Bleeding is a fairly common and unpleasant complication of therapy among patients with acute coronary syndrome (ACS). Traditionally, it has been thought of as “the price to pay” for such procedures. However, evidence now suggests that such bleeding is preventable and that its prevention is associated with much better patient outcomes.
The incidence of major bleeding in patients with ACS ranges from about 2 to 5 percent. Age, female gender, renal insufficiency and history of bleeding are independent risk factors for an increased risk of bleeding (P<0.01). [Eur Heart J 2003;24:1815-1823]
Another important risk factor for bleeding in patients with ACS is overdosing with antithrombotic therapy, which is actually quite common. Data from the CRUSADEa Initiative found that 26 percent of 18,436 patients with high risk non-ST segment elevation myocardial infarction (NSTEMI) received an excessive dose of glycoprotein (GP) IIb/IIIa inhibitor treatment. Crucially, patients at higher risk of bleeding – women and elderly patients in particular – are more likely to be overdosed. [Circulation 2006;114:1380-1387]
Bleeding risk in patients with cardiovascular disease is not confined to the acute phase of treatment. Dual antiplatelet therapy with aspirin and clopidogrel significantly increased the risk of moderate bleeding over a 12-month period compared with placebo (2.1 percent versus 1.3 percent, respectively; P<0.001) in non-acute patients with stable vascular disease or risk factors for vascular disease. Corresponding rates of severe bleeding were 1.7 percent and 1.3 percent, respectively (P=NS). This study analyzed data from the randomized controlled CHARISMAb trial which involved a total of 15,603 patients. After 1 year, differences in bleeding rates between the two treatment groups were not significantly different. [Circulation 2010;121:2575-2583]
Bleeding associated with high death ratePatients who bleed have a poor prognosis. A pooled analysis of data from more than 30,000 patients with ACS included in three large studies – OASISc Registry, OASIS-2 and the CUREd trial – showed that patients with major bleeding had a five-fold higher risk of death at 30 days compared with those who did not (12.8 percent versus 2.5 percent, respectively; P<0.0001). [Circulation 2006;114:774-782]
In the ACUITYe trial, which involved 13,819 patients with moderate- to high-risk ACS, major bleeding was a significant independent predictor of 30-day mortality (hazard ratio 7.55, 95% CI 4.68 to 12.18; P<0.0001). [J Am Coll Cardiol 2007:27;49(12):1362-1368]
What is particularly interesting is that an analysis of data from the ACUITY study showed that the impact of bleeding was not limited to the short term. Indeed, major bleeding was associated with an increased risk of death for up to 1 year (hazard ratio 3.5, 95% CI 2.7 to 4.4; P<0.001). [Eur Heart J 2009;30:1457-1466]
These findings lead us to believe that bleeding may be triggering certain mechanisms which have a negative impact on long term outcome or survival. Physiological factors that may be associated with morbidity or mortality and which may be directly or indirectly attributed to bleeding include hemodynamic compromise, hyper-adrenergic state, transfusion-induced microcirculatory disorder, nitric oxide depletion, immunologic effects, inflammatory response, and discontinuation of antithrombotic treatment.
The impact of blood transfusionsIt is interesting to note that blood transfusions can have quite a deleterious impact in patients with ACS. Analysis of the ACUITY study data showed blood transfusions to be associated with a 4.5-fold increase in mortality risk. [Eur Heart J 2009;30:1457-1466] These findings are consistent with those from an earlier pooled analysis of data from 24,112 patients with ACS included in GUSTOf IIb, PURSUITg and PARAGONh B trials. This study showed that those who underwent a blood transfusion (N=2,401) had a significantly higher risk of 30-day mortality compared with those who did not receive a blood transfusion (8 percent versus 3.02 percent; P<0.001). [JAMA 2004;292:1555-1562]
Poor outcomes with blood transfusions may occur in part due to alterations in the morphology of red blood cells (RBCs) during the storage of the blood. Indeed, storing blood for any length of time can result in 2,3-diphosphoglycerate depletion (leading to decreased ability to unload oxygen in the microcirculation), nitric oxide depletion (leading to vasoconstriction), and adenosine triphosphate reductions (leading to structural and functional changes in RBCs).
Outcome with blood transfusion may also depend on site of access. A multivariate analysis of the MORTALi trial results showed a significant reduction in 1-year mortality rates when radial versus femoral venous transfusion was used (odds ratio 0.85 [95% CI 0.73 to 0.99; P=0.042]). [Heart 2008;94(
:1019-1025]
Prevention of bleedingReducing the rate of bleeding has been shown to significantly improve outcomes in patients with ACS. [N Engl Med J 2006;354:1464-1476]
As a general guide, several factors should be considered when attempting to minimize the likelihood of any bleeding in such patients. First, the demographic characteristics of each individual patient should be examined in order to define bleeding risk. If antithrombotic agents are indicated, these should be administered at appropriate dosages. Importantly, aspirin should be given at the lowest possible proven dose expected to be effective. Combinations of antithrombotic agents should be avoided unless there is a clear and proven indication for such an approach. For blood transfusions, radial vascular access is preferred over femoral vascular access.
Some existing antithrombotic therapies may cause less bleeding than others in certain patient populations. Furthermore, newer compounds are in development which may have antithrombotic effects without causing unwanted bleeding. The protease-activated receptor (PAR)-1 antagonist vorapaxar [SCH-530348] is one such example. [Eur Heart J 2010;31:17-28; doi: 10.1093/eurheartj/ehp504]
Source: mims.com
