Unstable angina / non ST elevation myocardial infarction complications of bleeding and transfusion prognosis


 * ; ; Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.

Prognosis
Regardless of which bleeding definition is utilized, multiple studies have demonstrated a clear association between bleeding in the NSTEMI population and adverse outcomes including death, stroke, MI and unplanned revascularization.

Clinical trial data

 * Moscucci and colleagues examined the GRACE registry of 24,045 patients with ACS (including unstable angina, NSTEMI, and STEMI) and found an association between GRACE major bleeding and increased in-hospital mortality.
 * An analysis by Rao et al., examined 26,452 ACS-patients enrolled in the PURSUIT, PARAGON B, and GUSTO IIb trials and demonstrated an increased in risk between bleeding severity and 30-day and 6-month death.
 * Eikelboom et al., and Manoukian et. al., have described a similar, significant association between major bleeding in NSTEMI and unstable angina patients and adverse outcomes.

Prognosis between TIMI and GRACE scales: Therefore, bleeding defined by clinical events is likely more important in terms of prognosis rather than bleeding defined solely on the basis of reductions in hemoglobin concentration.
 * The prognostic significance of different bleeding definitions (GUSTO vs TIMI) was assessed by Rao and colleagues.
 * Both GUSTO and TIMI bleeding were associated with an increased risk for 30-day death or MI when examined separately. When both definitions were included in the same model, increasing GUSTO bleeding severity was associated with a stepwise increase in the adjusted hazard of death or MI, whereas TIMI bleeding did not correlate with prognosis.

Mechanisms of Bleeding and Increased Mortality

 * Despite the strong association between bleeding and adverse ischemic events, the direct causality of bleeding complications and adverse ischemic events remains uncertain.

1. Anemia and Anemia induced Hemodynamic Compromise:
 * During NSTEMI/unstable angina, oxygen delivery to the hypoxic myocardium is normally augmented by a compensatory coronary vasodilatory response.
 * Stenotic coronary vessels are devoid of the vasodilatory response and therefore compensatory increases in heart rate and myocardial contractility are employed to maintain systemic oxygen demands.
 * The pathophysiology underlying poor outcomes in anemic-NSTEMI patients may be explained by the combination of reduced oxygen delivery to the already hypoxic myocardium and the high myocardial oxygen demand secondary to the compensatory increases in heart rate and stroke volume.

'''Bleeding therefore, may worsen myocardial ischemia in the NSTEMI patient by inducing a mild anemia and state of tissue hypoperfusion. The subsequent, compensatory tachycardiac and upregulated myocardial contractility state result in a deleterious, myocardial oxygen supply and demand disparity.'''

2. Potentiation of the inflammatory response:
 * Bleeding events precipitate recurrent ischemic events by potentiating the inflammatory response through activation of the platelet and coagulation cascades.

3. Reception of packed red blood cells:
 * Mechanistic studies have shown that transfusion of red cells paradoxically does not improve oxygen delivery.
 * Stored blood is characterized by an increased affinity for oxygen because of decreased 2,3 DPG levels.
 * Stored RBCs have alterations in their morphology and adhesion properties which many speculate increases the risk of vessel occlusion.
 * Stored RBCs, devoid of NO produces vasoconstriction, platelet aggregation, and ineffective oxygen delivery.
 * Nitric oxide is essential for oxygen uptake into tissues and is the most potent vasodilator.

The synergistic effects of high oxygen affinity and ineffective oxygen delivery of RBC transfusion may account, in part, for poor outcomes among transfused NSTEMI patients.

4. Cessation of antiplatelet and/or antithrombin therapies:
 * Analyzing the GRACE database of NSTEMI patients who suffered major bleeding (n=506) within 2 days of admission, Spencer and colleagues discovered that NSTEMI patients with a bleeding event were less likely to have received ASA, thienopyridines, unfractionated heparin or low-molecular-weight heparin during their hospitalization.
 * Mortality rates among ACS patients who experienced a major bleeding event were higher if aspirin (OR, 7.55 (95% CI, 4.43 to 12.88)); thienopyridines, (OR, 8.91 (95% CI, 4.39 to 18.12)); and unfractionated heparin, (OR, 1.91 (95% CI, 1.09 to 3.36)) were discontinued, compared to NSTEMI patients who experienced a major bleeding event but continued therapy with these agents.