Lucas Petri Damiani

Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial

Importance The effects of recruitment maneuvers and positive end-expiratory pressure (PEEP) titration on clinical outcomes in patients with acute respiratory distress syndrome (ARDS) remain uncertain. Objective To determine if lung recruitment associated with PEEP titration according to the best respiratory-system compliance decreases 28-day mortality of patients with moderate to severe ARDS compared with a conventional low-PEEP strategy. Design, Setting, and Participants Multicenter, randomized trial conducted at 120 intensive care units (ICUs) from 9 countries from November 17, 2011, through April 25, 2017, enrolling adults with moderate to severe ARDS. Interventions An experimental strategy with a lung recruitment maneuver and PEEP titration according to the best respiratory–system compliance (n = 501; experimental group) or a control strategy of low PEEP (n = 509). All patients received volume-assist control mode until weaning. Main Outcomes and Measures The primary outcome was all-cause mortality until 28 days. Secondary outcomes were length of ICU and hospital stay; ventilator-free days through day 28; pneumothorax requiring drainage within 7 days; barotrauma within 7 days; and ICU, in-hospital, and 6-month mortality. Results A total of 1010 patients (37.5% female; mean [SD] age, 50.9 [17.4] years) were enrolled and followed up. At 28 days, 277 of 501 patients (55.3%) in the experimental group and 251 of 509 patients (49.3%) in the control group had died (hazard ratio [HR], 1.20; 95% CI, 1.01 to 1.42; P = .041). Compared with the control group, the experimental group strategy increased 6-month mortality (65.3% vs 59.9%; HR, 1.18; 95% CI, 1.01 to 1.38; P = .04), decreased the number of mean ventilator-free days (5.3 vs 6.4; difference, −1.1; 95% CI, −2.1 to −0.1; P = .03), increased the risk of pneumothorax requiring drainage (3.2% vs 1.2%; difference, 2.0%; 95% CI, 0.0% to 4.0%; P = .03), and the risk of barotrauma (5.6% vs 1.6%; difference, 4.0%; 95% CI, 1.5% to 6.5%; P = .001). There were no significant differences in the length of ICU stay, length of hospital stay, ICU mortality, and in-hospital mortality. Conclusions and Relevance In patients with moderate to severe ARDS, a strategy with lung recruitment and titrated PEEP compared with low PEEP increased 28-day all-cause mortality. These findings do not support the routine use of lung recruitment maneuver and PEEP titration in these patients. Trial Registration clinicaltrials.gov Identifier: NCT01374022

Effects of Bariatric Surgery in Obese Patients With Hypertension: The GATEWAY Randomized Trial (Gastric Bypass to Treat Obese Patients With Steady Hypertension)

Background: Recent research efforts on bariatric surgery have focused on metabolic and diabetes mellitus resolution. Randomized trials designed to assess the impact of bariatric surgery in patients with obesity and hypertension are needed. Methods: In this randomized, single-center, nonblinded trial, we included patients with hypertension (using ≥2 medications at maximum doses or >2 at moderate doses) and a body mass index between 30.0 and 39.9 kg/m2. Patients were randomized to Roux-en-Y gastric bypass plus medical therapy or medical therapy alone. The primary end point was reduction of ≥30% of the total number of antihypertensive medications while maintaining systolic and diastolic blood pressure <140 mm Hg and 90 mm Hg, respectively, at 12 months. Results: We included 100 patients (70% female, mean age 43.8±9.2 years, mean body mass index 36.9±2.7 kg/m2), and 96% completed follow-up. Reduction of ≥30% of the total number of antihypertensive medications while maintaining controlled blood pressure occurred in 41 of 49 patients from the gastric bypass group (83.7%) compared with 6 of 47 patients (12.8%) from the control group with a rate ratio of 6.6 (95% confidence interval, 3.1–14.0; P<0.001). Remission of hypertension was present in 25 of 49 (51%) and 22 of 48 (45.8%) patients randomized to gastric bypass, considering office and 24-hour ambulatory blood pressure monitoring, respectively, whereas no patient submitted to medical therapy was free of antihypertensive drugs at 12 months. A post hoc analysis for the primary end point considering the SPRINT (Systolic Blood Pressure Intervention Trial) target reached consistent results, with a rate ratio of 3.8 (95% confidence interval, 1.4–10.6; P=0.005). Eleven patients (22.4%) from the gastric bypass group and none in the control group were able to achieve SPRINT levels without antihypertensives. Waist circumference, body mass index, fasting plasma glucose, glycohemoglobin, low-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, and 10-year Framingham risk score were lower in the gastric bypass than in the control group. Conclusions: Bariatric surgery represents an effective strategy for blood pressure control in a broad population of patients with obesity and hypertension. Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT01784848.

Atorvastatin for high-risk statin-naïve patients undergoing noncardiac surgery: The Lowering the Risk of Operative Complications Using Atorvastatin Loading Dose (LOAD) randomized trial

Background Preliminary evidence suggests that statins may prevent major perioperative vascular complications. Methods We randomized 648 statin‐naïve patients who were scheduled for noncardiac surgery and were at risk for a major vascular complication. Patients were randomized to a loading dose of atorvastatin or placebo (80 mg anytime within 18 hours before surgery), followed by a maintenance dose of 40 mg (or placebo), started at least 12 hours after the surgery, and then 40 mg/d (or placebo) for 7 days. The primary outcome was a composite of all‐cause mortality, nonfatal myocardial injury after noncardiac surgery, and stroke at 30 days. Results The primary outcome was observed in 54 (16.6%) of 326 patients in the atorvastatin group and 59 (18.7%) of 316 patients in the placebo group (hazard ratio [HR] 0.87, 95% CI 0.60‐1.26, P = .46). No significant effect was observed on the 30‐day secondary outcomes of all‐cause mortality (4.3% vs 4.1%, respectively; HR 1.14, 95% CI 0.53‐2.47, P = .74), nonfatal myocardial infarction (3.4% vs 4.4%, respectively; HR 0.76, 95% CI 0.35‐1.68, P = .50), myocardial injury after noncardiac surgery (13.2% vs 16.5%; HR 0.79, 95% CI 0.53‐1.19, P = .26), and stroke (0.9% vs 0%, P = .25). Conclusion In contrast to the prior observational and trial data, the LOAD trial has neutral results and did not demonstrate a reduction in major cardiovascular complications after a short‐term perioperative course of statin in statin‐naïve patients undergoing noncardiac surgery. We demonstrated, however, that a large multicenter blinded perioperative statin trial for high‐risk statin‐naïve patients is feasible and should be done to definitely establish the efficacy and safety of statin in this patient population.

Effect of Loading Dose of Atorvastatin Prior to Planned Percutaneous Coronary Intervention on Major Adverse Cardiovascular Events in Acute Coronary Syndrome: The SECURE-PCI Randomized Clinical Trial

Importance The effects of loading doses of statins on clinical outcomes in patients with acute coronary syndrome (ACS) and planned invasive management remain uncertain. Objective To determine if periprocedural loading doses of atorvastatin decrease 30-day major adverse cardiovascular events (MACE) in patients with ACS and planned invasive management. Design, Setting, and Participants Multicenter, double-blind, placebo-controlled, randomized clinical trial conducted at 53 sites in Brazil among 4191 patients with ACS evaluated with coronary angiography to proceed with a percutaneous coronary intervention (PCI) if anatomically feasible. Enrollment occurred between April 18, 2012, and October 6, 2017. Final follow-up for 30-day outcomes was on November 6, 2017. Interventions Patients were randomized to receive 2 loading doses of 80 mg of atorvastatin (n = 2087) or matching placebo (n = 2104) before and 24 hours after a planned PCI. All patients received 40 mg of atorvastatin for 30 days starting 24 hours after the second dose of study medication. Main Outcomes and Measures The primary outcome was MACE, defined as a composite of all-cause mortality, myocardial infarction, stroke, and unplanned coronary revascularization through 30 days. Results Among the 4191 patients (mean age, 61.8 [SD, 11.5] years; 1085 women [25.9%]) enrolled, 4163 (99.3%) completed 30-day follow-up. A total of 2710 (64.7%) underwent PCI, 333 (8%) underwent coronary artery bypass graft surgery, and 1144 (27.3%) had exclusively medical management. At 30 days, 130 patients in the atorvastatin group (6.2%) and 149 in the placebo group (7.1%) had a MACE (absolute difference, 0.85% [95% CI, −0.70% to 2.41%]; hazard ratio, 0.88; 95% CI, 0.69-1.11; P = .27). No cases of hepatic failure were reported; 3 cases of rhabdomyolysis were reported in the placebo group (0.1%) and 0 in the atorvastatin group. Conclusions and Relevance Among patients with ACS and planned invasive management with PCI, periprocedural loading doses of atorvastatin did not reduce the rate of MACE at 30 days. These findings do not support the routine use of loading doses of atorvastatin among unselected patients with ACS and intended invasive management. Trial Registration clinicaltrials.gov Identifier: NCT01448642

Ticagrelor vs Clopidogrel After Fibrinolytic Therapy in Patients With ST-Elevation Myocardial Infarction: A Randomized Clinical Trial

Importance The bleeding safety of ticagrelor in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy remains uncertain. Objective To evaluate the short-term safety of ticagrelor when compared with clopidogrel in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy. Design, Setting and Participants We conducted a multicenter, randomized, open-label with blinded end point adjudication trial that enrolled 3799 patients (younger than 75 years) with ST-segment elevation myocardial infarction receiving fibrinolytic therapy in 152 sites from 10 countries from November 2015 through November 2017. The prespecified upper boundary for noninferiority for bleeding was an absolute margin of 1.0%. Interventions Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter). Patients were randomized with a median of 11.4 hours after fibrinolysis, and 90% were pretreated with clopidogrel. Main Outcomes and Measures The primary outcome was thrombolysis in myocardial infarction (TIMI) major bleeding through 30 days. Results The mean (SD) age was 58.0 (9.5) years, 2928 of 3799 patients (77.1%) were men, and 2177 of 3799 patients (57.3%) were white. At 30 days, TIMI major bleeding had occurred in 14 of 1913 patients (0.73%) receiving ticagrelor and in 13 of 1886 patients (0.69%) receiving clopidogrel (absolute difference, 0.04%; 95% CI, −0.49% to 0.58%; P < .001 for noninferiority). Major bleeding defined by the Platelet Inhibition and Patient Outcomes criteria and by the Bleeding Academic Research Consortium types 3 to 5 bleeding occurred in 23 patients (1.20%) in the ticagrelor group and in 26 patients (1.38%) in the clopidogrel group (absolute difference, −0.18%; 95% CI, −0.89% to 0.54; P = .001 for noninferiority). The rates of fatal (0.16% vs 0.11%; P = .67) and intracranial bleeding (0.42% vs 0.37%; P = .82) were similar between the ticagrelor and clopidogrel groups, respectively. Minor and minimal bleeding were more common with ticagrelor than with clopidogrel. The composite of death from vascular causes, myocardial infarction, or stroke occurred in 76 patients (4.0%) treated with ticagrelor and in 82 patients (4.3%) receiving clopidogrel (hazard ratio, 0.91; 95% CI, 0.67-1.25; P = .57). Conclusions and Relevance In patients younger than 75 years with ST-segment elevation myocardial infarction, delayed administration of ticagrelor after fibrinolytic therapy was noninferior to clopidogrel for TIMI major bleeding at 30 days. Trial Registration clinicaltrials.gov Identifier: NCT02298088

Diabetes and Cardiovascular Events In High-Risk Patients: Insights from a Multicenter Registry in a Middle-Income Country

AIMS The aim of this study was to determine the rate of major clinical events and its determinants in patients with previous cardiovascular event or not, and with or without diabetes from a middle-income country. METHODS REACT study is a multicenter registry conducted between July 2010 and May 2013 in Brazil. Patients were eligible if they were over 45years old and high cardiovascular risk. Patients were followed for 12months; data were collected regarding adherence to evidence-based therapies and occurrence of clinical events (all-cause mortality, non-fatal cardiac arrest, myocardial infarction, or stroke). RESULTS A total of 5006 subjects was included and analyzed in four groups: No diabetes and no previous cardiovascular event, n=430; diabetes and no previous cardiovascular event, n=1138; no diabetes and previous cardiovascular event, n=1747; and diabetes and previous cardiovascular event, n=1691. Major clinical events in one-year follow-up occurred in 332 patients. A previous cardiovascular event was associated with a higher risk of having another event in the follow-up (HR 2.31 95% CI 1.74-3.05, p<0.001), as did the presence of diabetes (HR 1.28 95% CI 1.10-1.73, p=0.005). In patients with diabetes,failure to reach HbA1c targetswas related topoorer event-free survival compared to patients with good metabolic control (HR 1.70 95% CI 1.01-2.84, p=0.044). CONCLUSIONS In Brazil, diabetes confers high risk for major clinical events, but this condition is not equivalent to having a previous cardiovascular event. Moreover, not so strict targets for HbA1c in patients with diabetes and previous cardiovascular events might be considered.

The role of diffusion tensor imaging tractography for Gamma Knife thalamotomy planning.

OBJECTIVE The role of tractography in Gamma Knife thalamotomy (GK-T) planning is still unclear. Pyramidal tractography might reduce the risk of radiation injury to the pyramidal tract and reduce motor complications. METHODS In this study, the ventralis intermedius nucleus (VIM) targets of 20 patients were bilaterally defined using Iplannet Stereotaxy Software, according to the anterior commissure-posterior commissure (AC-PC) line and considering the localization of the pyramidal tract. The 40 targets and tractography were transferred as objects to the GammaPlan Treatment Planning System (GP-TPS). New targets were defined, according to the AC-PC line in the functional targets section of the GP-TPS. The target offsets required to maintain the internal capsule (IC) constraint of < 15 Gy were evaluated. In addition, the strategies available in GP-TPS to maintain the minimum conventional VIM target dose at > 100 Gy were determined. RESULTS A difference was observed between the positions of both targets and the doses to the IC. The lateral (x) and the vertical (z) coordinates were adjusted 1.9 mm medially and 1.3 mm cranially, respectively. The targets defined considering the position of the pyramidal tract were more medial and superior, based on the constraint of 15 Gy touching the object representing the IC in the GP-TPS. The best strategy to meet the set constraints was 90° Gamma angle (GA) with automatic shaping of dose distribution; this was followed by 110° GA. The worst GA was 70°. Treatment time was substantially increased by the shaping strategy, approximately doubling delivery time. CONCLUSIONS Routine use of DTI pyramidal tractography might be important to fine-tune GK-T planning. DTI tractography, as well as anisotropy showing the VIM, promises to improve Gamma Knife functional procedures. They allow for a more objective definition of dose constraints to the IC and targeting. DTI pyramidal tractography introduced into the treatment planning may reduce the incidence of motor complications and improve efficacy. This needs to be validated in a large clinical series.

Rationale and design of the Statins Evaluation in Coronary procedUres and REvascularization: The SECURE-PCI Trial

Background: Previous evidence suggests that acute treatment with statins reduce atherosclerotic complications, including periprocedural myocardial infarction, but currently, there are no large, adequately powered studies to define the effects of early, high‐dose statins in patients with acute coronary syndrome (ACS) and planned invasive management. Objectives: The main goal of Statins Evaluation in Coronary procedUres and REvascularization (SECURE‐PCI) Trial is to determine whether the early use of a loading dose of 80 mg of atorvastatin before an intended percutaneous coronary intervention followed by an additional dose of 80 mg 24 hours after the procedure will be able to reduce the rates of major cardiovascular events at 30 days in patients with an ACS. Design: The SECURE‐PCI study is a pragmatic, multicenter, double‐blind, placebo‐controlled randomized trial planned to enroll around 4,200 patients in 58 different sites in Brazil. The primary outcome is the rate of major cardiovascular events at 30 days defined as a composite of all‐cause mortality, nonfatal acute myocardial infarction, nonfatal stroke, and coronary revascularization. Summary: The SECURE PCI is a large randomized trial testing a strategy of early, high‐dose statin in patients with ACS and will provide important information about the acute treatment of this patient population.

Ticagrelor versus Clopidogrel After Fibrinolytic Therapy in Patients With ST-Elevation Myocardial Infarction: Rationale and Design of the TicagRElor in pAtients with ST elevation myocardial infarction treated with Thrombolysis (TREAT) trial

Background The safety and efficacy of ticagrelor in patients with ST‐elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remain uncertain. Objectives The primary objective of the TicagRElor in pAtients with ST elevation myocardial infarction treated with Thrombolysis (TREAT) trial is to evaluate the short‐term safety of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy. Key secondary objectives are to assess the safety and efficacy of ticagrelor compared with clopidogrel at 12‐months. Design The TREAT trial is a multicenter, randomized, phase III, Prospective randomized open blinded end‐point (PROBE) study that enrolled 3,799 patients in 152 sites from 10 countries. Following administration of fibrinolytic therapy patients were randomized to a loading dose of ticagrelor 180 mg or clopidogrel 300 mg followed by a maintenance dose of ticagrelor 90 mg twice daily or clopidogrel 75 mg/day for 12‐months. The primary outcome is the rate of TIMI major bleeding at 30‐days and will be assessed for non‐inferiority using an intention‐to‐treat analysis. Co‐treatments include aspirin and anticoagulants. Other evidence based therapies are also recommended. Secondary efficacy outcome include a composite of death from vascular causes, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack or other arterial thrombotic event. All‐cause mortality as well as individual components of the combined efficacy endpoint will also be ascertained. Summary TREAT is an international randomized controlled trial comparing ticagrelor with clopidogrel in STEMI patients treated with fibrinolytic therapy. The results of this trial will inform clinical practice and international guidelines.

Recurrent and non-recurrent feline injection-site sarcoma: computed tomographic and ultrasonographic findings

Objectives This study describes the sonographic and computed tomographic (CT) characteristics of primary and recurrent feline injection-site sarcomas (FISSs). Methods Between 2005 and 2013, 32 cats were selected for prospective and retrospective studies. Tumor shape and margins, presence of thickening of the adipose tissue, muscular and bone involvement, pre- and postcontrast attenuation, blurring of fat planes, calcification and liquefactive necrosis, intratumoral areas and skip metastasis were analyzed in CT scans. Echogenicity, echotexture, tumor margins and peritumoral tissue characteristics were analyzed by ultrasound (US). Results Irregular shape (62.5%) with digitiform projections (100.0%), mixed (peripheral and intratumoral) contrast enhancement (67.7%), blurring of fat planes (68.8%) and signs of liquefactive intratumoral necrosis (68.8%) were the prevailing CT findings. Ultrasonography revealed irregular tumor margins, peripheral hyperechoic capsule-like rim, heterogeneous echotexture, and hyperechoic tissue contiguous with the formations and thickening of adjacent subcutaneous tissues in all cases. Mixed echogenicity with areas suggestive of tumor liquefactive necrosis was documented in 83.3% of cases. Skip metastases were highly correlated with tumor recurrence (P = 0.001). The incidence of muscular involvement tended to be higher (P = 0.003) in tumors presenting with thickening of adjacent adipose tissue. Conclusions and relevance CT and US features common to FISS lesions were highlighted in this study. The imaging modalities employed allowed assessment of peritumoral inflammation, particularly adipose tissue inflammation. Imaging data may contribute to FISS diagnosis, therapeutic planning and patient follow-up.