Actual versus ideal body weight dosing of sugammadex in morbidly obese patients offers faster reversal of rocuronium- or vecuronium-induced deep or moderate neuromuscular block: a randomized clinical trial.

BACKGROUND: This randomized, double-blind trial evaluated sugammadex-mediated recovery time from rocuronium- or vecuronium-induced moderate (M-) or deep (D-) neuromuscular block in morbidly obese adults dosed by actual (ABW) or ideal body weight (IBW). METHODS: Adults with BMI ≥40 kg/m2 were randomized to 1 of 5 groups: M-neuromuscular block, sugammadex 2 mg/kg ABW; M-neuromuscular block, sugammadex 2 mg/kg IBW; M-neuromuscular block, neostigmine 5 mg, and glycopyrrolate 1 mg; D-neuromuscular block, sugammadex 4 mg/kg ABW; or D-neuromuscular block, sugammadex 4 mg/kg IBW. Supramaximal train of four (TOF) stimulation of the ulnar nerve (TOF-watch SX®) monitored recovery. Primary endpoint was time to TOF ratio ≥ 0.9 for ABW and IBW groups pooled across neuromuscular blocking agent (NMBA)/blocking depth, analyzed by log-rank test stratified for agent and depth. Prespecified safety outcomes included treatment-emergent bradycardia, tachycardia, and other arrhythmias, and adjudicated hypersensitivity and anaphylaxis. RESULTS: Of 207 patients randomized, 188 received treatment (28% male, BMI 47 ± 5.1 kg/m2, age 48 ± 13 years). Recovery was 1.5 min faster with ABW vs IBW dosing. The sugammadex 2 mg/kg groups recovered 9-fold faster [time 0.11-fold, 95% CI 0.08 to 0.14] than the neostigmine group. ABW (5.3%) and IBW (2.7%) groups had similar incidences of recovery time > 10 min (95% CI of difference: - 4.8 to 11.0%); 84% for neostigmine group. Re-curarization occurred in one patient each in the 2 mg/kg IBW and neostigmine groups. Prespecified safety outcomes occurred with similar incidences. CONCLUSIONS: ABW-based sugammadex dosing yields faster reversal without re-curarization, supporting ABW-based sugammadex dosing in the morbidly obese, irrespective of the depth of neuromuscular block or NMBA used. TRIAL REGISTRATION: Registered on November 17, 2017, at ClinicalTrials.gov under number NCT03346070 .

Neuromuscular Blocking Agents and Reversal Agents Among Hospitalized Children: A Cerner Database Study.

Background: Sugammadex (Bridion) was approved by the US Food and Drug Administration (FDA) in December 2015 for the reversal of neuromuscular block (NMB) induced by rocuronium and vecuronium bromide in adults undergoing surgery and approved for use in both adults and children in the European Union in 2008. Sugammadex use in children has been reported in the United States, but to what extent is not clear. Aims: The aim was to describe the utilization pattern of NMB agents and factors associated with the use of reversal agents (neostigmine and sugammadex) in US children. Methods: Cross-sectional study of children with exposure to NMB agents between 2015 and 2017 in the Cerner Health Facts® database, which is an electronic health record (EHR) database across 600 facilities in the United States. Logistic regression estimated factors associated with the use of sugammadex vs neostigmine. Results: A total of 27 094 pediatric clinical encounters were exposed to neuromuscular blocking agents (NMBAs), in which 21 845 were exposed to rocuronium (76%), vecuronium (18%), or both (6%). Among children with exposure to rocuronium and vecuronium, the use of sugammadex was 1.7% in 2016 and 7.6% in 2017. The multivariable logistic model suggested that children who were older (age 12-17 years vs 0-1 year; odds ratio [OR] 1.96; 95% confidence interval [CI], 1.36-2.83), Hispanic or Latino ethnicity and other ethnicities (vs non-Hispanic or Latino; OR 2.03 and 1.56; 95% CI, 1.55-2.67 and 1.15-2.13, respectively), in teaching facilities (OR 1.26; 95% CI, 1.00-1.59), or admitted through emergency departments (OR 1.65; 95% CI, 1.06-2.58) were independently more likely to receive sugammadex than neostigmine after controlling for other covariates. Conclusions: In Cerner Health Facts database 2015 to 2017, among children, rocuronium was more commonly used than vecuronium, and sugammadex use was observed since 2016. Sugammadex and neostigmine users varied by demographic, clinical, and site-level characteristics.

The impact of intra-abdominal pressure on perioperative outcomes in laparoscopic cholecystectomy: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Laparoscopic cholecystectomy involves using intra-abdominal pressure (IAP) to facilitate adequate surgical conditions. However, there is no consensus on optimal IAP levels to improve surgical outcomes. Therefore, we conducted a systematic literature review (SLR) to examine outcomes of low, standard, and high IAP among adults undergoing laparoscopic cholecystectomy. METHODS: An electronic database search was performed to identify randomized controlled trials (RCTs) that compared outcomes of low, standard, and high IAP among adults undergoing laparoscopic cholecystectomy. A Bayesian network meta-analysis (NMA) was used to conduct pairwise meta-analyses and indirect treatment comparisons of the levels of IAP assessed across trials. RESULTS: The SLR and NMA included 22 studies. Compared with standard IAP, on a scale of 0 (no pain at all) to 10 (worst imaginable pain), low IAP was associated with significantly lower overall pain scores at 24 h (mean difference [MD]: - 0.70; 95% credible interval [CrI]: - 1.26, - 0.13) and reduced risk of shoulder pain 24 h (odds ratio [OR] 0.24; 95% CrI 0.12, 0.48) and 72 h post-surgery (OR 0.22; 95% CrI 0.07, 0.65). Hospital stay was shorter with low IAP (MD: - 0.14 days; 95% CrI - 0.30, - 0.01). High IAP was not associated with a significant difference for these outcomes when compared with standard or low IAP. No significant differences were found between the IAP levels regarding need for conversion to open surgery; post-operative acute bleeding, pain at 72 h, nausea, and vomiting; and duration of surgery. CONCLUSIONS: Our study of published trials indicates that using low, as opposed to standard, IAP during laparoscopic cholecystectomy may reduce patients' post-operative pain, including shoulder pain, and length of hospital stay. Heterogeneity in the pooled estimates and high risk of bias of the included trials suggest the need for high-quality, adequately powered RCTs to confirm these findings.

Added value of MRI to X-ray in guiding the extent of surgical resection in diabetic forefoot osteomyelitis: a review of pathologically proven, surgically treated cases.

OBJECTIVE: This study retrospectively evaluated the added value of MRI over X-ray in guiding the extent of amputation in a cohort of patients with surgically treated, pathologically proven osteomyelitis. MATERIALS AND METHODS: A database search revealed 32 cases of pathology-proven diabetic forefoot osteomyelitis between 2006 and 2016, in which X-ray, MRI, and surgery occurred within 30 days. Data collection included extent of osteomyelitis reported on imaging and extent of subsequent amputation using a point system. Added value of MRI over X-ray in guiding surgical resection was stated if the X-ray was negative, MRI was positive, and there was MRI-surgical concordance; if both modalities were positive, X-ray was discordant whereas the MRI was concordant; or if MRI detected an abscess. Two-tailed Fisher's exact test compared proportions. RESULTS: In 9 cases that were positive on both modalities, MRI identified an average of 1.2 additional bone segments of disease. There was surgical agreement with X-ray in 3 out of 31 cases (9.7%, 95%CI 0-20.1) and with MRI in 17 out of 31 cases (55%, 37.3-72.4; p < 0.0001). There was an added value of MRI over X-ray in guiding surgical treatment in 64.5% of cases (95% CI 47.7%-81.4%). MRI added value in 5 out of 9 X-rays positive for osteomyelitis and in 15 out of 22 negative (p value was not significant). CONCLUSION: Magnetic resonance imaging demonstrated added value over X-ray in guiding surgical management in both X-ray-negative and -positive cases. Although multiple factors are involved in determining the degree of surgical excision, MRI is a clinically useful component of the diagnostic algorithm in patients who undergo surgical treatment.

Operating room first case start times: a metric to assess systems-based practice milestones?

BACKGROUND: Resident competence in peri-operative care is a reflection on education and cost-efficiency. Inspecting pre-existing operating room metrics for performance outliers may be a potential solution for assessing competence. Statistical correlation of problematic benchmarks may reveal future opportunities for educational intervention. METHODS: Case-log database review yielded 3071 surgical cases involving residents over the course of 5 years. Surgery anticipated and actual start times were evaluated for delays and residents were assessed using the days of resident training performed at the time of each corresponding case. Other variables recorded included day of week, attending anesthesiologist name, attending surgeon name, patient age, sex, American Society of Anesthesiologists physical status classification (ASA PS), and in-patient versus day surgery status. Mixed-effect, multi-variable, linear regression determined independent determinants of delay time. RESULTS: The analysis identified day of the week (F = 25.65, P < 0.0001), days of training (F = 8.39, P = 0.0038), attending surgeon (F = 2.67, P < 0.0001), and anesthesiology resident (F = 1.67, P = 0.0012) as independent predictors of delay time for first-start cases, with an overall regression model F = 3.09, r2 = 0.186, and P < 0.0001. CONCLUSIONS: The day of the week and attending surgeon demonstrated significant impact of case delay compared to resident days trained. If a learning curve for first-case start punctuality exists for anesthesiology residents, it is subtle and irrelevant to operating room efficiency. The regression model accounted for only 19% of the variability in the outcome of delay time, indicating a multitude of additional unidentified factors contributing to operating room efficiency.

Plantar talar head contusions and osteochondral fractures: associated findings on ankle MRI and proposed mechanism of injury.

OBJECTIVE: To evaluate the significance of plantar talar head injury (PTHI) in predicting osseous and soft tissue injuries on ankle MRI. MATERIALS AND METHODS: The IRB approved this HIPAA-compliant retrospective study. The study group consisted of 41 ankle MRIs with PTHI that occurred at our institution over a 5 ½ year period. Eighty MRIs with bone injuries in other locations matched for age, time interval since injury, and gender formed a control group. Injuries to the following structures were recorded: medial malleolus, lateral malleolus/distal fibula, posterior malleolus, talus, calcaneus, navicular, cuboid, lateral, medial and syndesmotic ligaments, spring ligament complex, and extensor digitorum brevis (EDB) muscle. Twenty separate logistic regressions determined which injuries PTHI predicted, using the Holm procedure to control for family-wise alpha at 0.05. RESULTS: PTHI strongly predicted the occurrence of injuries involving the anterior process of the calcaneus [24 % of cases, odds ratio (OR) 12.66], plantar components of the spring ligament (27 %, OR 9.43), calcaneal origin of the EDB and attachment of the dorsolateral calcaneocuboid ligament (22 %, OR 7.22), cuboid (51 %, OR 6.58), EDB (27 %, OR 5.49), anteromedial talus (66 %, OR 4.78), and posteromedial talus (49 %, OR 4.48). PTHI strongly predicted lack of occurrence of syndesmotic ligament injury (OR 19.6). The PTHI group had a high incidence of lateral ligamentous injury (78 %), but not significantly different from the control group (53 %). CONCLUSIONS: PTHI is strongly associated with injury involving the transverse tarsal joint complex. We hypothesize it results from talo-cuboid and/or talo-calcaneal impaction from a supination injury of the foot and ankle.

The efficacy of ticagrelor is maintained in women with acute coronary syndromes participating in the prospective, randomized, PLATelet inhibition and patient Outcomes (PLATO) trial.

AIMS: The aim of this study was to assess the relationship between sex and clinical outcomes and treatment-related complications in patients with ST-elevation or non-ST-elevation acute coronary syndromes (ACS) randomized to treatment with ticagrelor or clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) trial. METHODS: The associations between sex subgroup and the primary composite outcomes, secondary outcomes, and major bleeding endpoints as well as interaction of sex subgroup with treatment effects were analysed using Cox proportional-hazards models. RESULTS: Sex was not significantly associated with the probability of the primary composite endpoint [adjusted hazard ratio (HR): 1.02 (0.91-1.16)], or other adverse cardiovascular endpoints. Ticagrelor was similarly more effective than clopidogrel in reducing rates of the primary endpoint in women 11.2 vs. 13.2% [adjusted HR: 0.88 (0.74-1.06)] and men 9.4 vs. 11.1% [adjusted HR: 0.86 (0.76-0.97)] (interaction P-value 0.78), all-cause death in women 5.8 vs. 6.8% [adjusted HR: 0.90 (0.69-1.16)] and men 4.0 vs. 5.7% [adjusted HR: 0.80 (0.67-0.96)] (interaction P-value 0.49), and definite stent thrombosis in women 1.2 vs. 1.4% [adjusted HR: 0.71 (0.36-1.38)] and men 1.4 vs. 2.1% [adjusted HR: 0.63 (0.45-0.89)] (interaction P-value 0.78). The treatments did not differ for PLATO-defined overall major bleeding complications in women [adjusted HR: 1.01 (0.83-1.23)] or men [adjusted HR: 1.10 (0.98-1.24)]. Sex had no significant association with these outcomes (interactions P = 0.43-0.88). CONCLUSION: Female sex is not an independent risk factor for adverse clinical outcomes in moderate-to-high risk ACS patients. Ticagrelor has a similar efficacy and safety profile in men and women.

Reduction in first and recurrent cardiovascular events with ticagrelor compared with clopidogrel in the PLATO Study.

BACKGROUND: We sought to evaluate the effect of potent platelet inhibition after acute coronary syndrome on total (ie, first and recurrent) occurrences of any of the primary outcome events (e.g., cardiovascular death, myocardial infarction, and stroke) as well as on other ischemic events, such as urgent revascularization, (severe) recurrent ischemia, transient ischemic attacks, and arterial thrombotic events. METHODS AND RESULTS: In the PLATelet inhibition and patient Outcomes (PLATO) study, 18 624 patients presenting with acute coronary syndromes randomly received ticagrelor (n=9333) or clopidogrel (n=9291). Cox proportional hazard models were used to calculate time to first event and hazard ratios. Total events were compared using a Poisson regression model, and time to second event or death was calculated with the Wei Lin Weissfeld method. Patients randomized to ticagrelor had 1057 total primary end point events versus 1225 for patients on clopidogrel (rate ratio, 0.86; 95% confidence interval, 0.79-0.93; P=0.003). The number of additional events was numerically lower for ticagrelor (189 versus 205; P=0.40), resulting in a hazard for time to second event/death of 0.80 (95% confidence interval, 0.70-0.90; P<0.001) and a number needed to treat of 54. For cardiovascular death/myocardial infarction/stroke/(severe) recurrent ischemia/transient ischemic attack/arterial thrombotic events, total events were fewer with ticagrelor (2030 versus 2290; rate ratio, 0.88; 95% confidence interval, 0.82-0.95; P<0.001), with fewer recurrent events with ticagrelor (740 versus 834; P=0.01) and a highly significant concurrent reduction in hazard for time to second event or death of 0.83 (95% confidence interval, 0.75-0.91; P<0.001). Recurrent PLATO major or Thrombolysis in Myocardial Infarction (TIMI) major non-coronary artery bypass graft bleeding events were infrequent and not different between the two therapies (P=0.96 and 0.38, respectively). CONCLUSIONS: In PLATO, treatment with ticagrelor compared with clopidogrel resulted in a reduction in total events, including first and subsequent recurrent cardiovascular events, when compared with clopidogrel. These types of analyses demonstrate an even greater absolute benefit of ticagrelor over clopidogrel than previously reported. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov/. Unique identifier: NCT00391872.

Unmet Needs and Burden of Caregivers of Patients Being Evaluated for a Liver Transplant Are Similar to Those of Cancer Caregivers.

BACKGROUND: The caregivers (CG) of patients with serious illnesses often experience stress and psycho-social issues. High burden is expected for CG of patients for whom liver transplant (LT) is the only curative option. This study aims to measure the burden, unmet needs, and quality of life (QoL) of CG of patients being evaluated for LT. METHODS: This cross-sectional study enrolled CG of patients being evaluated for LT. CaTCoN (Caregiving Tasks, Consequences and Needs Questionnaire) was used to assess caregiving consequences and needs related to interactions with healthcare professionals (HCPs). ZBI-12 (Zarit Burden Interview) was used to assess CG burden, and PROMIS-29 (Patient Reported Outcomes Measurement Information System) to assess QoL. Caregivers completed the study instruments in person, while they were in the clinic. CaTCoN scores from our study were compared with cancer caregivers' historical data. RESULTS: 18 CG were enrolled, mean age 54 [14] years; 72% were white and 77% were women. 61% worked full time; 45% provided >20 hours of care per week. Two-thirds cared for patients with alcoholic liver disease. All CaTCoN scores were no different from CGs of cancer patients (all P > .05). The total ZBI score (mean SD 12.4 [8.3]) did not differ from published scores for CG of cancer patients (12.0 [8.5]). 44% had high (≥12) ZBI scores reflecting "high burden." Their PROMIS-29 T scores, compared to those with low burden, showed more anxiety (P = .01), depression (P = .04), fatigue (P = .02) and deteriorated social function (P = .009). Physical function and social function were diminished among these CGs compared to the general population (P < .0001). CONCLUSION: CGs of patients being evaluated for LT suffer from high burden similar to cancer CGs and have reduced physical and social function. Despite the small sample size, the data completion rate was almost 100%.

ST-elevation acute coronary syndromes in the Platelet Inhibition and Patient Outcomes (PLATO) trial: insights from the ECG substudy.

BACKGROUND: Ticagrelor, when compared with clopidogrel, reduced the 12-month risk of vascular death/myocardial infarction and stroke in patients with ST-elevation acute coronary syndromes intended to undergo primary percutaneous coronary intervention in the PLATelet inhibition and patient Outcomes (PLATO) trial. This prespecified ECG substudy explored whether ticagrelor's association with vascular death and myocardial infarction within 1 year would be amplified by (1) the extent of baseline ST shift and (2) subsequently associated with fewer residual ST changes at hospital discharge. METHODS AND RESULTS: ECGs were evaluated centrally in a core laboratory in 3122 ticagrelor- and 3084 clopidogrel-assigned patients having at least 1 mm ST-elevation in 2 contiguous leads as identified by site investigators on the qualifying ECG. Patients with greater ST-segment shift at baseline had higher rates of vascular death/myocardial infarction within 1 year. Among those who also had an ECG at hospital discharge (n=4798), patients with ≥50% ΣST-deviation (ΣST-dev) resolution had higher event-free survival than those with incomplete resolution (6.4% versus 8.8%, adjusted hazard ratio 0.69 (0.54-0.88), P=0.003). The extent of ΣST-dev resolution was similar irrespective of treatment assignment. The benefit of ticagrelor versus clopidogrel on clinical events was consistent irrespective of the extent of baseline ΣST-dev (P(interaction)=0.728). When stratified according to conventional times from symptom onset, ie, ≤3 hours, 3 to 6 hours, >6 hours, the extent of baseline ΣST-dev declined progressively over time. As time from symptom onset increased beyond 3 hours, the benefit of ticagrelor appeared to be more pronounced; however, the interaction between time and treatment was not significant (P=0.175). CONCLUSIONS: Ticagrelor did not modify ΣST-dev resolution at discharge nor was its benefit affected by the extent of baseline ΣST-dev. These hypothesis-generating observations suggest that the main effects of ticagrelor may not relate to the rapidity or the completeness of acute reperfusion, but rather the prevention of recurrent vascular events by more powerful platelet inhibition or other mechanisms. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

Cystatin C- and creatinine-based estimates of renal function and their value for risk prediction in patients with acute coronary syndrome: results from the PLATelet Inhibition and Patient Outcomes (PLATO) study.

BACKGROUND: The estimated glomerular filtration rate (eGFR) independently predicts cardiovascular death or myocardial infarction (MI) and can be estimated by creatinine and cystatin C concentrations. We evaluated 2 different cystatin C assays, alone or combined with creatinine, in patients with acute coronary syndrome. METHODS: We analyzed plasma cystatin C, measured with assays from Gentian and Roche, and serum creatinine in 16 279 patients from the PLATelet Inhibition and Patient Outcomes (PLATO) trial. We evaluated Pearson correlation and agreement (Bland-Altman) between methods, as well as prognostic value in relation to cardiovascular death or MI during 1 year of follow up by multivariable logistic regression analysis including clinical variables, biomarkers, c-statistics, and relative integrated discrimination improvement (IDI). RESULTS: Median cystatin C concentrations (interquartile intervals) were 0.83 (0.68-1.01) mg/L (Gentian) and 0.94 (0.80-1.14) mg/L (Roche). Overall correlation was 0.86 (95% CI 0.85-0.86). The level of agreement was within 0.39 mg/L (2 SD) (n = 16 279). The areas under the curve (AUCs) in the multivariable risk prediction model with cystatin C (Gentian, Roche) or Chronic Kidney Disease Epidemiology Collaboration eGFR (CKD-EPI) added were 0.6914, 0.6913, and 0.6932. Corresponding relative IDI values were 2.96%, 3.86%, and 4.68% (n = 13 050). Addition of eGFR by the combined creatinine-cystatin C equation yielded AUCs of 0.6923 (Gentian) and 0.6924 (Roche) with relative IDI values of 3.54% and 3.24%. CONCLUSIONS: Despite differences in cystatin C concentrations, overall correlation between the Gentian and Roche assays was good, while agreement was moderate. The combined creatinine-cystatin C equation did not outperform risk prediction by CKD-EPI.

Percutaneous extraction of ePTFE-coated ICD leads: a single center comparative experience.

BACKGROUND: Percutaneous extraction of standard implantable cardioverter-defibrillator leads is often complicated by ingrowth of fibrotic tissue into the shocking coils. Leads with GORE™ expanded polytetrafluoroethylene (ePTFE) coating (W. L. Gore & Associates, Inc., Newark, DE, USA) designed to inhibit fibrosis are in use, but clinical data regarding their extraction are lacking. The study's purpose was to examine the feasibility, efficacy, and safety of percutaneous extraction involving defibrillator leads coated with ePTFE. METHODS: We analyzed our database to identify all percutaneously extracted leads with ePTFE-coated shocking coils. Lead and procedure characteristics were compared to a cohort of noncoated leads of similar implant duration. RESULTS: One hundred fifty-six leads were extracted from 145 patients; 57 ePTFE-coated leads, with a mean implant duration of 621 days, were extracted and compared to 99 noncoated leads, with a mean implant duration of 763 days (P = 0.0641). Mean extraction time was 5 minutes for coated leads versus 9.75 minutes for noncoated leads (P = 0.0001). Extraction time of less than 1 minute was more frequent with coated leads (61% vs 35%, P = 0.0025). Adjunct extraction tools were required less frequently with coated leads than noncoated leads (39% vs 63%, P = 0.0071). There was no fibrosis where ePTFE covered the shocking coils. Alternatively, 23 of 99 (23%) noncoated leads demonstrated fibrosis adherent to the shock coil. There were no procedure-related complications in either group. CONCLUSIONS: Compared to noncoated leads, ePTFE-coated leads are associated with shorter extraction times and are less likely to require extraction tools for removal. The difference is likely related to the absence of fibrosis over the ePTFE-coated high-energy coils.

Feasibility of a Palliative Care Intervention within Routine Care of Hepatocellular Carcinoma: A Pilot Randomized Controlled Trial.

Background: Patients with hepatocellular cancer (HCC) are at risk for poor quality of life (QoL) and high symptom burden, coupled with limited treatment options. Palliative care (PC) can play an important role in reducing the suffering of this population, but remains underutilized. Aim: To demonstrate feasibility of an outpatient PC intervention within HCC care. Methods: This is a pilot randomized controlled trial conducted at an academic center. All stages of HCC patients (except Barcelona Clinic Liver Cancer stage D) with a scheduled hepatology appointment were eligible. Patients were randomized to receive PC intervention or usual care (control arm). In the PC arm, patients received PC from a PC provider at enrollment and at three months from the baseline visit, in addition to continued standard of care. Control arm received only standard care. All patients completed FACT-Hep (Functional Assessment of Cancer Therapy-Hepatobiliary Cancer) and modified Edmonton Symptom Assessment Scale at baseline and at three-month visit. Descriptive statistics were utilized to summarize questionnaires, and change in QoL and symptoms from baseline to three months were compared between the two study groups. Results: Of the 109 approached, 57 patients (52.3%) consented to enroll, and 52 (91%) completed the study. QoL and symptom burden assessments demonstrated impaired QoL and high symptom burden in both arms of the study. At least 50% of enrolled patients in each arm had some degree of fatigue, pain, sleep disturbance, and appetite loss, at baseline. Post-intervention, symptom burden and QoL improved in the intervention arm and remained same or worsened in the control group. All FACT-Hep scores decreased numerically among controls and increased numerically among patients in the PC intervention group. Conclusion: Outpatient PC intervention within routine HCC care is feasible, and can potentially improve QoL and symptoms.

Antiplatelet Treatment Patterns and Outcomes for Secondary Stroke Prevention in the United Kingdom.

INTRODUCTION: Stroke is a leading cause of death and disability worldwide. Antiplatelet therapies are recommended to reduce the risk of recurrent stroke in patients with ischemic stroke/transient ischemic attack (IS/TIA). This study evaluated outpatient antiplatelet treatment patterns and outcomes for secondary stroke prevention (SSP) among UK adults without atrial fibrillation who were hospitalized for IS/TIA. METHODS: This retrospective observational study utilized data from the UK Clinical Practice Research Datalink linked with Hospital Episode Statistics data (01/01/2011-30/06/2019). Treatment patterns included type and duration of treatments. Treatment outcomes included IS, myocardial infarction, major bleeding, and cardiovascular-related and all-cause mortality. Descriptive statistics were reported. RESULTS: Of 9270 patients, 13.9% (1292) might not receive antithrombotic therapy within 90 days of hospital discharge. Of 7978 patients who received antiplatelet therapies, most used clopidogrel (74.8%) or aspirin (16.7%) single antiplatelet therapy and clopidogrel + aspirin dual antiplatelet therapy (DAPT, 5.9%). At 1-year post-hospitalization, 36.9, 43.3, and 35.1% of those receiving these treatments discontinued them, respectively, and of the patients initiating DAPT, 62.3% switched to single antiplatelet therapy. At 1-year post-discharge, the incidence rate (per 100 person-years) of IS, myocardial infarction, major bleeding, cardiovascular-related mortality, and all-cause mortality among the treated were 6.5, 0.7, 4.1, 5.0, and 7.3, respectively, and among the untreated were 14.9, 0.7, 8.6, 28.1, and 39.8, respectively. CONCLUSIONS: In the United Kingdom, 13.9% of patients hospitalized for stroke might not have any antiplatelet treatment to prevent secondary stroke; among the treated, clopidogrel, aspirin, and DAPT were commonly used. These study findings suggest that improved anti-thrombotic therapies for long-term SSP treatment are needed, which may lead to higher treatment and persistence rates and, therefore, improved outcomes in this population.

Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial.

BACKGROUND: In the Platelet Inhibition and Patient Outcomes (PLATO) trial, a prespecified subgroup analysis showed a significant interaction between treatment and region (P=0.045), with less effect of ticagrelor in North America than in the rest of the world. METHODS AND RESULTS: Reasons for the interaction were explored independently by 2 statistical groups. Systematic errors in trial conduct were investigated. Statistical approaches evaluated the likelihood of play of chance. Cox regression analyses were performed to quantify how much of the regional interaction could be explained by patient characteristics and concomitant treatments, including aspirin maintenance therapy. Landmark Cox regressions at 8 time points evaluated the association of selected factors, including aspirin dose, with outcomes by treatment. Systematic errors in trial conduct were ruled out. Given the large number of subgroup analyses performed and that a result numerically favoring clopidogrel in at least 1 of the 4 prespecified regions could occur with 32% probability, chance alone cannot be ruled out. More patients in the United States (53.6%) than in the rest of the world (1.7%) took a median aspirin dose ≥300 mg/d. Of 37 baseline and postrandomization factors explored, only aspirin dose explained a substantial fraction of the regional interaction. In adjusted analyses, both Cox regression with median maintenance dose and landmark techniques showed that, in patients taking low-dose maintenance aspirin, ticagrelor was associated with better outcomes compared with clopidogrel, with statistical superiority in the rest of the world and similar outcomes in the US cohort. CONCLUSIONS: The regional interaction could arise from chance alone. Results of 2 independently performed analyses identified an underlying statistical interaction with aspirin maintenance dose as a possible explanation for the regional difference. The lowest risk of cardiovascular death, myocardial infarction, or stroke with ticagrelor compared with clopidogrel is associated with a low maintenance dose of concomitant aspirin. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

Ticagrelor versus clopidogrel in patients with acute coronary syndromes.

BACKGROUND: Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel. METHODS: In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation. RESULTS: At 12 months, the primary end point--a composite of death from vascular causes, myocardial infarction, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types. CONCLUSIONS: In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.)

Outcome and causes of renal deterioration evaluated by serial cystatin C measurements in acute coronary syndrome patients -- results from the PLATelet inhibition and patient Outcomes (PLATO) study.

BACKGROUND: To investigate if ticagrelor treatment and other clinical characteristics were associated with increased cystatin C concentrations and if a deterioration in estimated renal function was associated with worse outcome in patients with acute coronary syndromes (ACS). METHODS: Plasma cystatin C concentrations were determined within 24 hours of admission (baseline), at discharge, 1 month, and 6 months in the PLATO trial. The changes over time in relation to randomized treatment were analyzed by analysis of covariance. C-statistics and the relative Integrated Discrimination Improvement of the cystatin C concentrations regarding the primary outcome (cardiovascular death or myocardial infarction) was evaluated by multivariable analysis including background characteristics and biomarkers: N-terminal-pro-B-type natriuretic peptide and Troponin I. RESULTS: Mean cystatin C concentrations in 2133 ticagrelor- and 2162 clopidogrel-treated patients were at baseline (0.86 mg/L and 0.86 mg/L), discharge (1.01 mg/L and 0.98 mg/L) (P < .0005), 1 month (1.00 mg/L and 0.98 mg/L) (P = .12), and 6 months (1.00 mg/L and 0.99 mg/L) (P = .17), respectively. Age, heart failure, and type of ACS were major determinants of the cystatin C concentration. c Statistics and the relative Integrated Discrimination Improvement of the primary outcome for the baseline cystatin C concentration were 0.687 and 5.2%, compared to 0.684 and 4.5% at discharge (n = 4034) and 0.693 and 5.1% at one month (n = 3096), respectively. CONCLUSIONS: Mean cystatin C concentrations increased in ACS patients, most importantly determined by age. The initial greater increase in ticagrelor-treated patients was not sustained over time. Risk prediction did not improve with serial measurements of renal markers.

Prior smoking status, clinical outcomes, and the comparison of ticagrelor with clopidogrel in acute coronary syndromes-insights from the PLATelet inhibition and patient Outcomes (PLATO) trial.

BACKGROUND: Habitual smoking has been associated with increased platelet reactivity, increased risk of thrombotic complications and greater efficacy of clopidogrel therapy over placebo. In the PLATO trial, ticagrelor compared to clopidogrel in patients with acute coronary syndromes (ACS) reduced the primary composite end point of vascular death, myocardial infarction and stroke, without increasing overall rates of major bleeding. We evaluated the results in relation to smoking habits. METHODS: Interactions between habitual smokers (n = 6678) and in ex/nonsmokers (n = 11,932) and the effects of randomized treatments on ischemic and bleeding outcomes were evaluated by Cox regression analyses. RESULTS: Habitual smokers had an overall lower risk profile and more often ST-elevation ACS. After adjustment for baseline imbalances, habitual smoking was associated with a higher incidence of definite stent thrombosis (adjusted HR, 1.44 [95% CI, 1.07-1.94]); there were no significant associations with other ischemic or bleeding end points. The effects of ticagrelor compared to clopidogrel were consistent for all outcomes regardless of smoking status. Thus, there was a similar reduction in the primary composite end point for habitual smokers (adjusted HR, 0.83 [95% CI, 0.68-1.00]) and ex/nonsmokers (adjusted HR, 0.89 [95% CI, 0.79-1.00]) (interaction P = .50), and in definite stent thrombosis for habitual smokers (adjusted HR, 0.59 [0.39-0.91]) and ex/nonsmokers (adjusted HR, 0.69 [95% CI, 0.45-1.07]) (interaction P = .61). CONCLUSIONS: In patients hospitalized with ACS, habitual smoking is associated with a greater risk of subsequent stent thrombosis. The reduction of vascular death, myocardial infarction, stroke, and stent thrombosis by ticagrelor compared to clopidogrel is consistent regardless of smoking habits.

Cystatin C and estimated glomerular filtration rate as predictors for adverse outcome in patients with ST-elevation and non-ST-elevation acute coronary syndromes: results from the Platelet Inhibition and Patient Outcomes study.

BACKGROUND: We evaluated the predictive ability of cystatin C and creatinine-based estimations of glomerular filtration rate (eGFR), including the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation, in acute coronary syndrome (ACS) patients with (STE-ACS) or without (NSTE-ACS) ST elevation in a large contemporary ACS population. METHODS: Concentrations of cystatin C and creatinine, as well as eGFR at randomization, were measured in 16 401 patients in the Platelet Inhibition and Patient Outcomes (PLATO) study and evaluated as predictors of the composite end point of cardiovascular death or myocardial infarction within 1 year. Two Cox proportional hazards models were used, the first adjusting for clinical characteristics and the second for clinical characteristics plus the biomarkers N-terminal pro-B-type natriuretic peptide, troponin I, and C-reactive protein. RESULTS: The median cystatin C value was 0.83 mg/L. Increasing quartiles of cystatin C were strongly associated with poor outcome (6.9%, 7.1%, 9.5%, and 16.2%). The fully adjusted hazard ratios per SD of cystatin C in the NSTE-ACS and STE-ACS populations were 1.12 (95% CI 1.04-1.20) (n=8053) and 1.06 (95% CI 0.97-1.17) (n=5278), respectively. There was no significant relationship of cystatin C with type of ACS (STE or NSTE). c Statistics ranged from 0.6923 (cystatin C) to 0.6941 (CKD-EPI). CONCLUSIONS: Cystatin C concentration contributes independently in predicting the risk of cardiovascular death or myocardial infarction in NSTE-ACS, with no interaction by type of ACS. CKD-EPI exhibited the largest predictive value of all renal markers. Nevertheless, the additive predictive value of cystatin C or creatinine-based eGFR measures in the unselected ACS patient is small.

Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial.

AIMS More intense platelet-directed therapy for acute coronary syndrome (ACS) may increase bleeding risk. The aim of the current analysis was to determine the rate, clinical impact, and predictors of major and fatal bleeding complications in the PLATO study. METHODS AND RESULTS PLATO was a randomized, double-blind, active control international, phase 3 clinical trial in patients with acute ST elevation and non-ST-segment elevation ACS. A total of 18 624 patients were randomized to either ticagrelor, a non-thienopyridine, reversibly binding platelet P2Y(12) receptor antagonist, or clopidogrel in addition to aspirin. Patients randomized to ticagrelor and clopidogrel had similar rates of PLATO major bleeding (11.6 vs. 11.2%; P = 0.43), TIMI major bleeding (7.9 vs. 7.7%, P = 0.56) and GUSTO severe bleeding (2.9 vs. 3.1%, P = 0.22). Procedure-related bleeding rates were also similar. Non-CABG major bleeding (4.5 vs. 3.8%, P = 0.02) and non-procedure-related major bleeding (3.1 vs. 2.3%, P = 0.05) were more common in ticagrelor-treated patients, primarily after 30 days on treatment. Fatal bleeding and transfusion rates did not differ between groups. There were no significant interactions for major bleeding or combined minor plus major bleeding between treatment groups and age ≥75 years, weight <60 kg, region, chronic kidney disease, creatinine clearance <60 mL/min, aspirin dose >325 mg on the day of randomization, pre-randomization clopidogrel administration, or clopidogrel loading dose. CONCLUSION Ticagrelor compared with clopidogrel was associated with similar total major bleeding but increased non-CABG and non-procedure-related major bleeding, primarily after 30 days on study drug treatment. Fatal bleeding was low and did not differ between groups.