A fantastic talk by Steve McGloughlin at a recent ICN Victoria meeting on antibiotics and antibiotic resistance in the intensive care
Persistent life-threatening hemorrhage after administration of idarucizumab. Alhashem HM et al. Am J Emerg Med 2016 June 30 [Epub ahead of print]
Dabigatran (Pradaxa) is a direct thrombin inhibitor approved for stroke and embolism prophylaxis in patients with non-valve-related atrial fibrillation. When it was first released in 2008, a major disincentive to widespread use was the lack of a reliable reversal agent to treat major bleeds, or to administer before necessary invasive procedures.
In October 2015, the U.S. Food and Drug Administration approved idarucizumab (Praxbind), a monoclonal antibody that avidly binds to dabigatran. under its accelerated approval program. As described by an FDA release, this program:
. . . allowed drugs for serious conditions that filled an unmet medical need to be approved base on a surrogate endpoint.”
In the case of idarucizumab, the surrogate end-points involved normalization of laboratory parameters of anticoagulation. As far as I can determine, there have been no studies that demonstrate convincingly any clinical patient-oriented benefit. In fact, in the major study addressing this issue, it took a median of 11.4 hours to restore hemostatis after administration of idarucizumab. There was not control group, so we have no idea if this is better than simple watchful waiting. Clearly, it seems far too long to be useful in true life-threatening hemorrhage.
This case report illustrates the point.
A 65-year-old man recently started on dabigatran for atrial fibrillation presented to the emergency department weakness and dyspnea that started approximately 1 hours before. He gave a history of melena for 3 days. On arrival he ws tachycardia (122 ppm) and hypotensive (BP 74/52 mmHg.)
Digital rectal examination confirmed the presence of melena, and a nasogastric tube returned 300 ml bright red blood that did not clear with irrigation. The patient remained unstable despite administration of fluids and packed red blood cells.
The authors note that a markedly elevated thrombin time (120 sec, reference 15-19 sec) indicated significant dabigatran activity. After idarucizumab (5 gm) was administered intravenously. the coagulation tests improved but the patient remained unstable. Upper endoscopy revealed ongoing hemorrhage from a vessel in the duodenum. Several attempts to control the site of bleeding failed, and the patient ultimately underwent angiography with embolization of the gastroduodenal artery. This successfully stopped the bleeding and the patient was discharged after a 4-day hospital stay.
According to Wikipedia, the hospital acquisition cost of a 5 gm dose of idarucizumab is $3500. Although it clearly improves coagulation lab values, it is not clear if if stops significant or life-threatening hemorrhage, or allows for safer procedures such as hemodialysis.
An excellent post at REBEL EM discussed many of the problems with the major study of idarucizumab mentioned above, including industry sponsorship, lack of power, dicey inclusion criteria, and poor study design without blinding or randomization.
Bottom line: idarucizumab had accelerated approval by the FDA as a reversal agent for dabigatran because of biological plausibility. There is still no real proof of its effectiveness. However, in cases of truly life-threatening hemorrhage, many clinicians will no doubt administer the drug if no other treatment options seem available.
Eduardo Palencia Herrejón
Hospital Universitario Infanta Leonor, Madrid.
REMI, http://medicina-intensiva.com. Julio 2016.
- Surviving Sepsis Campaign International Guidelines for Management of Severe Sepsis and Septic Shock 2012. [PDF]
- Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Cook D, Crowther M, Meade M, Rabbat C, Griffith L, Schiff D, Geerts W, Guyatt G. Crit Care Med 2005; 33: 1565-1571. [PubMed]
- Enunciado: Enfermedad tromboembólica en pacientes críticos
- Sintaxis: thromboembolism[mh] AND critical illness[mh]
In most trauma textbooks, the most commonly injured solid organ is the spleen. There is a lot of work available that tells trauma professionals how to detect and manage spleen injuries. However, the treatment of the sequelae is less clear cut. We know that the platelet count generally rises after spleen injury, and especially if it is removed. We think we know that we should be on alert if the platelet count goes over 1 M per microliter (ul) to avoid thrombisis.
What happens during the usual hospital course? Is venous thrombosis actually a problem? A group at St. Michael’s Hospital in Toronto performed a 5 year retrospective review of their patients with splenic injury to try to answer these questions. Children and patients with known pre-existing coagulopathy or that were taking anticoagulants were excluded. All were managed with prophylactic low molecular heparin, although the specific product or protocol were not described.
Here are the factoids:
- A total of 156 patients were enrolled over 5 years. - This is a relatively low number (31/year). In contrast, here in bustling metropolitan St. Paul we see 80-100 per year.
- Nonoperative management was performed in 84% of cases, with angio-embolization added in another 8%. The other 8% were taken to OR, where most underwent splenectomy. - This is spot on with national data. However, looking at their injury grade breakdown, it seems like they take out a higher than usual number of low grade spleens.
- Platelet count rose steadily after admission, peaking at day 16-17.
- Splenectomy patients had a mean peak platelet count of 890K/ul.
- Nonop management patients had a mean peak of 604K/ul.
- Extreme thrombocytosis (counts > 1M/ul) occurred in 25 patients (16%). It occurred in 41% of splenectomy patients, but only 6% of nonop patients.
- Although DVT and PE occurred in these patients (8%, which seems a bit high), there was no association with thrombocytosis, extreme thrombocytosis, or aspirin use. - This is most likely due to the small size of the study.
Bottom line: This small study provides some interesting and important information regarding the platelet count trend after splenic injury. Although there was not enough power to look at the association with DVT, PE, and the value of aspirin treatment for extreme thrombocytosis, the platelet count trend info was very interesting. It looks like we should be checking a platelet count about 2-3 weeks after injury to make sure it’s not reaching extreme levels. This can be scheduled during their postop or post-discharge visit. A reminder should also be sent to the primary care physician to be on the lookout for extreme thrombocytosis for the first three weeks post-injury.
Reference: Thrombocytosis in splenic trauma: In-hospital course and association with venous thromboembolism. Injury, in press, 2016.