Anticoagulation in type 2 myocardial infarctions: Lessons learned from the rivaroxaban in type 2 myocardial infarctions feasibility trial.

Background: Type 2 myocardial infarction (T2MI) occurs when myocardial oxygen demand exceeds myocardial oxygen supply. T2MIs occur more frequently and have worse outcomes compared to Type 1 myocardial infarction caused by an acute plaque rupture. No clinical trial evidence is available to guide pharmacological therapies in this high-risk population. Methods: The Rivaroxaban in Type 2 Myocardial Infarction (R2MI) trial (NCT04838808) was a trainee-led, pragmatic, pilot study that randomised patients with a T2MI to either rivaroxaban 2.5 mg twice daily or placebo. The trial was stopped early due to low recruitment. Investigators explored the challenges of conducting the trial in this population. This was supplemented by a retrospective chart review of 10,000 consecutive troponin assays undertaken during the study period. Results: Over a 1-year period, 276 patients with T2MI were screened for inclusion of which only 7 (2.5%) were randomised in the trial. Study investigators identified trial design and participant population factors that limited recruitment. These included: heterogeneity of patient presentation, poor clinical prognosis, and lack of dedicated non-trainee study personnel. The major limitation to recruitment was the frequency of identified exclusion criterion. The retrospective chart review identified 1715 patients with an elevated high-sensitivity troponin level, of which 916 (53%) were adjudicated to be related to T2MI. Of these, 94.5% possessed an exclusion criterion for the trial. Conclusion: Patients with a T2MI are challenging to recruit into clinical trials involving oral anticoagulation. Future studies should account for only ∼1 in every 20 screened individuals being a candidate for study recruitment.

Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice.

Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO2 and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia.

Plasma methemoglobin as a potential biomarker of anemic stress in humans.

PURPOSE: Transfusion of allogeneic red blood cells (RBCs) is one of the main treatments of acute anemia secondary to blood loss and fluid resuscitation within the operating room. Decisions to transfuse blood are based largely on intermediate biological markers (hemoglobin, arterial oxygen saturation, blood pressure, heart rate) which may not accurately reflect inadequacy of tissue oxygen delivery. Based on experimental studies, we hypothesized that anemia-induced tissue hypoxia activates adaptive mechanisms which promote local vascular nitric oxide (NO) production to improve tissue perfusion and survival during acute anemia. Hemoglobin (Hb) oxidation to methemoglobin (MetHb) may be a byproduct of such local NO production. Therefore, we tested the hypothesis that MetHb is a biomarker of hypoxic-anemic stress during acute hemodilution associated with cardiopulmonary bypass. METHODS: With institutional ethics approval, routine laboratory arterial blood gas and co-oximetry values were obtained from 295 patients undergoing heart surgery during February 1 to September 30, 2010, and the values were assessed retrospectively. All samples with an arterial oxygen saturation value ≥ 90% were included (n = 1,421). The maximal change in Hb associated with hemodilution on cardiopulmonary bypass was determined within 48 hr of surgery (n = 180). A chart review was performed to determine the incidence of RBC transfusion and exogenous nitrate administration. All anonymous data were analyzed by linear regression to determine the relationship between Hb and MetHb. A Wilcoxon Signed Rank Test and Student's t test were used to determine changes in Hb, MetHb, and carboxyhemoglobin (CarboxHb) levels. All data are presented as mean and significance was assigned at P < 0.05. RESULTS: A significant decrease in Hb [118 (20) g x L(-1) vs 94 (18) g x L(-1)] was associated with an increase in MetHb [0.88 (0.22)% vs 0.95 (0.24)%] (P < 0.001 for both), but not CarboxHb [1.08 (0.47)% vs 1.08 (0.49)%]. Regression analysis revealed a significant relationship between the change in Hb and MetHb (F = 40.3; P < 0.001) but not between the change in Hb and CarboxyHb (F = 0.2; P = 0.694). This correlation was not influenced by RBC transfusion or exogenous nitrate use. CONCLUSIONS: A negative correlation was observed between the change in Hb and MetHb in patients undergoing cardiac surgery and cardiopulmonary bypass. These data support the previously unreported hypothesis that MetHb may be a marker of anemic stress associated with reduced tissue perfusion during acute hemodilution in humans. Further prospective studies are needed to determine if these changes in MetHb are linked to adverse outcomes in patients undergoing cardiac surgery.