Anticoagulants, Antibiotics and Medical Devices: Advancing Critically

By Amanda Decimo, MSN, MPH, CRNA, from the IARS, AUA and SOCCA 2019 Annual Meetings*

Presenters Ian Welsby, MD, Noreen Murphy, MD, and Peter Von Homeyer, MD, FASE, delved into the latest developments in the field of Critical Care and how these advances are shaping the landscape of anesthesiology as a whole during the SOCCA Education Session I: Critical Advances, Critical Care.

Dr. Welsby, Duke University School of Medicine, discussed new anticoagulants on the market and how they affect clinical practice. Direct oral anticoagulants (DOACs) have been in use since 2010, and warfarin use has declined. Dr. Welsby focused his lecture on three DOACs commonly used in the U.S.

Dabigatran is a competitive, thrombin inhibitor. It has a long half-life but has BID dosage. There is no need to monitor coagulation or platelets. Dabigatran dosing decreases with amiodarone, which is an important consideration, as non-valvular atrial fibrillation is the main indication and market for all of these drugs. With renal impairment dosage must be reduced; it’s contraindicated with creatine clearance <30. Dabigatran has fallen out of favor with increased use in rivaroxaban and apixaban, due to fewer side effects.

Rivaroxaban was the first oral Factor Xa inhibitor. It has a broad half-life of 5-13 hours, yet has a once daily dosage, convenient for marketing. It is also dependent on renal clearance, primarily a concern with higher dosages. It is important to consider the elderly may have poor renal clearance of drugs despite normal creatinine; this drug can linger in those patients.

Apixaban is also an oral Factor Xa inhibitor. It is uniquely eliminated primarily via the GI tract, and only 25% renal excretion. It has a short half-life, it goes away quickly. This is ideal for patients who don’t mind BID dosing.

Are DOACs better than warfarin? While there are drug interactions with DOACs, there are not nearly as complicated as warfarin interactions. Less intracranial hemorrhage and bleeding occur with DOACs because anticoagulation is more predictable; we are less likely to see an INR of 10 in patients on these drugs. They are indicated for non-valvular atrial fibrillation, DVT, and CVA prevention. DOACs are NOT recommended for valvular associated atrial fibrillation, and DOACs are NOT recommended for patients with mechanical valves.

Monitoring is not required for the DOACs. However, during certain situations, such as en route to the OR, this information can guide whether or not to use costly reversal agents. For dabigatran, thrombin time is useful. Additionally, if PTT is elevated, the drug is still around; if PTT is normal, the test is inconclusive. For Factor Xa (rivaroxaban and apixaban) inhibitors, anti-Xa assays of 0 reflect no drug, while positive assays cannot be quantified.

Reversal Agents:

Idarucizumab is FDA approved for dabigatran reversal, with an excellent safety profile. Effects last about 24 hours, long enough for emergency surgery. However, dabigatran is not used very much.

Andexanet is an expensive reversal agent that binds to factor Xa inhibitors. Safety issues surrounding this drug, which binds to tissue factor pathway inhibitor, may be procoagulant effects. Bolus and infusion of the drug are required to prevent anticoagulation reoccurrence. Despite adequate hemostasis, study outcomes of patients reversed with andexanet have been fairly morbid. However, it is only FDA approved and currently reversal option for Xa inhibitors.

Peter Von Homeyer, MD, FASE, University of Washington Medicine, provided an update on the development of mechanical support devices. Long-term mechanical support was first initiated in 1998 with a 48% reduced risk of death compared with medical management; however, these patients had significantly increased neurological and bleeding complications.

Ten years later, the Hartman II trial introduced a continuous flow device. This was a game-changer for LVAD therapy. There were fewer malfunctions and complications with the newer device. Currently, all left ventricular assistive devices (LVADs) are third-generation, which have miniaturized centrifugal pumps. These pumps have greater inflow and less traumatic blood flow. Despite advances, neurologic and hematologic complications remain a concern. There were concerns over increased stoke with the newer device, likely due to challenges in postoperative blood pressure management.

The best pump currently available is a fully magnetically levitated left ventricular device with centrifugal-flow. It has improved survival, less incidence of stroke, and reduced need for replacement compared to the traditional pump.

Current research is focused on appropriate patent selection and minimizing complications, and on better selection of existing devices instead of new device development. Future LVAD development is focused on less traumatic blood flow through the device as most patients eventually develop Von Willebrand syndrome as a result of this traumatic flow.

Cardiogenic shock management remains a challenge despite revascularization advances. Mortality rates of 50% for ACS-MI with cardiogenic shock are discouraging. Mortality increases with the number and doses of inotropes and vasopressors.  Early recognition is key, yet cardiogenic shock is not a clear-cut diagnosis. Patients often present with a mixed clinical picture. Important research includes improving identification and triage of patients in the field who are in cardiogenic shock to tertiary facilities that offer these assistive devices. Temporary mechanical support can offer these patients a bridge to long-term management or transplantation.

Extracorporeal membrane oxygenation (ECMO) for pulmonary support is indicated as adjunct treatment for respiratory failure such as severe ARDS, H1N1 flu, and acute right heart failure. Unfortunately, ECMO is highly invasive and expensive but beneficial for select patients. Complications include bleeding, limb ischemia, and neurologic. No more large randomized control trials will likely occur due to cost, but investigation of resource utilization and minimizing side effects will be meaningful.

Noreen Murphy, MD, University of Wisconsin School of Medicine and Public Health, warned the audience about what a world without effective antibiotics looks like – a somber reality we may soon face.

Why has the pipeline for new antibiotic development dried up? The FDA drug approval process is lengthy and expensive. There is no financial return for pharmaceutical drug companies with antibiotic development. Other drugs require chronic or long-term use, such as chemotherapy or cardiovascular drugs, but antibiotics are typically stopped within 10 days. Appropriate antibiotic stewardship calls for safeguarding specialized antibiotics for appropriate patients; hence widespread use of newly developed antibiotics does not occur. And drug companies are following the money.

New non-traditional treatments are on the horizon that enhance patient immune response, but are not likely to replace antibiotic therapy. These therapies include vaccines, monoclonal antibodies, probiotics, virulence disruptors, lysins, antibiotic potentiators, and immunomodulators.

New FDA Approved Antibiotics:

Eravacycline is a broad spectrum tetracycline indicated for complicated intra-abdominal infections. It is not approved for UTIs.

Omadacycline is a broad spectrum tetracycline indicated for community-acquired bacterial pneumonia and acute bacterial skin infections. It does not need renal or hepatic dose adjustments.

Plazomicin is an aminoglycoside indicated for complicated UTIs and for ESBL and carbapenem-resistant enterobacter.

Delafloxacin is a fluoroquinolone primarily used for acute skin and soft tissue infections. It is unique because it works in lower pH environments, such as abscess.

Meropenem/Vaborbactam is used for complicated UTI and carbapenem-resistant organisms; it costs $1200/day.

Antibiotic stewardship programs help to optimize the treatment of infections and reduce the development of antimicrobial resistance. Key components include education; documentation of dose, duration, and indication of antibiotic use; facility specific treatment plans, and antibiotic time-outs in the ICU.

As a global society, poor antibiotic stewardship is equally important at home and abroad.  Dr Murphy reminded, “Where there is no transmission of infection, there is no need for antimicrobial treatment, thus reducing the development of resistance.”  She reminded the audience locally of the importance of good hand hygiene, timely removal of indwelling catheters, immunizations, appropriate food management, and condom use. Global considerations include improved access to medical care and improved sanitation with access to clean water. Only with effective stewardship and prevention, can we stay ahead of the ever-changing antimicrobial resistance challenges.

*Coverage from the SOCCA Education Session I: Critical Advances, Critical Care during the SOCCA 2019 Annual Meeting