Tranexamic Acid and GI Bleeding

Tranexamic acid is often used to reduce bleeding, particularly after surgery and may reduce bleeding-related death in patients with trauma. It remains unclear if tranexamic acid reduces deaths in patients who present with acute GI bleeding.

An international, multicenter, randomized, placebo-controlled trial examined this question. Adult patients with acute GI bleeding were randomly assigned to either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). The primary outcome was death due to bleeding within 5 days of randomization. 12 009 patients were randomly allocated to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%).

Death due to bleeding within 5 days of randomization occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82-1·18).

Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39).

Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98).

In other words, this large clinical trial showed that tranexamic acid did not reduce death from gastrointestinal bleeding but may result in higher venous thromboembolic events. Thus, IV tranexamic acid is not useful in patients with acute GI bleeding.

Vaso-Occlusive Crisis in Sickle Cell Patients

Hemoglobin S (HbS) is an abnormal form of hemoglobin and is transmitted through genetically from parents to a child. Normal hemoglobin is mostly made up of 4 globin chains; 2 alpha chains and 2 beta chains. The underlying problem is a single mutation in the beta-chain of the hemoglobin where adenine nucleotide is replaced with a thymidine nucleotide resulting in a missense mutation and changing the amino acid glutamate at no. 6 position with valine. This change in amino acids from glutamate to valine results in changes in the 3-dimensional structure of the beta-chain of hemoglobin. These changes include 1) lower affinity for oxygen, 2) ability to join with other hemoglobin molecules and form polymers, 3) increase oxidation of the RBC cell membrane proteins.

Normal hemoglobin gets oxygenated in the lungs and carries oxygen to the tissues. Oxygen is released in the tissues and hemoglobin gets deoxygenated and returns back to the lungs for oxygenation. Normal hemoglobin remains soluble within the RBC throughout this process. On the other hand, deoxygenated HbS starts forming long filamentous through polymerization of hemoglobin molecules. Importantly, the process takes several seconds in fresh red blood cells (RBC) before polymerizations occurs and there is sufficient time for RBCs to return back to the lungs and get oxygenated.

However, some cells continue to get stuck in blood vessels resulting in completion of polymerization and breakdown of RBCs within the vessels (called intravascular hemolysis). This chronic, slow process of premature destruction of RBC in sickle cell patients is the reason for chronic anemia as well as other slowly developing manifestations of sickle cell disease.

In sickle cell vaso-occlusive crisis, large number of blood vessels are blocked resulting in marked pain and morbidity. Typically, the crisis is precipitated by some event, such as dehydration or an infection. The event stimulates the vascular endothelium making them sticky through expression of cell-binding receptors on the surface. These receptors then bind with other receptors on the surface of RBCs, white blood cells, and platelets resulting in blockage of the vessel lumen. The red blood cells with HbS are already primed to binding with other cells through expression of certain proteins as well as exposure of certain lipid products on the surface. Thus, the vaso-occlusive crisis results from the interaction of HbS containing RBC, endothelium, white blood cells, and platelets.

Direct Oral Anticoagulants vs Warfarin in Older Patients With Atrial Fibrillation and Ischemic Stroke

This observational study examined 11,662 patients with atrial fibrillation who had had an ischemic stroke and were anticoagulation naïve, patients discharged while receiving:

1. Direct oral anticoagulants (DOACs) had more days at home post-discharge
2. Were less likely to experience major adverse cardiovascular events, all-cause mortality, all-cause readmissions, cardiovascular readmissions, or hemorrhagic strokes
3. Had a small but significant increase in gastrointestinal bleeding.

Overall, DOACs appear to be an effective and safe treatment option compared with warfarin for patients with atrial fibrillation who have ischemic stroke and may be even more beneficial despite a small in crease in gastrointestinal bleeding.

Perioperative Direct Oral Anticoagulant Use

This study of 3007 patients with atrial fibrillation who were undergoing surgery enrolled patients to have:

1. Direct Oral Anticoagulants (DOACs) were omitted 1-day before a low-bleeding-risk procedure
2. DOACs were omitted 2 days before a high-bleeding-risk procedure
3. Patients with renal impairment had the pre-operative omission duration readjusted

Study investigators found that the perioperative risk of bleeding and arterial thromboembolism were low with this simplified strategy. The 30-day postoperative rate of major bleeding was 1.35% (95% CI, 0%-2.00%) in the apixaban cohort, 0.90% (95% CI, 0%-1.73%) in the dabigatran cohort, and 1.85% (95% CI, 0%-2.65%) in the rivaroxaban cohort. The rate of arterial thromboembolism was 0.16% (95% CI, 0%-0.48%) in the apixaban cohort, 0.60% (95% CI, 0%-1.33%) in the dabigatran cohort, and 0.37% (95% CI, 0%-0.82%) in the rivaroxaban cohort.

DOACs	Bleeding Risk	Arterial Thromboembolism
Apixaban	1.35	0.16
Dabigatran	0.90	0.60
Rivaroxaban	1.85	0.37

Apixaban in ESRD and Atrial Fibrillation

Patients with ESRD (end-stage renal disease) are usually prescribed coumadin when they need anticoagulation; the reason being that we know very little (or not at all) about the effect of new oral anticoagulants in patients with ESRD.

In this study, Siontis et al performed a retrospective cohort study of Medicare beneficiaries with ESRD and atrial fibrillation, the later an indication for anticoagulation. Outcomes were compared between patients who were treated with apixaban versus patients who were treated with warfarin. Authors examined the survival difference between the two groups for stroke or systemic embolism, major bleeding, gastrointestinal bleeding, intracranial bleeding, and death using Kaplan–Meier analyses and hazard ratios (HRs) and 95% CIs were obtained using Cox regression analyses.

Authors found that there was no difference in stroke and systemic embolism between the two groups. However, the group taking apixaban had 28% lower risk of major bleed.

While this is retrospective data, and clinical trial data is lacking, this study will support the use of new oral anticoagulants in ESRD patients.

Antidote for Dabigatran

Until recently, warfarin (also known as Coumadin), a vitamin K antagonist (VKA), had been the only available oral anticoagulant. The use of warfarin has been always complicated by many issues including its narrow therapeutic index and multiple drug and diet interactions affected its safety, compliance, and efficacy. Patients needed regular and close monitoring of the its anticoagulant effect (how thin is blood?). Despite regular monitoring, patients suffered bleeding complications when blood was too thin (supra-therapeutic range) or blood was thin within the desired range but other patient factors (such as trauma/injury) resulted in bleeding.

A very common use of warfarin is for anticoagulation in patients who suffer from atrial fibrillation. With increasing age, the risk of atrial fibrillation increases and atrial fibrillation is common older individuals. Patients with atrial fibrillation can develop a clot in the left atrium of the heart and this clot can dislodge and go to other parts of the body. If this dislodged clot goes to arteries that supply blood to the brain, it usually results in large stroke. The risk of stroke with atrial fibrillation varies from person to person but can be calculated using a CHADS2 score and may vary from 1.8% per year to 18% per year without anticoagulation.

The above noted problems with warfarin prompted the development of new oral anticoagulants that target key coagulation proteins. Within past few years, FDA has approved several new oral anticoagulants that don’t require regular monitoring with blood tests and have very few drug interactions. However, one limitation with these new anticoagulants is lack of an antidote that can quickly reverse the effect of these drugs in cases of emergency, such as when a patient is bleeding. On the other hand, vitamin K can be used to reverse the effect of warfarin. Several pharmaceutical companies and other research groups are trying to develop agents that can effectively reverse the effects of these new anticoagulants.

Pollack and colleagues have published in this issue of the New England Journal of Medicine a trial of such an antidote of dabigatran, an oral thrombin inhibitor that is approved for the prevention of stroke in patients with non-valvular atrial fibrillation and for the prevention and treatment of venous thromboembolism. Investigators used idarucizumab, a monoclonal antibody fragment that binds dabigatran with an affinity that is 350 times as high as that of dabigatran’s affinity with thrombin (a coagulant protein through which dabigatran acts). In blood, idarucizumab binds free and thrombin-bound dabigatran and neutralizes its activity. In this prospective cohort study, investigators examined the safety of 5 g of intravenous idarucizumab and its inhibitory effect on dabigatran in patients who had serious bleeding (group A) or who required an urgent procedure (group B). Investigators determined the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab (primary endpoint).

Of the 90 patients who received idarucizumab (51 patients in group A and 39 in group B), idarucizumab normalized the blood coagulation in 88 to 98% of the patients often within minutes. Concentrations of unbound dabigatran was below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, bleeding was controlled at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated.

As noted above idarucizumab is specific for dabigatran and is unlikely to be effective with other new oral antocagulants. However, various reversal agents and/or strategies, nonspecific to dabigatran, are available to physicians, including prothrombin complex concentrates, activated prothrombin complex concentrates, or recombinant factor VIIa.