Risks of Bleeding and Transfusion January 7, 2018 Henry Green, MD, FACC, FACP

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1 Risks of Bleeding and Transfusion January 7, 2018 Henry Green, MD, FACC, FACP Introduction Antithrombotic drugs are protective in acute coronary syndromes, reduce the risk of embolism in atrial fibrillation, and are used to prevent coronary stent thrombosis. Thus, they are often used in various combinations in cardiac patients. Unfortunately, all of them carry a risk of bleeding. Anemia and bleeding are also frequent occurrences with coronary bypass surgery. Bleeding is associated with both a short-term and a long-term increase in mortality. While the majority opinion holds that this relationship is causal, it has not been scientifically established. Management often involves blood transfusions, which have risks of their own. Most bleeding is iatrogenic. In choosing a management approach, it is important to consider the patient's relative risks of bleeding and thrombosis. Consequences of bleeding There is no standard definition for major bleeding. Some criteria include intracranial bleeding, gastrointestinal bleeding, bleeding into another vital organ, access site hemorrhage requiring intervention, 5 cm hematoma, drop in Hgb of 4 g, reoperation for bleeding, transfusion of at least 2 units, bleeding leading to hospitalization, hemodynamic compromise, etc. The incidence of significant bleeding after treatment of non-st-elevation acute coronary syndromes ranges from 1 to 10%, depending on the definition used and the population under study. However even minor bleeding leads to increased risk. Bleeding can be immediately fatal, as in the case of intracranial bleeding, hypotension, ischemia, or arrhythmias; but there are less obvious consequences as well. Anemia and hypoperfusion reduce oxygen delivery. Tachycardia and increased stroke volume increase oxygen demand. Reflex stimulation of the neurohormonal system results in wall stress, remodeling, interstitial fibrosis, and myocyte loss. Bleeding prompts the physician to withhold antithrombotic therapy, which can lead to further ischemia. ACE inhibitors are also withdrawn. Even in the absence of such occurrences, major bleeding is an independent predictor of 30-day, 6-month and 1-year mortality. Eikelbloom et al reported a five-fold increase in the risk of death. Steinberg found an 8.1% incidence of all-cause mortality at 30 days.the more serious the bleed, the greater the hazard. Nonfatal complications, such as stroke, stent thrombosis and myocardial infarction are also increased. There are a number of proposed explanations for this. Platelet activation can occur. Experimental evidence suggests that increased generation of erythropoietin due to bleeding may induce a prolonged prothrombotic state by activating platelets and inducing plasminogen activator inhibitor-1. The more severe the bleeding, the greater is this effect. In addition, once bleeding has occurred, physicians may be more likely to withhold antithrombotic agents. It is not entirely clear to what extent these events are related to transfusion, comorbidities, or the bleeding itself. Complications of transfusions It has long been recognized that blood transfusions can cause hemolytic reactions and coagulopathy. Other transfusion-related complications include acute lung injury, 1

2 immunosuppression, and transmission of infection. More recently, other complications have been recognized. Transfusion itself is associated with increased in-hospital and one-year mortality. The 30-day mortality may increase as much as ten-fold. However, there is not clear evidence of a causal relationship at present. Chatterjee et al found an increased mortality in patients with acute coronary syndromes who received liberal transfusions, compared with those who had limited or no transfusions (hazard ratio 2.25). Rao et al came to similar conclusions. In contrast, Heddle et al found no difference in mortality whether stored or fresh blood was transfused. However they could not determine if there was a difference in non-fatal events. Stored red cells become depleted of 2,3 diphosphoglycerate, resulting in a high oxygen affinity. Thus, transfused blood does not deliver oxygen efficiently. Normal red cells are capable of distributing nitric oxide to microvascular cells, promoting vasodilatation in zones of hypoxia. They lose this ability with storage. In addition, red cells in banked blood are less deformable, and cannot traverse smaller capillaries, which can lead to plugging of those vessels. They also acquire other undesirable properties (fragility, aggregability, increased adhesion to the endothelium). These defects worsen with increasing duration of storage. Platelet reactivity is increased as well as increased aggregation. Banked blood also contains cytokines, which can induce tissue factor production, and activate coagulation. Several other procoagulant properties of stored red cells have been suspected. These detrimental effects increase with the duration of storage, which may be up to 42 days. It has been demonstrated that older banked blood is associated with a higher mortality after cardiac surgery than newer blood. In spite of these observations, a large study by Halmin et al did not show increased mortality related to length of storage. A number of attempts are currently being made to improve the safety of transfusions. These include correction of intracellular ph, restoration of the depleted components and removal of leukocytes, Recommendations While we surely do not want our patients to bleed to death, some restraint should be exercised in prescribing transfusions. An exception might be the older patient, or those who have had an acute myocardial infarction. Doyle suggests that a specific value of hemoglobin as such should not automatically prompt a transfusion without considering the clinical settings. Patients with evidence of ischemia would likely benefit from transfusion, while those who are stable have little to gain. A restrictive transfusion policy may be in the best interests of many patients. A euvolemic patient with a hemoglobin of 9 g/dl will usually do well, unless there is ongoing myocardial ischemia. It is generally agreed that transfusion is not of value when the hemoglobin is greater than 10 g/dl, and possibly of benefit when it is less than 6 g/dl. Between these values, treatment is generally based on comorbidities and risks of organ ischemia (Shander).The 2

3 American College of Physicians recommends withholding transfusions if the hemoglobin is greater than 7 to 8 grams. Guidelines differ among authoritative groups, particularly in the case of patients with acute coronary syndromes (see Carson et al). Treatment should be individualized, based on each patient s risk of bleeding versus risk of thrombosis. Various parameters have been employed in this regard. Some of the risk factors for clotting are also potential risk factors for hemorrhage. In some cases, patients at high risk for bleeding might be considered for medical therapy rather than revascularization. In others, the operative technique can be modified when indicated. The selection of aggressive antithrombotic therapy is appropriate in some but not all patients. The CRUSADE bleeding score, has been found to be effective in predicting risk in non-stelevation myocardial infarction. It is available at Ducrocq et al developed the following risk score to anticipate the likelihood of significant bleeding in patients receiving antithrombotic therapy over the subsequent two years. They had no explanation for reduced risk in patients with hypercholesterolemia. Factor Points Age Peripheral arterial disease 1 Congestive heart failure 2 Diabetes 1 Hypercholesterolemia absent 1 Hypertension 2 Current smoking 2 Former smoker 1 ASA 1 Other antiplatelet 2 ASA + other antiplatelet 3 Oral anticoagulants 4 Total points 2 year risk % % % % There is a marked increased bleeding risk with a score above 10 Very recently, the HAS-BLED score (Lip et al) has been developed which assigns one point each to the following risk factors: 1. Hypertension - SBP > Abnormal renal or liver function (1 point each) CrCl < Stroke before entry 4. Bleeding history history of clinically significant bleeding 5. Labile INR - < 60% of the time in therapeutic range 6. Elderly age > 75 at entry 7. Drugs aspirin or NSAID (one point), current alcohol use > 20 U/week ( one point) In their study, the risk of bleeding on warfarin ranged from 1% for a score of 0 to about 10% if the score was 4 points. 3

4 Additional bleeding risks have been proposed by other authors, such as female sex, increased heart rate, recent gastrointestinal bleeding, and the use of the intraaortic balloon pump. Hochholzer et al found that the use of GIIb/IIIa inhibitors also increased the risk. Chen states that, in the decision to use anticoagulants for atrial fibrillation, more weight should be given to stroke risk than the risk of bleeding. It is not known whether these scores will apply with the use of the new oral antithrombotic agents, such as dabigatran. Avoiding bleeding and anemia Acute coronary syndromes (ACS) Even in the absence of an invasive strategy, the interventions used for managing ACS usually involve heparin, platelet antagonists and often thrombolytic therapy. Any of these can promote gastrointestinal, intracranial or other bleeding manifestations. Salisbury et al studied patients with acute myocardial infarction who were not anemic on admission, but whose hemoglobin decreased during hospitalization. The anemia was due to a variety of factors, such as percutaneous interventions or even from frequent blood draws. Regardless of the cause, the anemia often persisted after discharge. It was associated with increased morbidity and mortality. The more severe anemias resulted in the worst outcomes. Another concern is that guideline-driven therapy promotes the use of oral anticoagulants in many patients with atrial fibrillation. Some of them receive antiplatelet drugs or a glycoprotein IIb/IIIa inhibitor because of concomitant coronary artery disease. This increases their risk of bleeding. There seems to be a lack of consensus regarding this dilemma. Paikin offers a reasonable compromise: 1. If possible, avoid drug-eluting stents in patients who require warfarin. 2. Limit clopidogrel therapy to the shortest time consistent with the guidelines. 3. Use the lowest effective dose of aspirin (or eliminate it see below). 4. Use acid-suppressing therapy to reduce the risk of gastrointestinal bleeding. 5. With warfarin, aim for an INR of In patients with low risk of stroke or high risk of bleeding, do not use warfarin. 7. In those with high risk of stroke but low risk of bleeding use triple therapy (warfarin, aspirin and clopidogrel). The WOEST trial concluded that patients who require both warfarin and antiplatelet therapy have less bleeding and equally good outcomes if treated without aspirin (i.e. given clopidogrel and warfarin alone). The selection of antithrombotic agents should be guided in part by the risk of bleeding. Dosing of drugs, especially GIIb/IIIa inhibitors, must take into account the patient s body weight, age and renal function. Fondaparinux is a safer drug than heparin from the standpoint of bleeding, although it can result in catheter thrombosis. 4

5 The used of bivalirudin instead of heparin plus GIIb/IIIa inhibitors is associated with a nonsignificant (8%) increase in MI, but a highly significant reduction in major bleeding (50%). Both bleeding and myocardial infarction have comparable effects on mortality. The tradeoff appears to favor its use, at least in patients who have higher risk of bleeding. Prasugrel and ticagrelor are more effective antiplatelet drugs than clopidogrel, but are associated with a higher incidence of major bleeding. Intracranial bleeding is a risk in patients with a history of stroke or transient ischemic attack, and they are contraindicated in this group. The risk is also greater in patients over 75 years of age, although some suggest that a 5 mg dose of prasugrel might be used in this group. These drugs can be advantageous in patients who are at greater risk of infarction, provided this is not outweighed by the bleeding risk. Coronary artery bypass surgery (CABG) In the case of cardiac surgery, preoperative anemia itself is generally not considered a risk factor for an adverse outcome. Rather a poor prognosis is more apt to be due to associated comorbidities. If surgery can be postponed, anemia might be corrected preoperatively with iron and/or erythropoietin. Many patients tolerate anemia for several weeks, while their hemoglobin is restored with iron therapy. This may not apply as well to older patients. Most cardiac surgical procedures are done using extracorporeal circulation. Priming the pump requires the addition of fluids, resulting in hemodilution and lowering the hematocrit. If the patient was already anemic, red blood cells may also be added. In addition, blood loss during surgery is inevitable. A number of approaches may limit blood loss during surgery. Off-pump coronary bypass operation is one alternative. The use of a bypass pump that requires minimum priming volume offers the advantage of less hemodilution. Blood conservation techniques should always be used. Hajjar et al performed a randomized, double-blinded controlled trial and found that a liberal transfusion policy (maintaining hematocrit over 30%) was non-inferior to a restrictive one (target hematocrit 24%). Of interest is that they used fresh red cells (mean storage time 3 days). In contrast, Mazer et al found that restricting transfusions to patients with a hemoglobin of < 7.5 g was non-inferior to a more liberal policy in patients undergoing cardiac surgery. Percutaneous intervention (PCI) The femoral approach commonly results in hematomas at the puncture site. Even this has been found to be non-trivial. Post-procedural arterial compression is the usual control measure. The problem can be lessened by the application of closure devices, although they are not perfect. Even retroperitoneal bleeding can occur, often with disastrous results. When a femoral approach is used, it should be done under fluoroscopic or ultrasound guidance to reduce the chance of retroperitoneal hemorrhage. Use of a smaller sheath also reduces the likelihood of significant bleeding. Use of the radial artery approach appears to be the single most effective way to reduce major bleeding with PCI. 5

6 The decision to transfuse is influenced by the clinical presentation of the patient as well as the completeness of revascularization. Probably a more liberal approach to transfusion is appropriate in the setting of an acute myocardial infarction or ongoing ischemia. Patients initially presenting with anemia are more vulnerable. If feasible, correcting the anemia with iron and/or erythropoietin prior to intervention could be appropriate. Erythropoietin Overzealous use of this drug can result in life-threatening cardiovascular complications, including myocardial infarction, stroke and thromboembolism. Total correction of anemia is not advised. The product brochure carries a boxed warning, which should be consulted. The American College of Physicians recommends against using erythropoiesis-stimulating agents in patients with mild to moderate anemia and heart failure or coronary artery disease. Management of bleeding There is significant risk in interruption of antithrombotic or antiplatelet drugs following revascularization procedures. If possible, bleeding should be controlled by local treatment such as pressure or packing. Antithrombotic and antiplatelet drugs can then be reintroduced as soon as possible. Gastrointestinal bleeding can be treated endoscopically or with the use of a proton pump inhibitor. Reversal of antithrombotic agents can be done in the following ways: Unfractionated heparin: infuse protamine sulfate at a dose of 1 mg per 100 u of unfractionated heparin given over the previous 4 hours. The infusion should be less than 100 mg over 2 hours, with 50% of the dose given initially and subsequent doses titrated according to bleeding response. Protamine sulfate is associated with a risk of hypotension and bradycardia, and for this reason it should be given no faster than 5 mg/min. Time since last heparin dose: Protamine dose per 100 units of heparin: 0-30 minutes mg minutes mg > 2 hr mg Low-molecular-weight heparin (LMWH): can be inhibited by 1 mg of protamine sulfate for each 1 mg of LMWH given over the previous 4 hours. At 8-12 hours, half that dose is recommended. After 12 hours, no protamine is indicated. However, protamine sulfate only partially neutralizes the anticoagulant effect of LMWH. In cases in which protamine sulfate is unsuccessful in abating bleeding associated with LMWH use, guidelines allow for the use of recombinant factor VIIa (NovoSeven). This agent has not been fully studied, and is very costly (a single dose of 40 μg/kg costs from $3,000 to $4,000). It has also been reported to result in increased risk of thrombotic complications. Fondaparinux: in healthy volunteers given fondaparinux, recombinant factor VIIa normalized coagulation times and thrombin generation within 1.5 hours, with a sustained effect for 6 hours. Aspirin: transfuse 1 unit of platelets. Desmopressin has also been used. 6

7 Clopidogrel: transfuse 2 units of platelets. Other treatments that can be considered include desmopressin, antifibrinolytic drugs (aprotinin, aminocaproic acid, tranexamic acid), and recombinant factor VIIa, although none of these treatments directly reverse the plateletinhibitory effects of clopidogrel. Glycoprotein IIb/IIIa inhibitors. Eptifibatide and tirofiban: transfusion of platelets is ineffective. Eptifibatide has a half-life 2.5 hr. That of tirofiban is 2 hr. Abciximab can be treated with platelet transfusion. References: Pocock SJ et al. Prognostic modeling of individual patient risk and mortality impact of ischemic and hemorrhagic complications. Circulation 2010; 121:43-51 Van de Werf F. Balancing benefit and bleeding risk of antithrombotic agents in the individual patient with an acute coronary syndrome. Circulation 2010; 121:5-7 Eikelboom JW and Hirsh J. Bleeding and management of bleeding. European Heart Journal Supplements (2006) 8 (Supplement G), G38-G45 Gardner TJ. To transfuse or not to transfuse. Circulation 2007; 116: Doyle BJ et al. Bleeding, blood transfusion, and increased mortality after percutaneous coronary intervention. Jour Am Coll Cardiol 2009;53: Ducrocq G et al. Risk score to predict serious bleeding in stable outpatients with or at risk of atherothrombosis. Eur Heart J 2010; 10: Nikolsky E et al. Development and validation of a prognostic risk score for major bleeding in patients undergoing percutaneous coronary intervention via the femoral approach. Eur Heart J 2007; 28: Mehran R et al. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol 2010; 55: An on-line bleeding risk calculator is available at Gutierrez A and Rao SV. Incidence, outcomes and management of bleeding in non-st-eleation acute coronary syndromes. Cleveland Clin J Med 2010; 77: Hajjar LA et al. Transfusion requirements after cardiac surgery. JAMA 2010; 304: Shander AS and Goodnough LT. Blood transfusion as a quality indicator in cardiac surgery. JAMA 2010; 304: Paikin JS et al. Triple antithrombotic therapy in patients with atrial fibrillation and coronary artery stents. Circulation 2010; 121: Lip GHY et al. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol 2011; 57: Chen WT et al. Association between CHADS 2 risk factors and anticoagulation-related bleeding. Mayo Clin Proc 2011; 86: Salisbury AC et al. Recovery from hospital-acquired anemia after acute myocardial infarction and effect on outcomes after hospitalization for acute myocardial infarction. Am J Card 2011; 108: Doyle B. There will be blood. J Am Coll Cardiol Intv 2009; 2:54-55 Feng MC et al. A new riski scheme to predict warfarin-associated hemorrhage. J Am Coll Cardiol 2011;58: Hochholzer W et al. Predictors of bleeding and time dependence of association of bleeding with mortality: insights from the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel thrombolysis in myocardial infarction 38 7

8 (TRITON TIMI 38). Circulation 2011; 123: Eikelboom JW et al. Adverse effects of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114: Subherwal S et al. Admission international normalized ratio levels, early strategies and major bleeding risks among non-st-segment elevation myocardial infarction patients on home warfarin therapy. Circulation 2012; 125: Mehran R et al. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol 2010; 55: Bavry AA summary of the WOEST trial published on line at Chatterjee S et al. Association of blood transfusion with increased mortality in myocardial infarction. JAMA Intern Med 2013;173: Rao SV et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004; 292: Qaseem A et al. Treatment of anemia in patients with heart disease: a clinical practice guideline from the American College of Physicians. Ann Int Med 2013; 159: Singh D et al. Anticoagulation and antiplatelet therapy in acute coronary syndromes. Cleveland Clinic J Med 2014; 81: Salpeter SR et al. Impact of more restrictive blood transfusion strategies on clinical outcomes. Am J Med 2014; 127: Singh M. Bleeding avoidance strategies during percutaneous coronary interventions. J Am Coll Cardiol 2015; 65: Ng VG et al. Impact of bleeding and bivalrudin therapy on mortality risk in women undergoing percutaneous coronary intervention. Am J Cardiol 2016; 117: Smilowitz NR et al. Association between bleeding, anemia and transfusion with long-term mortality following noncardiac surgery. Am J Med 2016; 129: Heddle NM et al. Effect of short-term vs. long-term blood storage after transfusion. N Engl J Med 2016; 375: Steinberg BA et al. Management of major bleeding in patients with atrial fibrillation treated with non-vitamin K antagonist oral anticoagulants compared with warfari in clinical practice. Am J Cardiol 2017; 119: Halmin M et al. LengthofStorageofRedBloodCellsandPatientSurvivalAfter BloodTransfusion. Ann Int Med 2017;166: Carson JL et al. Indications for and adverse effects of red-cell transfusion. N Engl J Med 2017; 377: Mazer CD et al. Restrictive or liberal red-cell transfusion for cardiac surgery. N Engl J Med 2017; 377: