Daily Archives: September 19, 2024
Summary: Perioperative Management of Patients Taking Direct Oral Anticoagulants
19 Sep, 2024 | 21:12h | UTCDirect oral anticoagulants (DOACs)—including apixaban, rivaroxaban, edoxaban, and dabigatran—are increasingly used for stroke prevention in atrial fibrillation and for treating venous thromboembolism. Effective perioperative management of DOACs is essential to minimize bleeding and thromboembolic risks during surgical and nonsurgical procedures. Below are practical recommendations focused on the perioperative management of patients taking DOACs, based on a recent JAMA review article.
Elective Surgical or Nonsurgical Procedures
Classify Bleeding Risk of Procedures:
- Minimal Risk:
- Minor dental procedures (e.g., cleaning, extractions)
- Minor dermatologic procedures (e.g., skin lesion removal)
- Cataract surgery
- Low to Moderate Risk:
- Endoscopic procedures without high-risk interventions
- Cholecystectomy
- Inguinal hernia repair
- High Risk:
- Major surgery (e.g., cancer surgery, joint replacement)
- Procedures involving neuraxial anesthesia
- Endoscopic procedures with high-risk interventions (e.g., large polyp removal)
DOAC Management Strategies:
- Minimal Bleeding Risk Procedures:
- Option 1: Continue DOACs without interruption.
- Option 2: For added safety, withhold the morning dose on the day of the procedure (especially for twice-daily DOACs like apixaban and dabigatran).
- Low to Moderate Bleeding Risk Procedures:
- Preoperative:
- Discontinue DOACs 1 day before the procedure.
- This allows approximately 2 half-lives for drug clearance.
- Postoperative:
- Resume DOACs 1 day after the procedure, ensuring adequate hemostasis.
- Preoperative:
- High Bleeding Risk Procedures:
- Preoperative:
- Discontinue DOACs 2 days before the procedure.
- This allows approximately 4-5 half-lives for drug clearance.
- Postoperative:
- Resume DOACs 2-3 days after the procedure, based on bleeding risk and hemostasis.
- Preoperative:
Evidence Supporting These Strategies:
- The PAUSE study demonstrated that standardized interruption protocols without heparin bridging result in low rates of:
- Thromboembolism: 0.2%–0.4%
- Major Bleeding: 1%–2%
Postoperative DOAC Resumption:
- Assess surgical-site hemostasis before resuming DOACs.
- Delay resumption if there is ongoing bleeding or concerns about hemostasis.
- For high bleeding risk procedures, consider a longer delay (2–3 days).
Perioperative Heparin Bridging:
- Not recommended for patients on DOACs.
- Bridging increases bleeding risk without reducing thromboembolism.
- DOACs have rapid offset and onset, making bridging unnecessary.
Special Considerations
Patients with Impaired Renal Function:
- For CrCl 30–50 mL/min:
- Dabigatran: Extend preoperative discontinuation by an additional day.
- For CrCl <30 mL/min:
- Dabigatran is contraindicated.
- For other DOACs, consider extending discontinuation to 3–4 days before surgery.
Patients Undergoing Neuraxial Anesthesia:
- Discontinue DOACs for 3 days (apixaban, edoxaban, rivaroxaban) or 4 days (dabigatran) before the procedure.
- Minimizes risk of spinal or epidural hematoma.
Dental Procedures:
- Generally safe to continue DOACs.
- For added safety:
- Omit or delay the dose on the day of the procedure.
- Employ local hemostatic measures (e.g., tranexamic acid mouthwash).
Endoscopic Procedures:
- Low-risk procedures (e.g., diagnostic endoscopy without biopsy):
- Follow standard DOAC interruption for low to moderate bleeding risk.
- High-risk procedures (e.g., polypectomy of large polyps):
- Extend DOAC discontinuation by an additional day pre- and post-procedure.
Patients Unable to Resume Oral Medications Postoperatively:
- Use prophylactic low-molecular-weight heparin (LMWH) until oral intake is possible.
- Avoid therapeutic-dose LMWH due to bleeding risk.
Emergent, Urgent, or Semiurgent Procedures
Risks:
- Higher bleeding risk: Up to 23%
- Thromboembolism risk: Up to 11%
Management Strategies:
- Assess Time Since Last DOAC Dose:
- If within 48 hours, consider that significant anticoagulant effect may persist.
- Laboratory Testing (if available):
- DOAC Level Testing:
- ≥50 ng/mL: Consider using reversal agents.
- <50 ng/mL: May proceed without reversal agents.
- DOAC Level Testing:
- Use of Reversal Agents:
- For Dabigatran:
- Idarucizumab (5 g IV)
- For Factor Xa Inhibitors (apixaban, rivaroxaban, edoxaban):
- Andexanet alfa (dosing based on last dose timing and amount)
- Prothrombin Complex Concentrates (PCCs): If andexanet alfa is unavailable or contraindicated.
- For Dabigatran:
- Proceeding Without Testing:
- If testing is unavailable and last DOAC dose was within 48 hours, consider reversal agents.
- If >48 hours since last dose, may proceed without reversal.
Considerations:
- Reversal agents are expensive and may carry thrombotic risks.
- Use should be judicious, weighing risks and benefits.
- Consult hematology or thrombosis experts when possible.
Key Takeaways
- Elective Procedures:
- Utilize standardized protocols based on procedural bleeding risk.
- Routine preoperative DOAC level testing is unnecessary.
- Avoid heparin bridging.
- Emergent/Urgent Procedures:
- Reversal agents may be appropriate when significant DOAC levels are present.
- Decision to use reversal agents should consider bleeding risk, time since last dose, and availability of DOAC level testing.
- Patient Communication:
- Ensure patients understand the plan for DOAC interruption and resumption.
- Provide clear instructions regarding timing and dosing.
- Interdisciplinary Coordination:
- Collaborate with surgical teams, anesthesiologists, and pharmacists.
- Use electronic medical records and clinical decision support tools to enhance communication.
Conclusion
By applying standardized perioperative management protocols, clinicians can effectively balance the risks of bleeding and thromboembolism in patients taking DOACs who require surgical or nonsurgical procedures. These strategies simplify decision-making, avoid unnecessary interventions like heparin bridging, and promote patient safety.
Summary: Community-Acquired Pneumonia
19 Sep, 2024 | 17:21h | UTCIntroduction
Community-acquired pneumonia (CAP) is a significant cause of morbidity and mortality, accounting for approximately 1.4 million emergency department visits, 740,000 hospitalizations, and 41,000 deaths annually in the United States. Effective management of CAP requires prompt and accurate diagnosis, appropriate antimicrobial therapy, and consideration of adjunctive treatments. This summary highlights key practice points from a review article in JAMA related to the diagnosis and treatment of CAP for medical professionals.
Diagnosis of CAP
Clinical Presentation
- Signs and Symptoms: Suspect CAP in patients presenting with two or more of the following:
- Fever (>38 °C) or hypothermia (≤36 °C)
- Leukocytosis (>10,000/μL) or leukopenia (<4,000/μL)
- New or increased cough
- Dyspnea
Radiographic Confirmation
- Chest Imaging: Obtain a chest radiograph for all patients with suspected CAP to identify air space opacities or infiltrates.
- Chest CT: Consider if the chest radiograph is inconclusive but clinical suspicion remains high.
- Differential Diagnosis: Rule out other causes of symptoms and radiographic findings, such as pulmonary embolism, heart failure, or malignancy.
Microbiological Testing
- Viral Testing:
- SARS-CoV-2 and Influenza: Test all patients for COVID-19 and influenza during periods of community transmission, as results influence treatment decisions and infection control measures.
- Bacterial Testing:
- Indications: Reserve sputum and blood cultures for patients with severe CAP or risk factors for methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa.
- Risk Factors:
- Previous infection or colonization with MRSA or P. aeruginosa.
- Hospitalization with parenteral antibiotics within the past 90 days.
Treatment of CAP
Empirical Antimicrobial Therapy
- Hospitalized Patients without Risk Factors for Resistant Bacteria:
- First-Line Therapy: β-lactam plus macrolide combination.
- Example: Ceftriaxone (1-2 g IV daily) plus azithromycin (500 mg IV or orally daily).
- Alternative: Respiratory fluoroquinolone monotherapy (e.g., levofloxacin) if β-lactam/macrolide therapy is contraindicated.
- First-Line Therapy: β-lactam plus macrolide combination.
- Patients with Severe CAP:
- Similar to non-severe CAP but ensure coverage for atypical pathogens.
- Consider Corticosteroids: Early administration (within 24 hours) of systemic corticosteroids may reduce mortality.
- Outpatients without Comorbidities:
- First-Line Therapy: Amoxicillin (1 g orally three times daily) or doxycycline (100 mg orally twice daily).
- Outpatients with Comorbidities:
- Combination Therapy: Amoxicillin/clavulanate (500 mg/125 mg orally three times daily) plus azithromycin (500 mg on day 1, then 250 mg daily).
Duration of Therapy
- Minimum Duration: Treat for a minimum of 3 days if the patient achieves clinical stability (normal vital signs) within 72 hours.
- Extended Duration: Extend to 5 days or more if the patient does not meet stability criteria by day 3 or has complications.
- Transition to Oral Therapy: Switch from intravenous to oral antibiotics when the patient can tolerate oral intake.
Antimicrobial Stewardship
- Avoid Unnecessary Antibiotics: Do not initiate antibiotics for confirmed viral CAP without evidence of bacterial coinfection.
- De-escalation: Narrow antibiotic coverage based on culture results and clinical improvement.
- Monitor for Adverse Effects: Be vigilant for antibiotic-associated complications, such as Clostridioides difficile infection.
Adjunctive Therapies
- Corticosteroids:
- Severe CAP: Administer systemic corticosteroids (e.g., hydrocortisone 200 mg/day) within 24 hours of diagnosis to reduce mortality and complications.
- Non-severe CAP: Routine use is not recommended due to lack of benefit and potential harm.
Secondary Prevention
- Vaccinations:
- Pneumococcal Conjugate Vaccine: Recommend for eligible patients to prevent future pneumococcal infections.
- Influenza Vaccine: Annual vaccination to reduce the risk of influenza-associated pneumonia.
- COVID-19 and RSV Vaccines: Encourage vaccination per current guidelines.
- Lifestyle Modifications:
- Smoking Cessation: Strongly advise quitting smoking to reduce the risk of CAP and improve respiratory health.
- Alcohol Moderation: Counsel patients on reducing excessive alcohol intake.
- Management of Comorbidities:
- Optimize treatment for chronic conditions such as chronic obstructive pulmonary disease (COPD), heart failure, and diabetes.
Key Practice Points
- Diagnostic Evaluation:
- Use a combination of clinical signs, symptoms, and radiographic findings to diagnose CAP.
- Test all patients for SARS-CoV-2 and influenza during times of community prevalence.
- Reserve extensive pathogen testing for severe cases or those at risk for resistant organisms.
- Antimicrobial Therapy:
- Initiate empirical antibiotics promptly based on disease severity and risk factors.
- Prefer β-lactam/macrolide combination therapy for most hospitalized patients.
- Limit the duration of antibiotics to the shortest effective course to reduce resistance and adverse effects.
- Use of Corticosteroids:
- Consider early corticosteroid therapy in patients with severe CAP to improve outcomes.
- Avoid routine corticosteroid use in non-severe CAP due to potential risks.
- Antimicrobial Stewardship:
- Reassess antibiotic therapy daily and de-escalate based on clinical response and microbiological data.
- Transition to oral antibiotics when appropriate.
- Preventive Measures:
- Promote vaccinations and lifestyle changes to prevent recurrent CAP.
- Address and manage underlying health conditions that may predispose to CAP.
Conclusion
Effective management of CAP involves prompt diagnosis using clinical and radiographic criteria, appropriate empirical antimicrobial therapy tailored to disease severity and risk factors, and consideration of adjunctive treatments such as corticosteroids in severe cases. Antimicrobial stewardship principles should guide therapy duration and de-escalation to minimize resistance and adverse effects. Preventive strategies, including vaccinations and lifestyle modifications, are essential to reduce the incidence of CAP and improve patient outcomes.
Phase 2 RCT: Axatilimab Demonstrates Efficacy in Refractory Chronic GVHD by Targeting CSF1R-Dependent Macrophages
19 Sep, 2024 | 16:05h | UTCBackground: Chronic graft-versus-host disease (GVHD) is a significant long-term complication of allogeneic hematopoietic stem-cell transplantation, affecting approximately half of recipients and leading to substantial morbidity and mortality. Standard therapies often fail to induce durable responses in patients with refractory or recurrent disease. CSF1R-dependent monocytes and macrophages are key mediators of chronic GVHD, contributing to inflammation and fibrosis. Axatilimab, a CSF1R-blocking antibody, has shown promising activity in early studies.
Objective: To evaluate the efficacy and safety of axatilimab at three different doses in patients with recurrent or refractory chronic GVHD.
Methods: In this phase 2, multinational, randomized study (AGAVE-201), 241 patients aged ≥2 years with active chronic GVHD after at least two prior systemic therapies were randomized 1:1:1 to receive intravenous axatilimab at 0.3 mg/kg every 2 weeks (n=80), 1 mg/kg every 2 weeks (n=81), or 3 mg/kg every 4 weeks (n=80). Randomization was stratified by chronic GVHD severity and prior use of FDA-approved therapies (ibrutinib, ruxolitinib, or belumosudil). The primary endpoint was overall response rate (complete or partial response) within the first six cycles. The key secondary endpoint was a patient-reported reduction in symptom burden, defined as a decrease of more than 5 points on the modified Lee Symptom Scale (range 0–100).
Results: The overall response rate was 74% (95% CI, 63%–83%) in the 0.3 mg/kg group, 67% (95% CI, 55%–77%) in the 1 mg/kg group, and 50% (95% CI, 39%–61%) in the 3 mg/kg group, exceeding the predefined efficacy threshold in all groups. A clinically meaningful reduction in symptom burden was reported in 60%, 69%, and 41% of patients in the respective dose groups. Median time to response was less than 2 months across all groups. Organ-specific responses were observed in all affected organs, including skin, lungs, joints, and fascia.
The most common adverse events were dose-dependent transient laboratory abnormalities related to CSF1R blockade, such as elevations in liver enzymes and creatine kinase, which were not associated with clinical symptoms or end-organ damage. Periorbital edema occurred more frequently at higher doses. Adverse events leading to discontinuation occurred in 6% of patients in the 0.3 mg/kg group, 22% in the 1 mg/kg group, and 18% in the 3 mg/kg group. Serious infections were reported but were not dose-dependent.
Conclusions: Axatilimab demonstrated significant efficacy in patients with heavily pretreated recurrent or refractory chronic GVHD, with the highest response rates and best tolerability observed at the lowest dose tested (0.3 mg/kg every 2 weeks). Targeting CSF1R-dependent monocytes and macrophages may represent a novel therapeutic strategy in chronic GVHD.
Implications for Practice: Axatilimab offers a potential new treatment option for patients with chronic GVHD refractory to standard therapies, including those who have failed prior FDA-approved treatments. Clinicians should consider axatilimab as a therapeutic option while monitoring for transient laboratory abnormalities associated with CSF1R blockade. The lower dose appears to provide optimal efficacy with fewer adverse events.
Study Strengths and Limitations: Strengths include the randomized, multinational design and inclusion of patients with severe, refractory chronic GVHD who had received multiple prior therapies. Limitations include the lack of a comparator group, which may introduce outcome-reporting bias, and the small sizes of subgroups, limiting the generalizability of certain findings.
Future Research: Further studies are needed to confirm these results, assess long-term outcomes, and explore axatilimab in earlier lines of therapy and in combination with other treatments. Investigations into the use of axatilimab in other autoimmune diseases characterized by CSF1R-driven macrophage-mediated inflammation and fibrosis are also warranted.
RCT: Preoxygenation with Noninvasive Ventilation Reduced Hypoxemia during Emergency Intubation
19 Sep, 2024 | 12:53h | UTCBackground: Hypoxemia during tracheal intubation in critically ill adults increases the risk of cardiac arrest and death. Preoxygenation aims to mitigate this risk, but the optimal method remains uncertain. Noninvasive ventilation (NIV) may offer advantages over oxygen masks by providing positive pressure and higher inspired oxygen fractions, but evidence is limited.
Objective: To determine whether preoxygenation with noninvasive ventilation reduces the incidence of hypoxemia during tracheal intubation compared to preoxygenation with an oxygen mask among critically ill adults.
Methods: In a multicenter, pragmatic, unblinded, randomized trial conducted at 24 emergency departments and intensive care units in the United States, 1301 critically ill adults (age ≥18 years) undergoing tracheal intubation were randomized 1:1 to receive preoxygenation with either noninvasive ventilation (n=645) or an oxygen mask (n=656). Patients already receiving positive-pressure ventilation or at high risk of aspiration were excluded. In the NIV group, preoxygenation was administered using a tight-fitting mask connected to a ventilator, with an FiO₂ of 100%, expiratory pressure ≥5 cm H₂O, and inspiratory pressure ≥10 cm H₂O. In the oxygen-mask group, preoxygenation was provided using a nonrebreather mask or bag-mask device without manual ventilation, with oxygen flow ≥15 liters per minute. The primary outcome was hypoxemia during intubation, defined as oxygen saturation <85% between induction of anesthesia and 2 minutes after tracheal intubation.
Results: Hypoxemia occurred in 9.1% of patients in the NIV group versus 18.5% in the oxygen-mask group (difference –9.4 percentage points; 95% CI, –13.2 to –5.6; P<0.001). Cardiac arrest during intubation occurred in 0.2% of patients in the NIV group and 1.1% in the oxygen-mask group (difference –0.9 percentage points; 95% CI, –1.8 to –0.1). Aspiration occurred in 0.9% of patients in the NIV group and 1.4% in the oxygen-mask group (difference –0.4 percentage points; 95% CI, –1.6 to 0.7). No significant differences were observed in other adverse events.
Conclusions: Preoxygenation with noninvasive ventilation significantly reduced the incidence of hypoxemia during tracheal intubation among critically ill adults compared to preoxygenation with an oxygen mask, without increasing the risk of aspiration.
Implications for Practice: Preoxygenation with noninvasive ventilation should be considered for critically ill adults undergoing emergency tracheal intubation to reduce the risk of hypoxemia and potential cardiac arrest. Clinicians should ensure appropriate equipment and training are available for the use of NIV during preoxygenation.
Study Strengths and Limitations: Strengths include a large sample size, multicenter design across diverse emergency departments and ICUs, and pragmatic approach enhancing generalizability. Limitations include exclusion of patients already receiving positive-pressure ventilation or at high risk of aspiration, potentially limiting applicability to these populations. The unblinded design may introduce bias, although outcome data were collected by independent observers.
Future Research: Further studies are needed to evaluate the effectiveness of noninvasive ventilation for preoxygenation in patients at high risk of aspiration and to compare its efficacy with high-flow nasal cannula. Research should also assess long-term clinical outcomes and cost-effectiveness of implementing NIV for preoxygenation.