Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Rationale and design of PASSAT — patients’ satisfaction with local or general anaesthesia in video-assisted thoracoscopic surgery: study protocol for a randomised controlled trial with a non-randomised side arm

Abstract Background Although general anaesthesia (GA) with one-lung ventilation is the current standard of care, minor thoracoscopic surgery, i.e. treatment of pleural effusions, biopsies and small peripheral pulmonary wedge resections, can also be performed using local anaesthesia (LA), analgosedation and spontaneous breathing. Whilst the feasibility and safety of LA have been demonstrated, its impact on patient satisfaction remains unclear. Most studies evaluating patient satisfaction lack control groups or do not meet psychometric criteria. We report the design of the PASSAT trial (PAtientS’ SATisfaction in thoracic surgery – general vs. local anaesthesia), a randomised controlled trial with a non-randomised side arm. Methods Patients presenting for minor thoracoscopic surgery and physical eligibility for GA and LA are randomised to surgery under GA (control group) or LA (intervention group). Those who refuse to be randomised are asked to attend the study on the basis of their own choice of anaesthesia (preference arm) and will be analysed separately. The primary endpoint is patient satisfaction according to a psychometrically validated questionnaire; secondary endpoints are complication rates, capnometry, actual costs and cost effectiveness. The study ends after inclusion of 54 patients in each of the two randomised study groups. Discussion The PASSAT study is the first randomised controlled trial to systematically assess patients’ satisfaction depending on LA or GA. The study follows an interdisciplinary approach, and its results may also be applicable to other surgical disciplines. It is also the first cost study based on randomised samples. Comparison of the randomised and the non-randomised groups may contribute to satisfaction research. Trial registration German Clinical Trials Register, DRKS00013661. Registered on 23 March 2018

Prehospital volume resuscitation - Did evidence defeat the crystalloid dogma? An analysis of the TraumaRegister DGU (R) 2002-2012

Background: Various studies have shown the deleterious effect of high volume resuscitation following severe trauma promoting coagulopathy by haemodilution, acidosis and hypothermia. As the optimal resuscitation strategy during prehospital trauma care is still discussed, we raised the question if the amount and kind of fluids administered changed over the recent years. Further, if less volume was administered, fewer patients should have arrived in coagulopathic depletion in the Emergency Department resulting in less blood product transfusions. Methods: A data analysis of the 100 489 patients entered into the TraumaRegister DGU (R) (TR-DGU) between 2002 and 2012 was performed of which a total of 23512 patients (23.3 %) matched the inclusion criteria. Volume and type of fluids administered as well as outcome parameter were analysed. Results: Between 2002 and 2012, the amount of volume administered during prehospital trauma care decreased from 1790 ml in 2002 to 1039 ml in 2012. At the same time higher haemoglobin mean values, higher Quick's mean values and reduced mean aPTT can be observed. Simultaneously, more patients received catecholamines (2002: 9.2 to 2012: 13.0 %). Interestingly, the amount of volume administered decreased steadily regardless of the presence of shock. Fewer patients were in the need of blood products and the number of massive transfusions (>= 10 pRBC) more than halved. Discussion: The changes in volume therapy might have reduced haemodilution potentially resulting in an increase of the Hb value. During the period observed transfusion strategies have become more restrictiveand ratio based; the percentage of patients receiving MT halved as blood products may imply negative secondary effects. Furthermore, preventing administration of high blood product ratios result in less impairment of coagulation factors and inhibitors and an therfore improved coagulation. Conclusion: The volume administered in severely injured patients decreased considerably during the last decade possibly supporting beneficial effects such as minimizing the risk of coagulopathy and avoiding potential harmful effects caused by blood product transfusions. Despite outstanding questions in trauma resuscitation, principle evidence merges quickly into clinical practice and algorithms

Protective ventilation with high versus low positive end-expiratory pressure during one-lung ventilation for thoracic surgery (PROTHOR): study protocol for a randomized controlled trial

Background: Postoperative pulmonary complications (PPC) may result in longer duration of in-hospital stay and even mortality. Both thoracic surgery and intraoperative mechanical ventilation settings add considerably to the risk of PPC. It is unclear if one-lung ventilation (OLV) for thoracic surgery with a strategy of intraoperative high positive end-expiratory pressure (PEEP) and recruitment maneuvers (RM) reduces PPC, compared to low PEEP without RM. Methods: PROTHOR is an international, multicenter, randomized, controlled, assessor-blinded, two-arm trial initiated by investigators of the PROtective VEntilation NETwork. In total, 2378 patients will be randomly assigned to one of two different intraoperative mechanical ventilation strategies. Investigators screen patients aged 18 years or older, scheduled for open thoracic or video-assisted thoracoscopic surgery under general anesthesia requiring OLV, with a maximal body mass index of 35 kg/m2, and a planned duration of surgery of more than 60 min. Further, the expected duration of OLV shall be longer than two-lung ventilation, and lung separation is planned with a double lumen tube. Patients will be randomly assigned to PEEP of 10 cmH2O with lung RM, or PEEP of 5 cmH2O without RM. During two-lung ventilation tidal volume is set at 7 mL/kg predicted body weight and, during OLV, it will be decreased to 5 mL/kg. The occurrence of PPC will be recorded as a collapsed composite of single adverse pulmonary events and represents the primary endpoint. Discussion: PROTHOR is the first randomized controlled trial in patients undergoing thoracic surgery with OLV that is adequately powered to compare the effects of intraoperative high PEEP with RM versus low PEEP without RM on PPC. The results of the PROTHOR trial will support anesthesiologists in their decision to set intraoperative PEEP during protective ventilation for OLV in thoracic surgery. Trial registration: The trial was registered in clinicaltrials.gov (NCT02963025) on 15 November 2016