 62 years and 70% were men. The mean glycated hemoglobin was 7.7% and the mean duration of diabetes was 10.4 years. Approximately 32% had prior myocardial infarction, 7% had congestive heart failure and 24% had peripheral artery disease. Approximately 18% had no angina or angina equivalent. Angina class within 6 weeks was 1-2 in 43% of the patients and 3-4 in 9%.The mean left ventricular ejection fraction was 57%. Approximately 31% had three-vessel disease and 13% had proximal left anterior descending artery disease.Baseline characteristics were well balanced between the revascularization arm and the medical therapy alone arm. However, patients who were in the CABG stratum had more three-vessel disease (52% vs 20%) and more proximal left anterior descending artery disease (19% vs 10%).Procedures: The trial was a 2 x 2 factorial design and patients were randomly assigned to two treatment strategies. The first was randomization to revascularization or medical therapy. The second was randomization to insulin-sensitization therapy or insulin-provision therapy. Randomization was stratified based on the method of revascularization (PCI vs CABG) which was determined by the treating physician.In this review, we will focus on the first strategy of revascularization vs medical therapy.For patients randomized to the revascularization arm, the procedure was to be performed within 4 weeks after randomization. Patients in the medical arm could receive revascularization on follow up for any of the following: Progression of angina, acute coronary syndrome or severe ischemia.Patients were seen monthly for the first 6 months and every 3 months thereafter.Endpoints: The primary endpoint was death from any cause. Secondary end point was a composite of death, myocardial infarction, or stroke.Analysis was performed based on the intention-to-treat principle. The original sample size of 2,800 patients was not met, and therefore, the average follow up time was increased by 1.5 years to become 5.3 years. Using the new follow up duration, the study had 88% power to detect a 33% relative risk reduction of death (from 14.0% to 9.8%), and a 95% power to detect a 25% relative risk reduction in the secondary composite endpoint (from 24.0% to 18.0%).Results: Among the patients randomized to the revascularization arm, 95.4% underwent revascularization at 6 months compared to 13.0% of the patients randomized to the medical arm. At 5-years, 42.1% of the patients randomized to the medical arm had undergone revascularization. Among patients who underwent PCI in the revascularization arm, procedures were attempted on average of 1.5 lesions and 56.0% received a bare metal stent. Among patients who underwent CABG in the revascularization arm, 94.2% received an internal mammary artery graft and the mean number of distal anastomoses was 3.0.The average follow up time was 5.3 years.There was no significant difference in the primary outcome of all-cause death. Survival was 88.3% in the revascularization arm and 87.8% in the medical arm (difference: 0.5%; 95% CI: −2.0 - 3.1; p=0.97). There was also no significant difference for the secondary composite endpoint. Freedom from events for the secondary endpoint was 77.2% in the revascularization arm and 75.9% in the medical arm (difference: 1.3%; 95% CI, −2.2 - 4.9; p=0.70).Survival was not significantly different between both treatment strategies in the CABG stratum (86.4% with revascularization vs 83.6% with medical therapy; p= 0.33). However, patients in the CABG stratum had more freedom from the secondary composite endpoint (77.6% vs 69.5%; p= 0.01).In the PCI stratum, revascularization did not improve survival (89.2% with revascularization vs. 89.8% with medical therapy; p= 0.48) or freedom from the secondary composite endpoint (77.0% with revascularization vs 78.9% with medical therapy; p= 0.15).Conclusion: In patients with type 2 diabetes and stable coronary artery disease, revascularization compared to medical therapy did not improve the primary outcome of all-cause death, or the composite secondary outcome of death, myocardial infarction or stroke over an average follow up time of 5.3 years.The observed benefit of revascularization within the CABG stratum should be viewed as hypothesis-generating rather than conclusive evidence that CABG is superior to PCI in this patient population.One potential limitation of this trial is that the authors included patients who were candidates for either PCI or CABG without providing enough details on what makes someone not a candidate. This lack of clarity limits physicians' ability to fully understand which patients would have been suitable for inclusion.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

N Engl J Med 2016;375:2223-2235Background: Smaller randomized trials have shown that outcomes are not significantly different when patients with left main disease are treated with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). In the subgroup of patients with left main disease in the SYNTAX trial, outcomes were similar between PCI and CABG in patients with low or intermediate SYNTAX score but PCI was associated with worse outcomes in patients with high SYNTAX score.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial sought to assess if PCI was noninferior to CABG in patients with left main coronary artery disease.Patients: Eligible patients had left main stenosis of 70% or more. Patients with stenosis of 50% to 69% were enrolled if the stenosis was hemodynamically significant as determined by non-invasive or invasive testing. Patients were also required to have low or intermediate SYNTAX score defined as a score of 32 or less.Patients were excluded if they had prior PCI to the left main coronary artery, PCI to any other coronary artery within 1 year, prior CABG, a need for a concomitant cardiac surgery, elevated CK-MB, or life expectancy less than 3 years due to non-cardiac conditions.Baseline characteristics: The trial randomized 1,905 patients – 948 randomized to PCI and 957 to CABG.The average age of patients was 66 years and 77% were men. Approximately 74% had hypertension, 70% had hyperlipidemia, 29% had diabetes, 17% had prior myocardial infarction and 22% were current smokers. The average left ventricular ejection fraction was 57%.The clinical presentation was myocardial infarction within 7 days in 14% of the patients, unstable angina in 24%, stable angina in 53%, and silent ischemia or other in 8%.Distal left main bifurcation or trifurcation disease was present in 81% of the patients, and 2- or 3-vessel coronary artery disease was present in 51%. SYNTAX score based on a core laboratory evaluation was low (22 or less) in 36% of the patients, intermediate (23-32) in 40% and high (33 or more) in 24%. However, based on site assessment, SYNTAX score was low in 61% of the patients and intermediate in 39%.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo CABG or PCI using fluoropolymer-based cobalt–chromium everolimus-eluting stents (XIENCE, Abbott Vascular). Randomization was stratified based on the presence of diabetes, SYNTAX score (low vs intermediate) and study center.Dual antiplatelets were given for at least 12 months following PCI.CABG was performed with or without cardiopulmonary bypass based on the operator discretion. The use of arterial grafts was recommended.Endpoints: The primary endpoint was a composite of death from any cause, myocardial infarction and stroke at 3 years. Secondary endpoints included the components of the primary endpoint as well as repeat revascularization.Analysis was performed based on the intention-to-treat principle. Sample size was calculated based on non-inferiority. The sample size to provided 80% power with one-sided alpha of 0.025 was 1,900 patients. This calculation was based on an assumed 11% event rate in each study group and 4.2% absolute difference non-inferiority margin.The original sample size was 2,600 patients which would have provided 90% power. However, both were adjusted due to slow enrollment.Results: Among the 948 patients assigned to the PCI arm, 99% underwent the procedure. The mean number of stents implanted per patient was 2.4. Among the 957 patients assigned to the CABG arm, 96% underwent the surgery. The mean number of grafts per patient was 2.6. An internal mammary artery graft was used in 99% of the patients. The median follow up time was 3 years.The primary composite endpoint was not significantly different between CABG and PCI (14.7% with CABG vs 15.4% with PCI, absolute difference: 0.7%, upper bound of the 97.5% CI: 4.0%; p= 0.02 for non-inferiority). There was no significant difference in death from any cause (5.9% with CABG vs 8.2% with PCI; p= 0.11), myocardial infarction (8.3% with CABG vs 8.0% with PCI, p= 0.64) or stroke (2.9% with CABG vs 2.3% with PCI; p= 0.37). Ischemia-driven revascularization was higher with PCI (12.6% vs 7.5%; p

N Engl J Med 2012;367:2375-2384Background: The first large trial to compare PCI vs CABG was SYNTAX. In the subgroup of patients with diabetes, which made up approximately 25% of the trial population, PCI was associated with a higher rate of adverse events compared to CABG, primarily driven by higher rates of repeat revascularization in the PCI group.The Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial sought to assess the optimal revascularization strategy for patients with diabetes and multivessel coronary artery disease.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Patients: Eligible patients had diabetes and multivessel coronary artery disease defined as a stenosis of 70% or more in two or more major coronary arteries supplying at least two separate territories.Patients with left main stenosis of 50% or more were excluded as well as patients with severe congestive heart failure, prior CABG or valve surgery, stroke within 6 months, significant bleeding within 6 months, 2 or more chronic total occlusions in major coronary territories that are targets for revascularization, and patients with STEMI within 72 hours.Baseline characteristics: The trial randomized 1,900 patients – 953 randomized to PCI and 947 to CABG.The average age of patients was 63 years and 71% were men. The average HbA1c was 7.8 and 32% were using insulin. Approximately 26% had prior myocardial infarction and 16% were current smokers. The average left ventricular ejection fraction was 66%.Approximately 83% had three vessel disease and 6% of the lesions were classified as chronic total occlusions. The SYNTAX score was low (22 or less) in 35% of the patients, intermediate (23 - 32) in 45% and high (33 or more) in 20%.Procedures: Patients were randomized in a 1:1 ratio to undergo CABG or PCI using drug-eluting stents. The use of arterial conduits was encouraged for patients undergoing CABG.Dual antiplatelet therapy with aspirin and clopidogrel was recommended for at least 12 months following PCI.Endpoints: The primary endpoint was a composite of death from any cause, nonfatal myocardial infarction, and nonfatal stroke. Secondary analysis was performed based on the SYNTAX score and study center location; north America vs not.Analysis was performed based on the intention-to-treat principle. The estimated sample size was 1,900 patients to be followed up for at least 2 years. This sample size would provide 80% power to detect a 27% relative risk reduction in one treatment group based on an estimated event rate of 21.5% in the arm with higher event rate.It's important to note that the initial sample size was 2,400 patients but this was amended twice due to slow recruitment.Authors performed 3 interim analyses and therefore, the p value to indicate statistical significance for the primary outcome was adjusted to be 0.044.Results: Among 32,966 patients who were screened for inclusion, 3,309 (10%) were found eligible. Among eligible patients, 1,900 consented to the trial and were randomized. The breakdown for excluding patients was not provided. The median follow up time was 3.8 years (interquartile range: 2.5 - 4.9). In the PCI arm, the average number of lesions stented per patient was 3.5 and 34% underwent a staged procedure. In the CABG arm, the average number of vessels grafted was 2.9 and 94% had a left internal mammary artery graft.At 5-years, the primary outcome was lower in the CABG arm (18.7% vs 26.6%, absolute difference 7.9%, 95% CI: 3.3 – 12.5; p= 0.005). All-cause death was lower with CABG (10.9% vs 16.3%; p= 0.049) as well as myocardial infarction (6.0% vs 13.9%; p< 0.001). When examining the Kaplan-Meier curves for the primary endpoint as well as death (figure 1 of the manuscript), the curves start to diverge, in favor of surgery, at approximately 2-years of follow up.Stroke was higher with CABG (5.2% vs 2.4%; p= 0.03). Excess stroke in the CABG arm was largely within 30-days after the procedure (1.8% vs 0.3%).Major bleeding within 30-days after revascularization was not significantly different between both treatment groups (3.6% with CABG vs 2.4% with PCI; p= 0.13). Acute renal failure requiring dialysis within 30-days after revascularization was higher with CABG (0.8% vs 0.1%; p= 0.02).There were no significant subgroup interactions that included the SYNTAX score, sex, 2- or 3-vessel disease and study center location; north America vs not.Conclusion: In patients with diabetes and multi-vessel stable coronary artery disease, CABG was superior to PCI in reducing the primary endpoint that consisted of death from any cause, nonfatal myocardial infarction, and nonfatal stroke with a number need to treat (NNT) of approximately 13 patients over an average follow-up period of 3.8 years. All-cause death and myocardial infraction were significantly lower with CABG with a NNT of approximately 19 and 13, respectively. Stroke was higher with CABG with a number needed to harm (NNH) of 36 patients. CABG also increased the risk of acute renal failure requiring dialysis within 30-days after revascularization with a NNH of approximately 143.A key difference between this trial and the early CABG trials is the frequent use of internal mammary grafts in FREEDOM (94% vs 10%). Internal mammary grafts are resistant to atherosclerosis and have high patency rates. One possible explanation for the divergent results between this trial and SYNTAX, which also used arterial grafts frequently, is the follow up time. In SYNTAX, patients were followed for 1 year while FREEDOM followed patients up to 5 years and the curves for the primary outcome and death favoring CABG started to diverge at approximately 2 years.When deciding between CABG and PCI for patients meeting the trial's eligibility criteria, it's important to consider the early risks associated with surgery, with the benefits of CABG becoming more apparent after 2 years. Cardiology Trial's Substack is a reader-supported publication. 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N Engl J Med 1992;326:10-16Background: Revascularization with coronary artery bypass surgery improves symptoms in patients with chronic stable angina as seen in the European Coronary Surgery Study. Percutaneous transluminal coronary angioplasty (PTCA) is less invasive compared to surgery and is associated with less mortality and morbidity. Consequently, its use increased significantly in the late 1980s and early 1990s, driven by its perceived benefits over medical therapy alone due to the ability of PTCA to reduce coronary artery luminal stenosis.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The Angioplasty Compared to Medicine (ACME) study sought to test the hypothesis that PTCA improves symptoms in patients with single vessel sable coronary artery disease.Patients: Eligible patients were recruited from Veterans Affairs centers. Patients had to have 70 – 99% stenosis in the proximal two thirds of one major epicardial coronary artery plus one of the following: stable angina pectoris, very positive exercise-tolerance test (ST-segment depression ≥3 mm) or a myocardial infarction within the past 3 months.Baseline characteristics: The study screened 9,573 patients and among them only 212 (2.2%) were enrolled – 107 randomized to medical therapy and 105 to PTCA. The reasons for patients' exclusion were provided in table 1 of the manuscript. Some key exclusion criteria were previous CABG, unstable angina, prior PTCA, 3-vessel disease or lesions not suitable for PTCA.The average age of enrolled patients was 63 years. Approximately 30% had prior myocardial infarction, 53% had hypertension, 18% had diabetes, 1% had congestive heart failure, and 31% were current smokers. There were more employed participants in the PTCA arm 42% vs 29%. The average systolic blood pressure was 136 mm Hg. The average total cholesterol was 230 mg/dl.The average duration participants did on the treadmill was 8.8 minutes. Approximately 38% had LAD disease, 25% had LCx disease, and 37% had RCA disease.Procedures: All patients were admitted to the hospital. Anti-anginal medications were stopped for at least 24 hours and exercise stress test that included thallium Scintigraphy was performed. The test was considered positive if there was horizontal or down-sloping ST-segment depression ≥ 1.0 mm in one or more leads measured 80 msec after the J point that occurred during or after treadmill exercise testing. Patients who had angina during the test but did not meet the above criteria could be included if there was evidence on thallium scanning of a reversible defect in the area corresponding to the index lesion. If the test showed ischemia, patients were then assigned to PTCA or medical therapy.All patients received aspirin 325 mg/day. Patients in the medical arm received one or combination of the following: nitrates, beta-blockers or calcium channel blockers. Patients in the PTCA arm received calcium channel blockers before and for one month after the procedure, and nitroglycerin during and for 12 hours after the procedure.Patients were followed monthly. Patients were admitted to the hospital 6 months after randomization, for repeat exercise testing and coronary angiogram. For patients in the medical arm, this exercise testing was performed while they continued their anti-anginal medications. In contrast, patients in the PTCA arm stopped their anti-anginal medications for at least 24 hours before the test.Endpoints: The primary end points were changes in exercise tolerance, angina attacks and the use of nitroglycerin. Change in the degree of stenosis in the index lesion was measured as a secondary endpoint.Analysis was performed based on the intention-to-treat principle. The sample size to achieve 95% power at an alpha level of 0.05 was 192. This was based on the assumption that PTCA would increase exercise duration by 1-minute compared to medical therapy. To account for potential loss to follow-up, the recruitment goal was set at 200 patients.Results: Among the 105 patients assigned to PTCA, 95% underwent the procedure, and among them, the procedure was considered successful in 82%. Successful PTCA was defined >20% decrease in percent stenosis of all lesions in which dilation was attempted. Among the 107 patients assigned to medical therapy, 10% underwent PTCA.The mean duration from randomization to follow-up exercise testing was approximately 7 months. PTCA led to greater increase in exercise time compared to medical therapy alone (2.1 minutes vs 0.5 minutes; p< 0.0001) as well as time to onset of angina (2.6 minutes vs 0.8 minutes; p

N Engl J Med 2024;390:1372-1381Background: Beta-blockers are prescribed to the majority of patients with acute myocardial infarction. The bulk of evidence supporting this practice comes from trials published in the 1980s - BHAT and ISIS-I. Since the publication of these seminal trials, the care of patients with acute myocardial infarction has significantly changed with improvement in antiplatelet therapy, the addition of high-intensity statins and renin–angiotensin–aldosterone system antagonists in addition to early revascularization for STEMI patients. Furthermore, myocardial injury is now detected based on high-sensitivity troponin assays which can detect smaller myocardial infarctions. Therefore, there is a lack of evidence whether beta-blockers provide benefit for patients with acute myocardial infarction in the current era.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The Randomized Evaluation of Decreased Usage of Beta-Blockers after Acute Myocardial Infarction (REDUCE-AMI) trial sought to assess whether long-term oral beta-blocker treatment improves outcomes in patients with acute myocardial infarction and preserved left ventricular ejection fraction.Patients: Eligible patients were adults, 1 to 7 days after myocardial infarction who underwent coronary angiography and echocardiography. Patients were required to have obstructive coronary artery disease on coronary angiography defined as stenosis of ≥50%, a fractional flow reserve of ≤0.80, or an instantaneous wave-free ratio of ≤0.89 at any time point before randomization. Left ventricular Ejection fraction on echocardiogram had to be ≥50%. Patients were excluded if they had contraindications to beta-blockers or if the treating physician determined that treatment with beta-blockers is indicated for other conditions.Baseline characteristics: The trial randomized 2,508 patients to the beta-blockers group and 2,512 patients to the control group. The average age of patients was 65 years with 78% being men. About 20% were current smokers, 46% had hypertension, 14% had diabetes, 7% had prior myocardial infarction and < 1% had prior heart failure.The index event was STEMI in 35% of the patients. About 96% underwent percutaneous coronary intervention. The median heart rate was 74 bpm and the median systolic blood pressure was 151 mm Hg.Medications at discharge included aspirin in 97% of the patients, P2Y12 inhibitors in 96%, ACEi or ARBs in 80% and statins in 99%.Procedures: Patients were randomized 1:1 to receive metoprolol succinate (first choice), bisoprolol (second choice) or no beta-blockers. The target doses were at least 100 mg daily for metoprolol succinate and at least 5 mg daily for bisoprolol. Patients in the control group were discouraged from using beta-blockers; they did not receive placebo. If a patient was on beta-blocker therapy at the time of enrollment and was randomly assigned to the no–beta-blocker group, the beta-blocker had to tapered off over a period of 2 to 4 weeks.Endpoints: The primary end point was a composite of death from any cause or new myocardial infarction. Secondary end points were death from any cause, death from cardiovascular causes, myocardial infarction, hospitalization for atrial fibrillation as primary diagnosis, and heart failure hospitalization. There were three safety endpoints: 1- Hospitalization for bradycardia, second- or third-degree atrioventricular block, hypotension, syncope, or implantation of a pacemaker, 2- hospitalization for asthma or chronic obstructive pulmonary disease as a primary diagnosis and 3- hospitalization for stroke.Data on clinical end points were not centrally adjudicated but rather obtained from the SWEDEHEART registry and the Swedish Population Registry.Statistical analysis was performed based on the intention-to-treat principle. Before trial initiation, the estimated event rate in the control group was 7.2%/ year and at least 16.7% lower event rate in the beta-blocker group was considered clinically meaningful. During the trial, the actual event rate in control group was 3%/ year. Given this event rate, a 25% lower event rate in the beta-blocker group was considered clinically meaningful. A total of 379 primary end point events were needed in order to have 80% power at a two-sided alpha of 0.05, to detect the 25% lower event rate with beta-blockers. The estimated number of patients needed was about 5,000.Results: Among the patients who attended the SWEDEHEART registry, 1500/1831 (81.9%) of the beta-blocker group were still taking beta-blockers after 11 to 13 months; compared to 269/ 1886 (14.3%) in the no beta-blocker group.After a median follow up time of 3.5 years, beta-blockers did not the reduce the composite primary endpoint compared to no beta-blockers (7.9% vs 8.3%, HR: 0.96; 95% CI, 0.79 - 1.16; p= 0.64). There were no significant differences in death from any cause (3.9% vs 4.1%), death from cardiovascular causes (1.5% vs 1.3%), myocardial infarction (4.5% vs 4.7%), hospitalization for atrial fibrillation (1.1% vs 1.4%) or hospitalization for heart failure (0.8% vs 0.9%).Safety endpoints were also not significantly different between both groups; 3.4% vs 3.2% for the bradyarrhythmia, syncope or hypotension endpoint, 0.6% in both groups for the hospitalization for asthma or COPD endpoint and 1.4% vs 1.8% for hospitalization for stroke.There were no significant subgroup interactions.Conclusion: In patients with acute myocardial infarction who underwent coronary angiography and had preserved left ventricular systolic function, treatment with beta-blockers did not improve outcomes over a 3.5-year follow-up. Events were infrequent in the trial; 1.4% for cardiovascular death, 4.6% for recurrent myocardial infarction and 0.8% for hospitalization for heart failure. The low event rate in this population in the current era makes it difficult to demonstrate additional benefit with more therapies.The open-label design of the study may have introduced performance bias; however, this bias is expected to favor beta-blockers given the superiority design of the study. Another limitation, as noted by the authors, is that outcomes were obtained from the SWEDEHEART registry and the Swedish Population Registry and were not centrally adjudicated. However, this is expected to affect both groups equally.We believe the divergent results between this trial and older beta-blocker trials in myocardial infarction patients such as BHAT and ISIS-1 which were published in the 1980s, is due to the significant improvement in the management of acute myocardial infarction over time including improved medical therapy in addition to early revascularization for STEMI patients. This improved patient care has led to significantly lower mortality rates over time. For instance, all-cause death in the control arm of REDUCE-AMI is significantly lower than that of BHAT and ISIS-1, at 4.1% vs 9.8% and 11.9%, respectively. This is despite REDUCE-AMI having a longer follow-up period of 3.5 years compared to 2.1 years and 1 year in the earlier trials.In conclusion, this study does not provide evidence that beta-blockers improve outcomes for patients with acute myocardial infarction and preserved ejection fraction in the contemporary era.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.07.548090v1?rss=1 Authors: Sadhukhan, D., Biswas, A., Mishra, S., Maji, D., Mitra, P., Mukherjee, P., Podder, G., Ray, B. K., Biswas, A., Banerjee, T. K., Hui, S. P., Deb, I. Abstract: Background: Post-stroke cognitive impairment (PSCI) is a clinical outcome in around 30% of post-stroke survivors. BDNF is a major gene in this regard. It regulates and being regulated by circadian rhythm. The circadian genes are correlated with stroke timings at molecular level. However, studies suggesting the role of these on susceptibility to PSCI is limited. Aim: We aim here to determine a) genetic risk variants in circadian clock genes, BDNF and b) dysregulation in expression level of CLOCK, BMAL1 and BDNF, that may be associated with PSCI. Methods: BDNF (rs6265G/A, rs56164415C/T), CLOCK (rs1801260T/C, rs4580704G/C) and CRY2 (rs2292912C/G) genes variants were genotyped among 119 post-stroke survivors and 292 controls from Eastern part of India. In addition, we analysed their gene expression in PBMC from 15 PSCI cases and 12 controls. The mRNA data for BDNF was further validated by its plasma level through ELISA. Results: Among the studied variants, only rs4580704/CLOCK showed an overall association with PSCI (P = 0.001) and lower BMSE score. Its C allele showed a correlation with attention deficiency. The language and memory impairments showed association with rs6265/BDNF while the CC genotype of rs2292912/CRY2 negatively influenced language and executive function. A significant decrease in gene expression for CLOCK and BDNF in PBMC (influenced by specific genotypes) of PSCI patients was observed than controls. Unlike, Pro-BDNF, plasma level mBDNF was also lower in them. Conclusions: Our results suggest that the circadian genes and BDNF play a role in PSCI on both genetic and transcript level. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.29.518326v1?rss=1 Authors: Goody, P. R., Christmann, D., Goody, D., Nehl, D., Backer, K., Wilhelm-Juengling, K., Uchida, S., Moore, J. B., Zimmer, S., Bakhtiary, F., Pfeifer, A., Latz, E., Nickenig, G., Jansen, F., Hosen, M. R. Abstract: Rationale: Aortic valve stenosis (AVS) is a major contributor to cardiovascular death in the elderly population worldwide. MicroRNAs (miRNAs) are highly dysregulated in patients with AVS undergoing surgical aortic valve replacement (SAVR). However, miRNA-dependent mechanisms regulating inflammation and calcification or miRNA-mediated cell-cell crossstalk during the pathogenesis of AVS are still poorly understood. Here, we explored the role of extracellular vesicles (EV)-associated miR-145-5p, which we showed to be highly upregulated upon valvular calcification in AVS in mice and humans. Methods: Human TaqMan miRNA arrays identified dysregulated miRNAs in aortic valve tissue explants from AVS patients compared to non-calcified valvular tissue explants of patients undergoing SAVR. Echocardiographic parameters were measured in association with the quantification of dysregulated miRNAs in a murine AVS model. In vitro calcification experiments were performed to explore the effects of EV-miR-145-5p on calcification and crosstalk in valvular cells. To dissect molecular miRNA signatures and their effect on signaling pathways, integrated OMICS analyses were performed. RNA sequencing (RNA-seq), high-throughput transcription factor (TF) and proteome arrays showed that a number of genes, miRNAs, TFs, and proteins are crucial for calcification and apoptosis, which are involved in the pathogenesis of AVS. Results: Among several miRNAs dysregulated in valve explants of AVS patients, miR-145-5p was the most highly gender-independently dysregulated miRNA (AUC, 0.780, p-value, 0.01). MiRNA arrays utilizing patient-derived- and murine aortic-stenosis samples demonstrated that the expression of miR-145-5p is significantly upregulated and correlates positively with cardiac function based on echocardiography. In vitro experiments confirmed that miR-145-5p is encapsulated into EVs and shuttled into valvular interstitial cells. Based on the integrated OMICs results, miR-145-5p interrelates with markers of inflammation, calcification, and apoptosis. In vitro calcification experiments demonstrated that miR-145-5p regulates the ALPL gene, a hallmark of calcification in vascular and valvular cells. EV-mediated shuttling of miR-145-5p suppressed the expression of ZEB2, a negative regulator of the ALPL gene, by binding to its 3' untranslated region to inhibit its translation, thereby diminishing the calcification of target valvular interstitial cells. Conclusion: Elevated levels of pro-calcific and pro-apoptotic EV-associated miR-145-5p contribute to the progression of AVS via the ZEB2-ALPL axis, which could potentially be therapeutically targeted to minimize the burden of AVS. Keywords: aortic valve stenosis, microRNA, extracellular vesicles, cellular crosstalk, valvular calcification Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

When Senior Aerospace Weston wanted to become more efficient in the inspection of critical machined aerostructure parts, the company turned to Renishaw and its Equator™ gauging system. The Equator gauge has cut inspection times per part by around 75% and introduced more comprehensive component traceability. Background Senior Aerospace supplies a range of complex machined components and sub-assemblies for commercial aviation. At the company’s machine shop in Earby, 95% of output is for Airbus aircraft, mainly A320 and A321, but also A330, A380 and A350. Most of the components are aerostructure (wing and mainframe) components; everything from small items measuring 50mm, up to large engine pylon brackets and landing gear fittings. Challenge Some complex aerostructure parts were taking 10 minutes to inspect using Senior Aerospace’s existing CMMs. This would often cause bottlenecks and limitations around the CMMs. To address the problem, the company introduced manual inspection methods using traditional equipment and hard gauging with limited effect. With build-rates increasing, Senior Aerospace Weston recognised its responsibility to become more efficient with in-cycle measurement without compromising quality. “Inspection cycle time has been cut by 75%. Previously a manual measurement would be taken and recorded on paper; now, we have fully electronic reports with every dimension recorded. We can also use trend data to help identify potential areas for improvement in manufacturing.” Solution “We spoke with Renishaw and they proposed the Equator gauge, which is another level up from a traditional 3-axis CMM in terms of speed,” explains CMM Programmer Andy Wright. The thermally-insensitive Equator system is a flexible gauge that is designed to provide speed, repeatability and ease-of-use. “We have 70 parts that could fit on the gauging system, so there is high potential,” states Mr Wright, who is also impressed with the system’s ease of use. “No special skills are required; the operator simply loads the part into the fixture, lets the cycle run and receives an easy-to-read report.” Another factor behind the success of the project has been the sales and applications support from Renishaw: “The support we receive is first class,” says Mr Wright. “Renishaw is very quick to answer any queries, and it almost feels like we’ve been assigned our own special support team.” A key part of the support team for Senior Aerospace Weston is Renishaw Applications Engineer, Ed Clarke, who comments: “For any customer with a turnkey project, we will provide support for their project. If there are any queries, the customer can come directly to us for support.” Results Among the parts inspected at Senior Aerospace Weston using the Equator gauge is a titanium wing flap track component for Airbus. “Over the years, we have gone through several process iterations and various equipment solutions trying to measure the part quicker with the required accuracy, but inspection would regularly fail due to component complexity and tight tolerances,” concedes Mr Wright. “However, using the Equator gauge we have been able to achieve a process that delivers accurate gauging and repeatability. The Equator measures around 25 different features on this part, taking just 90 seconds in total.” “The in-cycle measurement time has been significantly reduced, with our operators now just reviewing an electronic report,” says Mr Wright. “Inspection cycle time has been cut by 75%. Previously a manual measurement would be taken and recorded on paper; now, we have fully electronic reports with every dimension recorded. We can also use trend data to help identify potential areas for improvement in our manufacturing process.” 

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.15.203307v1?rss=1 Authors: O'Reilly, D., Federolf, P. Abstract: Introduction: The aim of this study was to identify movement synergies during normal walking that can differentiate healthy adults in terms of gait adaptability at various speeds. To this end, the association between movement synergies and lower-limb coordination variability or Deviation Phase (DP) was investigated. A secondary aim of this study included an investigation into the moderating effect of these movement synergies on the relationship between DP and the smoothness of arm-swing motion quantified as the normalised jerk index (NJI). Method: A principal component analysis of whole-body marker trajectories from normal-walking treadmill trials at 0.8m/s, 1.2m/s and 1.6m/s was undertaken. Both DP and NJI were derived from approx. 8 minutes of perturbed-walking treadmill trials. Principal movement components, PMk, were derived and the RMS of the 2nd-order differentiation of these PMk (PAkRMS) were included as independent variables representing the magnitude of neuromuscular control in each PMk. The PAkRMS were input into separate maximal linear mixed-effects regression models to explain the variance in DP and (DP x NJI). A stepwise elimination of terms and comparison of models using Anova identified optimal models for both aims. Results: Among the first 7 validated PMk, PA4RMS (double support phase) was identified as an optimal model and demonstrated a significant negative effect on DP however this effect may differ considerably across walking-speeds. An optimal model for describing the variance in (DP x NJI) included a fixed-effect of PA6RMS (Left to Right side weight transfer). Within-participant clustering was prevalent within both optimal models. Interpretation: The hypotheses that individuals who exhibited greater control on specific kinematic synergies would exhibit variations during perturbed walking was substantiated. Supporting evidence for the role of movement synergies during the double-support phase of gait in proactively correcting balance was presented. The potential influence of leg dominance on gait adaptability was also discussed. Future studies should investigate further the role of walking-speed and leg dominance on movement synergies and look to generalize these findings to patient populations. Copy rights belong to original authors. Visit the link for more info

Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy. Sands BE1, Sandborn WJ, Van Assche G, Lukas M, Xu J, James A, Abhyankar B, Lasch K. BACKGROUND: Vedolizumab is a gut-selective α4β7 integrin antagonist for the treatment of moderately to severely active Crohn's disease (CD). Aims of this study were to characterize the efficacy and safety of vedolizumab induction and maintenance therapy in patients who were naïve to tumor necrosis factor-alpha (TNF-α) antagonist therapy (TNF-naïve) or who had discontinued TNF-α antagonist therapy because of inadequate response (i.e., primary nonresponse), loss of response, or intolerance (collectively classified as the TNF-failure population). METHODS: Post hoc analyses of the efficacy data for 516 TNF-naïve and 960 TNF-failure patients from the GEMINI 2 and GEMINI 3 trials were evaluated at weeks 6, 10, and 52 and included clinical remission (CD Activity Index [CDAI] score ≤150), enhanced clinical response (≥100-point decrease from baseline in CDAI score), durable clinical remission (remission at ≥80% of visits), and corticosteroid-free remission. Adverse events were summarized for the TNF-naïve and TNF-failure subgroups by treatment received. RESULTS: Among patients who responded to vedolizumab induction at week 6, 48.9% ...

Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy. Sands BE1, Sandborn WJ, Van Assche G, Lukas M, Xu J, James A, Abhyankar B, Lasch K. BACKGROUND: Vedolizumab is a gut-selective α4β7 integrin antagonist for the treatment of moderately to severely active Crohn's disease (CD). Aims of this study were to characterize the efficacy and safety of vedolizumab induction and maintenance therapy in patients who were naïve to tumor necrosis factor-alpha (TNF-α) antagonist therapy (TNF-naïve) or who had discontinued TNF-α antagonist therapy because of inadequate response (i.e., primary nonresponse), loss of response, or intolerance (collectively classified as the TNF-failure population). METHODS: Post hoc analyses of the efficacy data for 516 TNF-naïve and 960 TNF-failure patients from the GEMINI 2 and GEMINI 3 trials were evaluated at weeks 6, 10, and 52 and included clinical remission (CD Activity Index [CDAI] score ≤150), enhanced clinical response (≥100-point decrease from baseline in CDAI score), durable clinical remission (remission at ≥80% of visits), and corticosteroid-free remission. Adverse events were summarized for the TNF-naïve and TNF-failure subgroups by treatment received. RESULTS: Among patients who responded to vedolizumab induction at week 6, 48.9% ...

Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy. Sands BE1, Sandborn WJ, Van Assche G, Lukas M, Xu J, James A, Abhyankar B, Lasch K. BACKGROUND: Vedolizumab is a gut-selective α4β7 integrin antagonist for the treatment of moderately to severely active Crohn's disease (CD). Aims of this study were to characterize the efficacy and safety of vedolizumab induction and maintenance therapy in patients who were naïve to tumor necrosis factor-alpha (TNF-α) antagonist therapy (TNF-naïve) or who had discontinued TNF-α antagonist therapy because of inadequate response (i.e., primary nonresponse), loss of response, or intolerance (collectively classified as the TNF-failure population). METHODS: Post hoc analyses of the efficacy data for 516 TNF-naïve and 960 TNF-failure patients from the GEMINI 2 and GEMINI 3 trials were evaluated at weeks 6, 10, and 52 and included clinical remission (CD Activity Index [CDAI] score ≤150), enhanced clinical response (≥100-point decrease from baseline in CDAI score), durable clinical remission (remission at ≥80% of visits), and corticosteroid-free remission. Adverse events were summarized for the TNF-naïve and TNF-failure subgroups by treatment received. RESULTS: Among patients who responded to vedolizumab induction at week 6, 48.9% ...

Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy. Sands BE1, Sandborn WJ, Van Assche G, Lukas M, Xu J, James A, Abhyankar B, Lasch K. BACKGROUND: Vedolizumab is a gut-selective α4β7 integrin antagonist for the treatment of moderately to severely active Crohn's disease (CD). Aims of this study were to characterize the efficacy and safety of vedolizumab induction and maintenance therapy in patients who were naïve to tumor necrosis factor-alpha (TNF-α) antagonist therapy (TNF-naïve) or who had discontinued TNF-α antagonist therapy because of inadequate response (i.e., primary nonresponse), loss of response, or intolerance (collectively classified as the TNF-failure population). METHODS: Post hoc analyses of the efficacy data for 516 TNF-naïve and 960 TNF-failure patients from the GEMINI 2 and GEMINI 3 trials were evaluated at weeks 6, 10, and 52 and included clinical remission (CD Activity Index [CDAI] score ≤150), enhanced clinical response (≥100-point decrease from baseline in CDAI score), durable clinical remission (remission at ≥80% of visits), and corticosteroid-free remission. Adverse events were summarized for the TNF-naïve and TNF-failure subgroups by treatment received. RESULTS: Among patients who responded to vedolizumab induction at week 6, 48.9% ...

Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy. Sands BE1, Sandborn WJ, Van Assche G, Lukas M, Xu J, James A, Abhyankar B, Lasch K. BACKGROUND: Vedolizumab is a gut-selective α4β7 integrin antagonist for the treatment of moderately to severely active Crohn's disease (CD). Aims of this study were to characterize the efficacy and safety of vedolizumab induction and maintenance therapy in patients who were naïve to tumor necrosis factor-alpha (TNF-α) antagonist therapy (TNF-naïve) or who had discontinued TNF-α antagonist therapy because of inadequate response (i.e., primary nonresponse), loss of response, or intolerance (collectively classified as the TNF-failure population). METHODS: Post hoc analyses of the efficacy data for 516 TNF-naïve and 960 TNF-failure patients from the GEMINI 2 and GEMINI 3 trials were evaluated at weeks 6, 10, and 52 and included clinical remission (CD Activity Index [CDAI] score ≤150), enhanced clinical response (≥100-point decrease from baseline in CDAI score), durable clinical remission (remission at ≥80% of visits), and corticosteroid-free remission. Adverse events were summarized for the TNF-naïve and TNF-failure subgroups by treatment received. RESULTS: Among patients who responded to vedolizumab induction at week 6, 48.9% ...

Background: Public stigma against family members of people with mental illness is a negative attitude by the public which blame family members for the mental illness of their relatives. Family stigma can result in self social restrictions, delay in treatment seeking and poor quality of life. This study aimed at investigating the degree and correlates of family stigma. Methods: A quantitative cross-sectional house to house survey was conducted among 845 randomly selected urban and rural community members in the Gilgel Gibe Field Research Center, Southwest Ethiopia. An interviewer administered and pre-tested questionnaire adapted from other studies was used to measure the degree of family stigma and to determine its correlates. Data entry was done by using EPI-DATA and the analysis was performed using STATA software. Unadjusted and adjusted linear regression analysis was done to identify the correlates of family stigma. Results: Among the total 845 respondents, 81.18% were female. On a range of 1 to 5 score, the mean family stigma score was 2.16 (+/- 0.49). In a multivariate analysis, rural residents had significantly higher stigma scores (std. beta = 0.43, P < 0.001) than urban residents. As the number of perceived signs (std. beta = -0.07, P < 0.05), perceived supernatural (std. beta = -0.12, P < 0.01) and psychosocial and biological (std. beta = -0.11, P < 0.01) explanations of mental illness increased, the stigma scores decreased significantly. High supernatural explanation of mental illness was significantly correlated with lower stigma among individuals with lower level of exposure to people with mental illness (PWMI). On the other hand, high exposure to PWMI was significantly associated with lower stigma among respondents who had high education. Stigma scores increased with increasing income among respondents who had lower educational status. Conclusions: Our findings revealed moderate level of family stigma. Place of residence, perceived signs and explanations of mental illness were independent correlates of public stigma against family members of people with mental illness. Therefore, mental health communication programs to inform explanations and signs of mental illness need to be implemented.

Background: Feelings of gratitude and awe facilitate perceptions and cognitions that go beyond the focus of illness and include positive aspects of one's personal and interpersonal reality, even in the face of disease. We intended to measure feelings of gratitude, awe, and experiences of beauty in life among patients with multiple sclerosis and psychiatric disorders, particularly with respect to their engagement in specific spiritual/religious practices and their life satisfaction. Methods: We conducted a cross-sectional survey with standardized questionnaires to measure engagement in various spiritual practices (SpREUK-P) and their relation to experiences of Gratitude, Awe and Beauty in Life and life satisfaction (BMLSS-10). In total, 461 individuals (41 +/- 13 years; 68% women) with multiple sclerosis (46%) and depressive (22%) or other psychiatric disorders (32%) participated. Results: Among participants, 23% never, 43% rarely, 24% often, and 10% frequently experienced Gratitude. In contrast, 41% never, 37% rarely, 17% often, and 6% frequently experienced Awe. Beauty in Life was never experienced by 8% of the sample, and 28% rarely, 46% often, and 18% frequently experienced it. Gratitude (F=9.2; p=.003) and Beauty in Life (F=6.0; p=.015) were experienced significantly more often by women than men. However, the experience of Awe did not differ between women and men (F=2.2; n.s.). In contrast to our hypothesis, Gratitude/Awe cannot explain any relevant variance in patients' life satisfaction (R-2=.04). Regression analyses (R-2=.42) revealed that Gratitude/Awe can be predicted best by a person's engagement in religious practices, followed by other forms of spiritual practices and life satisfaction. Female gender was a weak predictor and underlying disease showed no effect. Conclusions: Gratitude/Awe could be regarded as a life orientation towards noticing and appreciating the positive in life - despite the symptoms of disease. Positive spirituality/religiosity seems to be a source of gratitude and appreciation in life, whereas patients with neither spiritual nor religious sentiments (R-S-) seem to have a lower awareness for these feelings.

Background: Adverse drug events are a frequent cause of emergency department presentations. Administrative data could be used to identify patients presenting with adverse drug events for post-market surveillance, and to conduct research in patient safety and in drug safety and effectiveness. However, such data sources have not been evaluated for their completeness with regard to adverse drug event reporting. Our objective was to determine the proportion of adverse drug events to outpatient medications diagnosed at the point-of-care in emergency departments that were documented in administrative data. Methods: We linked the records of patients enrolled in a prospective observational cohort study on adverse drug events conducted in two Canadian tertiary care emergency departments to their administrative data. We compared the number of adverse drug events diagnosed and recorded at the point-of-care in the prospective study with the number of adverse drug events recorded in the administrative data. Results: Among 1574 emergency department visits, 221 were identified as adverse drug event-related in the prospective database. We found 15 adverse drug events documented in administrative records with ICD-10 codes clearly indicating an adverse drug event, indicating a sensitivity of 6.8% (95% CI 4.0-11.2%) of this code set. When the ICD-10 code categories were broadened to include codes indicating a very likely, likely or possible adverse event to a medication, 62 of 221 events were identifiable in administrative data, corresponding to a sensitivity of 28.1% (95% CI 22.3-34.6%). Conclusions: Adverse drug events to outpatient medications were underreported in emergency department administrative data compared to the number of adverse drug events diagnosed and recorded at the point-of-care.

Background: Adverse reactions and medication errors are complications of drug use. Spontaneous reporting systems and pharmacoepidemiological studies incompletely detect the occurrence of these events in daily hospital care. In this study, the frequency and type of drug-related admissions and hospital-acquired adverse drug events (ADE) in Germany were assessed using routinely collected hospital data. Methods: The study was based on aggregated hospital routine data covering the period 2003 to 2007 and annually recorded as part of the further development of the German Diagnosis-Related Groups. The 505 ICD-10-codes indicating an ADE were categorized in seven groups according to their certainty. Primary diagnoses were considered as a proxy for drug-related admissions, and secondary diagnoses as a proxy for hospital-acquired ADE. Results: Among all hospital admissions, 5% were found to be at least possibly drug-induced and 0.7% very likely drug-induced. There was a significant increase in the overall rate of drug-related admissions over time (p < 0.038). Enterocolitis due to Clostridium difficile infection was the most frequent cause of a drug-related admission. About 4.5% of in-patients had experienced a hospital-acquired ADE. In addition, over the course of the study period, the overall frequency of hospital-acquired ADEs significantly increased (p < 0.001). Conclusions: In Germany, more than 5% of hospital episodes are either caused or complicated by an ADE. Between 2003 and 2007, there was a statistically significant increase in the overall rate and in some of the subcategories defined by the list of ICD-10-codes suspected to be indicative of an ADE. Before the use of routine data in pharmacovigilance and patient safety can be fully exploited, a further tailoring of both the ICD and the available variable set is needed.

Introduction: Coronary artery disease progression after primary coronary artery bypass grafting may, beside classical atherosclerosis risk factors, be depending on genetic predisposition. Methods: We investigated 192 CABG patients (18% female, age: 60.9 +/- 7.4 years). Clinically cardiac adverse events were defined as need for reoperation (n = 88; 46%), reintervention (n = 58; 30%), or angina (n = 89; 46%). Mean follow-up time measured 10.1 +/- 5.1 years. Gene polymorphisms (ApoE, NOS3, LIPC, CETP, SERPINE-1, Prothrombin) were investigated separately and combined (gene risk profile). Results: Among classical risk factors, arterial hypertension and hypercholesterinemia significantly influenced CAD progression. Single ApoE, NOS3 and LIPC polymorphisms provided limited information. Patients missing the most common ApoE epsilon 3 allele (5,2%), showed recurrent symptoms (p = 0,077) and had more frequently reintervention (p = 0,001). NOS3 a allele was associated with a significant increase for reintervention (p = 0,041) and recurrent symptoms (p = 0,042). Homozygous LIPC patients had a higher reoperation rate (p = 0.049). A gene risk profile enabled us to discriminate between faster and slower occurrence of cardiac adverse events (p = 0.0012). Conclusion: Single APOE, LIPC and NOS3 polymorphisms permitted limited prognosis of cardiac adverse events in patients after CABG. Risk profile, in contrast, allowed for risk stratification.

Background: The aim of this retrospective analysis was to evaluate the impact of trastuzumab-based regimens on the survival of patients with HER2-overexpressing metastatic breast cancer (MBC). The study specifically focussed on the influence of the continuation of trastuzumab-based treatment despite tumor progression on survival. Patients and Methods: Patients with HER2 overexpressing MBC were included in this retrospective analysis. HER2 overexpression was determined by the immunohistochemical staining score (DAKO Hercep Test (TM)). Trastuzumab was applied at a loading dose of 4 mg/kg and a maintenance dose of 2 mg/kg. Results: Among 136 HER2 overexpressing patients (DAKO score 3+), 66 patients received first-line trastuzumab, 47 patients received trastuzumab as second-line therapy and 23 patients received trastuzumab beyond disease progression. There was no significant difference regarding the duration of trastuzumab-based treatment (first-line: 29.5 weeks vs. second-line: 25 weeks). Moreover, there was no difference in the response rate (first-line: 37.9% vs. second-line: 35.7%) or the median survival (p = 0.47 log rank). Patients who received >= 2 trastuzumab-based regimens for MBC survived significantly longer compared to those who had received only 1 regimen (>= 2 regimens: 62.4 months vs. 1 regimen: 38.5 months; p = 0.01 log rank). Conclusions: Trastuzumab is highly effective in the treatment of HER2 overexpressing MBC. Compared to historical controls, overall survival appears to be markedly prolonged, particularly in patients who received sequential trastuzumab-based treatment beyond disease progression.

Background: The local recurrence rate of colorectal cancer has been significantly reduced due to the use of combined radiochemotherapy. Despite this improvement regarding locally advanced tumour recurrences, the treatment strategy for pre-treated patients remains difficult and unresolved. Patients and Methods: We analysed treatment and follow-up data of 14 patients with local recurrence of rectal cancer who were treated with radiation therapy (RT), chemotherapy (CT) and regional hyperthermia (RHT) from November 1997 to December 2001. Nine of these patients had received irradiation and CT (=pre-treated patients) in the past. For this group, 30.6-39.6 Gy RT, 5-fluorouracil (5-FU) as a continuous infusion over 5 days per week (350 mg/m(2)/24 h) combined with RHT twice a week was given. The 5 remaining patients (=not pre-treated) received conformal irradiation of 45 Gy with a boost between 9 and 14.4 Gy, combined with continuous infusion of 5-FU on days 1-4, and 29-33 (500 mg/m(2)/24 h), and RHT twice a week. Response to therapy was evaluated by means of computed tomography (CT) or magnetic resonance imaging (MRI) and by clinical follow-up. Results: Among 13 evaluated cases, the overall objective response rate was 54% (5 complete responses, 2 partial responses). At mean follow-up of 13.9 months (range 5-32 months) 7 patients were alive. Conclusion: The therapeutic regimen appears to be active in the treatment of local recurrences of rectal cancer. Larger-scaled studies are needed to evaluate the potency of hyperthermia in this therapeutic strategy.