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Mechanism of hemostasis defects and management of bleeding in patients with acute coronary syndromes
European Journal of Internal Medicine 21 (2010) 254–259
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European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Review article
Mechanism of hemostasis defects and management of bleeding in patients with acute coronary syndromes Pier Mannuccio Mannucci a,⁎, Massimo Franchini b a b
A. Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Medicine and Medical Specialties, IRCCS Cà Granda Foundation Maggiore Policlinico Hospital, Milan, Italy Immunohematology and Transfusion Center, Department of Pathology and Laboratory Medicine, University Hospital of Parma, Italy
a r t i c l e
i n f o
Article history: Received 25 January 2010 Received in revised form 5 March 2010 Accepted 10 March 2010 Available online 14 April 2010 Keywords: Hemostatic agents Blood transfusion Acute coronary syndromes Bleeding
a b s t r a c t The main cause of the hemostasis defects and related bleeding complications in patients with acute coronary syndromes (ACS) are the intake of multiple antithrombotic drugs, alone or concomitantly with invasive procedures such as coronary angiography and percutaneous coronary intervention (PCI). Antithrombotic drugs that impair several phases of hemostasis (platelet function, coagulation, and fibrinolysis) are causing bleeding particularly in elderly patients, in those underweight and with comorbidities such as renal insufficiency, diabetes, hypertension and malignancy. Identification of patients at high risk of bleeding is the most important preventive strategy, because the choice and dosages of drugs may to some extent be tailored to the degree of risk. Transfusions of blood products, which may become necessary in patients with major bleeding, should be used with caution, because they are associated with adverse cardiovascular events. To reduce the need of transfusion, the hemostatic drugs that decrease blood loss and transfusion requirements in cardiac surgery (antifibrinolytic amino acids, desmopressin, and recombinant factor VIIa) might be considered. However, the efficacy of these drugs in the control of bleeding complications is not unequivocally established in ACS and there is concern for an increased risk of thrombosis. In conclusion, evidence-based recommendations for the management of bleeding in patients with ACS are currently lacking, so that prevention through accurate assessment of the individual risk is the most valid strategy. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction In acute coronary syndromes (ACS) excessive bleeding may occur because patients have multiple hemostasis defects, owing to the inhibition of coagulation by anticoagulants such as heparins and direct thrombin inhibitors and of platelet function by inhibitors of aggregation such as aspirin, clopidogrel and anti-glycoprotein IIb/IIIa [1,2]. A hyperfibrinolytic state is induced by the therapeutic administration of tissue plasminogen activators or other fibrinolytic drugs to obtain thrombolysis. Cardiac surgery is another clinical condition typically associated with major blood loss, related to the large size of the surgical wound, decrease in platelet number during the circulation of blood in the extracorporeal oxygenator, hypocoagulability due to the use of heparin and its incomplete neutralization after pump discontinuation and acquired defects of platelet function often accompanied by hyperfibrinolysis [3,4]. In this review, we are analyzing current knowledge on the mechanism and management of bleeding complications in patients with ACS, focusing on preventive measures as well as on the potential therapeutic role of hemostatic
⁎ Corresponding author. Via Pace 9, 20122 Milan, Italy. Tel.: +39 02 55035421; fax: +39 02 50320723. E-mail address: [email protected] (P.M. Mannucci).
drugs. The benefits and risks of the latter drugs, well established in the frame of the complex defects of hemostasis occurring in cardiac surgery, are going to be used as a proxy of their potential use in patients with ACS who are bleeding. 2. Bleeding in acute coronary syndromes Bleeding complications in ACS are likely to increase in the next future, owing to the increasing age of the patient population, the availability of more and more potent antithrombotic drugs and the more and more extensive use of revascularization procedures. Bleeding may range from minor (e.g., nose bleeding, oozing from venous access sites) to life-endangering gastrointestinal, intracranial and retroperitoneal hemorrhages. That the combined use of multiple drugs which impair various phases of hemostasis is the leading cause of bleeding in ACS was recently confirmed by a large registry-based study carried out in Denmark. This study has clearly shown that the risk of fatal and non-fatal bleeding is proportional to the number and type of antithrombotic drugs used in patients with myocardial infarction [5], with an approximately 4-fold increased risk with triple therapy (two antiplatelet agents and an anticoagulant) compared with aspirin alone. Multiple antithrombotic drugs are used during and after PCI with stent deployment, a procedure carried out in 60 to 70% of patients with ACS who undergo diagnostic coronary angiography.
0953-6205/$ – see front matter © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2010.03.010
P.M. Mannucci, M. Franchini / European Journal of Internal Medicine 21 (2010) 254–259
Obviously these invasive procedures dramatically increase the risk of bleeding, that is more frequent in patients at high pre-procedural risk such as the elderly, the underweight, those with renal insufficiency and when excessive dosages of antithrombotic agents are administered [6]. Bleeding complications are more frequent in women, perhaps because of their smaller body weight in average and often older age than men at the time of occurrence of ACS. However, sexbased differences in vessel and blood function may contribute to increased bleeding rates in women. Concomitant anemia may also increase the risk of hemorrhagic complications in both sexes [7]. Major or moderately severe bleeding has a negative effect on prognosis in patients with ACS, as established by meta-analysis, large registries and clinical trials. Major bleeding is associated with an approximately 5-fold increased risk of death at 30 days, a 5-fold increase in myocardial infarction and a 3-fold increase in ischemic stroke [8–11]. Even though some believe that the relationship between bleeding and these adverse outcomes is not causal and that excess mortality is explained by more frequent comorbidities in bleeders [12], the perceived clinical relevance of this complication has recently prompted the addition of bleeding to the traditional triad of events (death, MI, and urgent revascularization) employed to evaluate the overall effect of antithrombotic drugs in patients with ACS undergoing PCI [13].
3. Use of blood transfusion Although blood transfusion may be a life-saving procedure for patients with hypovolemic shock, evidence of its general efficacy in ACS patients is not favorable [8]. Data from 3 large clinical trials totaling 24,112 patients with ACS were included in a meta-analysis to establish whether or not there was an association between blood transfusion and outcomes in patients with moderate to severe bleeding [14]. The need for transfusion was associated with an approximately 4-fold increased risk for 30-day mortality, even after adjustment for other predictive factors such as baseline and nadir hematocrit, the type of invasive procedures and comorbidities. Even though there are also contrasting data showing a favorable effect of blood transfusion on the rates of adverse outcomes [15], the intensive and liberal use of transfusions with the goal to maintain normal hemoglobin levels should be adopted with caution. Indeed, a Cochrane systematic review indicates that in surgical and medical patients needing red cell transfusion a restrictive transfusional regimen is associated with a 20% lower mortality and a 24% lower rates of cardiovascular events (myocardial infarction, arrhythmias, cardiac arrest, pulmonary edema, stroke and angina) [16]. Several pathophysiologic mechanisms may underlie the increased risks carried by transfusions, such as alterations in erythrocyte deformability, microvascular impairment, vasoconstriction, nitric oxide depletion in stored blood, alterations in oxygen affinity due to high 2,3-diphosphoglyceric acid levels and decrease in oxygen delivery to tissues [17]. These alterations may also explain the increased risk of postoperative complications and reduced survival after cardiac surgery when transfused red cells have been stored for prolonged periods [18]. A number of studies have documented the beneficial effect of leukocyte depletion (by means of filtration of transfused blood products) on the postoperative mortality in patients undergoing cardiac surgery [19,20]. For instance, in a randomized controlled trial [19], 7.8% of 305 patients receiving non-white cell (WBC)-reduced red cells died within 60 days after cardiac surgery, compared with 3.5% of 604 subjects receiving WBC-reduced cells. The postulated mechanisms of the benefits of leukoreduction in cardiac surgery include lower rates of postoperative infection, perhaps due to immunomodulatory effects of WBC in transfused blood, lack of alloimmunization against HLA antigens and of the systemic inflammatory response caused by neutrophils exposed to artificial surfaces in the extracorporeal circuit [21]. It must be emphasized again that the aforementioned advantages of leukoreduc-
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tion in the cardiac surgery setting can only be taken as a proxy of the advantages that transfused medical patients with ACS may obtain. 4. Prevention of bleeding Concerns on the increased mortality rate associated with major hemorrhage and the adverse effects of blood transfusion in patients with ACS emphasize the role of prevention, which should be tailored to the patient's individual risk of bleeding. Evaluation of this risk is based upon knowledge that there are comorbidities and/or patient features that increase this risk during antithrombotic therapy for ACS: older age (higher than 75 years), female sex, low body weight, renal insufficiency, severe hypertension, cerebrovascular disease, diabetes and alcoholism. Malignancy and previous gastrointestinal bleeding are also strong predictors of bleeding. There have been efforts to combine several risk factors in the attempt to develop bleeding risk scores meant to facilitate the choice and dosage of antithrombotic drugs for the medical treatment of ACS with or without PCI. For instance, a bleeding score validated in a large number of patients with ACS in the frame of CRUSADE [22] includes eight parameters as predictors of bleeding (hematocrit on admission, creatinine clearance, female sex, signs of congestive heart failure, peripheral vascular disease, diabetes, systolic blood pressure and heart rate on admission) (Table 1). According to CRUSADE, the risk of bleeding ranks from very low (score less than 20, predicted rate of major bleeding 3.1%), low (score between 21 and 30, predicted bleeding rate 5.5%), moderate (score 31–40, 8.6%) to high (score 41–50, 11.2%) and very high (score higher than 50, 19.5%) [22]. The relationships between different antithrombotic drugs, their dosage, the characteristics of the patient population, the clinical condition that led to the use of these drugs and the risk of hemorrhagic complications were recently reviewed in the frame of the American College of Chest Physicians (ACCP) guidelines [23]. The main conclusions were that unfractionated heparin is associated with less bleeding than low molecular weight heparins when administered as an adjunct to fibrinolytic therapy in ST-segment elevation myocardial infarction (data stemming from the SYNERGY trial) [24]. In unstable angina or non-STsegment elevation ACS, the anti-Xa inhibitor fondaparinux appears to cause less bleeding than low molecular weight or unfractionated heparin (OASIS-5 trial) [25]. The direct thrombin inhibitor bivalirudin is associated with a lower rate of bleeding than unfractionated heparin plus glycoprotein IIb/IIIa inhibitor (ACUITY [26] and HORIZONS-AMI [27] trials) (Table 2). The authors of the ACCP guidelines, after making these statements on the varying degrees of risk associated with different drugs in ACS, point out that between drug comparisons for the risk of bleeding are jeopardized by such uncontrolled variables as drug dosages and other characteristics and risk factors in the actually treated patients [23]. 5. Treatment of bleeding Table 3 summarizes the measures that should be considered for the general management of minor and major bleeding in patients with ACS treated with multiple antithrombotic drugs. In situations of minor bleeding not endangering life and organ functions, attempts should be made to avoid stopping antithrombotic drugs and to understand whether or not there are alterations of the hemostasis system by using simple exploratory laboratory tests. When bleeding is severe, antithrombotic drugs must be stopped but transfusional treatment should be avoided as long as possible. To this end, one should consider pharmacological approaches based upon drugs that potentiate hemostasis through various mechanisms. The hemostatic drugs that have been evaluated (mainly in cardiac surgery) to see whether or not they reduce blood loss and transfusional needs are the synthetic antifibrinolytic amino acids aminocaproic acid and tranexamic acid, the broadspectrum protease inhibitor aprotinin extracted from bovine lung, the synthetic derivative of the antidiuretic hormone desmopressin
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Fig. 1. Mechanism and points of action of drugs that potentiate the hemostatic mechanism. Abbreviations: DDAVP, desmopressin; rFVIIa, recombinant activated factor VII; TF, tissue factor; VWF, von Willebrand factor. The Roman numbers denote the corresponding coagulation factors, with the suffix a denoting the active enzymatic forms.
(DDAVP) and the activated form of coagulation factor VII produced by recombinant DNA technology (rFVIIa) [3,4] (Fig. 1). Aminocaproic acid (6-aminohexanoic acid) and tranexamic acid (4-aminomethyl cyclohexanecarboxylic acid) inhibit fibrinolysis by saturating the lysine-binding sites on the plasminogen molecule,
Table 1 Components of the CRUSADE bleeding score. Component
Range
Score
Baseline hematocrit (%)
b 31 31–33.9 34–36.9 37–39.9 ≥ 40 ≤ 15 N 15–30 N 30–60 N 60–90 N 90–120 N 120 ≤ 70 71–80 81–90 91–100 101–110 111–120 ≥ 121 Male Female No Yes No Yes No Yes ≤ 90 91–100 101–120 120–180 181–200 ≥ 201
9 7 3 2 0 39 35 28 17 7 0 0 1 3 6 8 10 11 0 8 0 7 0 6 0 6 10 8 5 1 3 5
Creatinine clearance (ml/min)
Heart rate (beats/min)
Sex Signs of heart failure Prior vascular disease Diabetes mellitus Systolic blood pressure (mmHg)
which are essential for binding of this precursor of the fibrinolytic enzyme plasmin to fibrin clots [28,29]. In cardiac surgery, both drugs reduce by approximately 30 to 40% the need for perioperative blood transfusion [30]. The main perceived risk of these drugs is thrombosis, owing to the inhibition of such an important antithrombotic system as fibrinolysis, even though a Cochrane systematic review does not support the views that thrombotic events are more frequent in treated patients [30]. Aprotinin is a broad-spectrum protease that inhibits mainly the fibrinolytic enzyme plasmin [31,32]. In cardiac surgery, the Cochrane review [30] summarized the results of as many as 61 trials and globally demonstrated a reduction by 30% of the need for allogeneic transfusion of red cells, platelets and fresh–frozen plasma, and a 60% reduction in the need for reoperation. However, the recent BART trial [33], carried out in 2331 patients undergoing complex cardiac operations at particularly high risk of excessive bleeding and randomized to receive aprotinin, tranexamic acid or aminocaproic acid, had to be interrupted because of a higher 30-day mortality in patients treated with aprotinin (6.0%), compared with rates of 3.9% in the tranexamic acid and 4.0% in the aminocaproic acid-treated patients [33]. The excess of deaths observed in aprotinin-treated patients were mainly due to atherothrombotic cardiovascular events. The BART trial also demonstrated that antifibrinolytic amino acids were slightly less effective than aprotinin in reducing blood loss and
Table 2 Rates of major bleeding in acute coronary syndromes according to different antithrombotic drugs. Trial
Drugs
Rate of major bleeding (%)
SYNERGY [24]
UHF enoxiparin Enoxiparin fondaparinux UHF/GPI bivalirudin UHF/GPI bivalirudin
7.6 9.1 5.0 3.1 11.8 9.1 10.8 6.8
OASIS-5 [25] ACUITY [26] HORIZON-AMI [27]
UHF denotes unfractionated heparin; GPI, glycoprotein IIb/IIIa inhibitors.
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Table 3 General approach to the management of minor and major bleeding associated with the use of antithrombotic drugs in patients with acute coronary syndromes. Minor bleeding – Avoid as much as possible to withdraw antithrombotic drugs – Measure global coagulation tests (prothrombin time, activated partial thromboplastin time and thrombin time) and complete blood count – Adopt conservative measures (see Table 2) – Watch evolution by assessing and monitoring vital signs and complete blood count Major bleeding – Withdraw antithrombotic drugs – Measure global coagulation tests (prothrombin time, activated partial thromboplastin time, thrombin time) and complete blood count – Consider red cell and platelet transfusions (see Table 2 for recommended dosages) – Consider administration of hemostatic drugs (first choice: antifibrinolytic amino acids; second choice: recombinant factor VIIa) (see Table 2 for recommended dosages)
transfusion requirements, but safer and much less expensive. These results have been strengthened by a recent meta-analysis by Henry et al. [34] of 49 trials involving 7439 cardiac surgery patients: the relative risk (RR) of more deaths after use of aprotinin than after tranexamic acid or aminocaproic acid was 1.43 (95% CI 0.98–2.08) and 1.49 (95% CI 0.98–2.28) respectively, and the reduction of transfusion requirements was similar for the three drugs 0.66 (95% CI 0.61–0.72) for aprotinin, 0.70 (95% CI 0.61–0.80) for tranexamic acid and 0.75 (95% CI 0.58–0.96) for aminocaproic acid. Hence, antifibrinolytic amino acids, which are safer and have a similar efficacy than aprotinin, they should be preferred to reduce blood loss and transfusion after cardiac surgery. However, it must be emphasized that randomized trials evaluating the efficacy of these agents in bleeding patients with ACS are lacking, so that cardiac surgery can only be considered a proxy of this medical situation. Desmopressin (DDAVP) is currently licensed only for the treatment of patients with mild to moderate hemophilia and von Willebrand disease [3,4]. In these congenital bleeding disorders the efficacy of desmopressin is well established, owing to its property to increase the plasma levels of factor VIII and of ultralarge von Willebrand factor multimers that are hyperactive in primary hemostasis [3,4]. This drug has also been used to reduce blood loss and transfusion requirements in cardiac surgery and in other medical and surgical situations associated with excessive bleeding [35,36]. According to a systematic review of 17 randomized double-blind, placebo-controlled trials including 1171 patients undergoing cardiac surgery [36], DDAVP significantly reduced postoperative blood loss by only 9%, and had no statistically significant effect on transfusion requirements [36]. However, a subgroup analysis showed that, although DDAVP was not efficacious when the 24-h postoperative blood loss in placebo-treated patients was in the lower or middle third of the distribution (687–1092 mL), blood losses were reduced by 34% when the 24-h blood loss in the placebo-treated patients was in the upper third of the distribution (N1092 mL) [36], suggesting that DDAVP may be clinically efficacious but only in patients at risk of excessive bleeding. However, two subsequent systemic reviews, that did not include a subgroup analysis on the effects of DDAVP as a function of the severity of blood loss in placebo-treated patients, found no demonstrable effect of the drug on transfusion requirements, need for re-thoracotomy or mortality [37,38]. Hence, it is difficult to propose DDAVP as first choice hemostatic agent.
Recombinant activated factor VII (FVIIa), produced by recombinant DNA technology, promotes hemostasis by binding to tissue factor exposed on the damaged vessel wall and in the extravascular space and generates small amounts of thrombin [39–41]. In turn, thrombin acts mainly through the generation of more thrombin on the platelet surface. Factor VIIa is also hemostatic through the inhibition of fibrinolysis, mediated by thrombin-induced activation of one of the principal inhibitors of fibrinolysis (TAFI, i.e., thrombin-activable fibrinolysis inhibitor) [42]. Recombinant FVIIa was initially developed to bypass the coagulation defect in patients with hemophilia A complicated by inhibitory anti-factor VIII antibodies, and is licensed for the treatment of bleeding episodes in these patients. The drug is also licensed for the control of bleeding in Glanzmann's thrombasthenia, a rare but severe defect of platelet function due to the deficiency or dysfunction of platelet glycoprotein IIb/IIIa. This inherited hemostatic defect is mimicked by the therapeutic use in ACS patients of inhibitors of this platelet receptor such as abciximab, tirofiban and eptifibatide. Recombinant FVIIa has been increasingly used off-label as a general hemostatic agent, and became an attractive option in patients bleeding for various etiologies, including several conditions associated with excessive blood loss due to the intake of antithrombotic drugs [43–45]. However, it must be emphasized that there is no randomized clinical trial showing its efficacy beside hemophilia and thrombasthenia, that the drug is very expensive and that the risk of thrombosis is looming large, particularly in ACS patients at high baseline risk of this complication. The hemostatic strategies that should be adopted for the management of bleeding in patients with ACS are summarized in Table 4. We emphasize that when there is a situation of excessive bleeding in these patients, before considering the use of hemostatic drugs and transfusional blood products, simple conservative measures should be implemented, such as the application of pressure to the bleeding site with or without the adoption of adjunctive local measures such as fibrin glues. When these measures fail, hemostatic drugs have the potential to prevent or stop bleeding and to avoid transfusion, but increase the likelihood of novel thrombotic events in patients who, like those with ACS, are at high baseline risk. It must be borne in mind that so far the available evidence on the clinical efficacy of the off-label use of hemostatic agents in ACS consists of case reports or small case series with no adequate control, and that the frequent parallel use in patients of other agents with a potentially favorable impact on hemostasis (such as fresh–frozen plasma and platelet concentrates) are confounding
Table 4 Possible strategies for treatment of minor and major bleeding in patients with acute coronary syndromes. Strategy
Principles of treatment
– Compression for minor bleeding, where site is accessible. – Fibrin glue application to bleeding site where accessible. Platelet transfusion – Only for severe bleeding or cases in which other measures fail and before invasive procedures. Dosage: one single donor apheresis unit (or 6–8 random donor units) is the standard dose for adult patients. – Use leukocyte-depleted platelets where available and possible, and repeat as appropriate until resolution of bleeding. Antifibrinolytic amino acids – Tranexamic acid: oral 10–25 mg/kg q8h; intravenous 10–15 mg/kg q8h. Aminocaproic acid: oral/intravenous 50–60 mg/kg q4h. Recombinant factor VIIa – Bolus injections: 80–100 µg/kg repeated 3 or more times. After bleeding stops, additional consolidation doses may help to decrease recurrence. Conservative measures
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Table 5 The pros and cons of various strategies to prevent or treat bleeding in patients with acute coronary syndromes. Product
Pros
Cons
Red cell concentrates Life saving in case of severe anemia, improvement of platelet function Plasma Platelet concentrates Antifibrinolytic amino acids Recombinant factor VIIa DDAVP
Transfusion-related side effects may adversely affect mortality and cardiovascular events Repletes both pro- and anticoagulants Transfusion-related side effects, fluid overload, very commonly underdosed Improve primary hemostasis: adequate thrombin production with levels Transfusion-related side effects 3 exceeding 50,000/mm Small volume, oral administration, low cost, proven efficacy and lack of No data from controlled trials on efficacy in ACS, theoretical risk of severe side effects in cardiac surgery thrombosis Small volume, data from uncontrolled studies and case reports High cost, no proven efficacy from controlled randomized trials in patients with ACS, theoretical risk of thrombosis Laboratory improvement of primary hemostasis, easy administration Efficacy in patients with ACS is not proven, risk of thrombosis
interpretation on the efficacy of these drugs. Table 5 shows the pro and cons of the different measures that can be used to stop bleeding in patients with ACS. 6. Conclusions Even though in ACS the balance is ultimately in favor of the use of antithrombotic agents, the risk of bleeding is looming large. The most important approach is prevention, which can be realized through a careful scrutiny of the pattern of risk factors in each patient. In spite of a high risk of bleeding, it is not recommended to withdraw the antithrombotic strategies and invasive procedures that are of proven efficacy in ACS. However, the combination of drugs and their dosages may be tailored and modified according to each patient and his/her category of risk. For instance, platelet glycoprotein IIb/IIIa inhibitors, often added to aspirin and clopidogrel in high-risk patients with ACS undergoing PCI, may be avoided. By the same token, double loading and maintenance doses of clopidogrel (600 and 150 mg daily), that are sometime used to circumvent poor responsiveness to this antiplatelet drug, should be avoided in the presence of a high risk of bleeding. In general, it is better to reduce dosages rather than to have to stop all antithrombotic treatments after the patient bled. If bleeding is life-threatening, blood transfusion should be considered. However, the concept that patients with coronary artery disease should be aggressively transfused owing to the putative adverse effects of anemia on their heart diseases has been challenged by the accumulating evidence that intensive transfusional regimens may increase mortality and cardiovascular events. Hemostatic drugs are definitely capable to reduce blood loss and transfusion requirements in cardiac surgery, and this favorable effect may be cautiously taken as a proxy of efficacy in ACS. Among them antifibrinolytic amino acids should be preferred for their higher safety and lower cost. However, it remains to be established whether or not these drugs are efficacious outside cardiac surgery, and particularly when bleeding occurs in patients with ACS. This question should be answered by controlled clinical trials, but we have no knowledge that these are being planned in ACS patients with major bleeding. Learning points • Acute coronary syndromes may be complicated by excessive bleeding, owing to the use of multiple antithrombotic drugs concomitantly with invasive procedures such as coronary angiography and percutaneous coronary intervention. • The risk of bleeding complications is proportional to the number and type of antithrombotic drugs, being smaller with aspirin alone and increasing stepwise with the number of drugs used. • Prevention is the most important goal, through the accurate evaluation of the risk of bleeding in each patient and by tailoring the number and dosages of antithrombotic drugs to the risk of bleeding.
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Contents lists available at ScienceDirect
European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Review article
Mechanism of hemostasis defects and management of bleeding in patients with acute coronary syndromes Pier Mannuccio Mannucci a,⁎, Massimo Franchini b a b
A. Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Medicine and Medical Specialties, IRCCS Cà Granda Foundation Maggiore Policlinico Hospital, Milan, Italy Immunohematology and Transfusion Center, Department of Pathology and Laboratory Medicine, University Hospital of Parma, Italy
a r t i c l e
i n f o
Article history: Received 25 January 2010 Received in revised form 5 March 2010 Accepted 10 March 2010 Available online 14 April 2010 Keywords: Hemostatic agents Blood transfusion Acute coronary syndromes Bleeding
a b s t r a c t The main cause of the hemostasis defects and related bleeding complications in patients with acute coronary syndromes (ACS) are the intake of multiple antithrombotic drugs, alone or concomitantly with invasive procedures such as coronary angiography and percutaneous coronary intervention (PCI). Antithrombotic drugs that impair several phases of hemostasis (platelet function, coagulation, and fibrinolysis) are causing bleeding particularly in elderly patients, in those underweight and with comorbidities such as renal insufficiency, diabetes, hypertension and malignancy. Identification of patients at high risk of bleeding is the most important preventive strategy, because the choice and dosages of drugs may to some extent be tailored to the degree of risk. Transfusions of blood products, which may become necessary in patients with major bleeding, should be used with caution, because they are associated with adverse cardiovascular events. To reduce the need of transfusion, the hemostatic drugs that decrease blood loss and transfusion requirements in cardiac surgery (antifibrinolytic amino acids, desmopressin, and recombinant factor VIIa) might be considered. However, the efficacy of these drugs in the control of bleeding complications is not unequivocally established in ACS and there is concern for an increased risk of thrombosis. In conclusion, evidence-based recommendations for the management of bleeding in patients with ACS are currently lacking, so that prevention through accurate assessment of the individual risk is the most valid strategy. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction In acute coronary syndromes (ACS) excessive bleeding may occur because patients have multiple hemostasis defects, owing to the inhibition of coagulation by anticoagulants such as heparins and direct thrombin inhibitors and of platelet function by inhibitors of aggregation such as aspirin, clopidogrel and anti-glycoprotein IIb/IIIa [1,2]. A hyperfibrinolytic state is induced by the therapeutic administration of tissue plasminogen activators or other fibrinolytic drugs to obtain thrombolysis. Cardiac surgery is another clinical condition typically associated with major blood loss, related to the large size of the surgical wound, decrease in platelet number during the circulation of blood in the extracorporeal oxygenator, hypocoagulability due to the use of heparin and its incomplete neutralization after pump discontinuation and acquired defects of platelet function often accompanied by hyperfibrinolysis [3,4]. In this review, we are analyzing current knowledge on the mechanism and management of bleeding complications in patients with ACS, focusing on preventive measures as well as on the potential therapeutic role of hemostatic
⁎ Corresponding author. Via Pace 9, 20122 Milan, Italy. Tel.: +39 02 55035421; fax: +39 02 50320723. E-mail address: [email protected] (P.M. Mannucci).
drugs. The benefits and risks of the latter drugs, well established in the frame of the complex defects of hemostasis occurring in cardiac surgery, are going to be used as a proxy of their potential use in patients with ACS who are bleeding. 2. Bleeding in acute coronary syndromes Bleeding complications in ACS are likely to increase in the next future, owing to the increasing age of the patient population, the availability of more and more potent antithrombotic drugs and the more and more extensive use of revascularization procedures. Bleeding may range from minor (e.g., nose bleeding, oozing from venous access sites) to life-endangering gastrointestinal, intracranial and retroperitoneal hemorrhages. That the combined use of multiple drugs which impair various phases of hemostasis is the leading cause of bleeding in ACS was recently confirmed by a large registry-based study carried out in Denmark. This study has clearly shown that the risk of fatal and non-fatal bleeding is proportional to the number and type of antithrombotic drugs used in patients with myocardial infarction [5], with an approximately 4-fold increased risk with triple therapy (two antiplatelet agents and an anticoagulant) compared with aspirin alone. Multiple antithrombotic drugs are used during and after PCI with stent deployment, a procedure carried out in 60 to 70% of patients with ACS who undergo diagnostic coronary angiography.
0953-6205/$ – see front matter © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2010.03.010
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Obviously these invasive procedures dramatically increase the risk of bleeding, that is more frequent in patients at high pre-procedural risk such as the elderly, the underweight, those with renal insufficiency and when excessive dosages of antithrombotic agents are administered [6]. Bleeding complications are more frequent in women, perhaps because of their smaller body weight in average and often older age than men at the time of occurrence of ACS. However, sexbased differences in vessel and blood function may contribute to increased bleeding rates in women. Concomitant anemia may also increase the risk of hemorrhagic complications in both sexes [7]. Major or moderately severe bleeding has a negative effect on prognosis in patients with ACS, as established by meta-analysis, large registries and clinical trials. Major bleeding is associated with an approximately 5-fold increased risk of death at 30 days, a 5-fold increase in myocardial infarction and a 3-fold increase in ischemic stroke [8–11]. Even though some believe that the relationship between bleeding and these adverse outcomes is not causal and that excess mortality is explained by more frequent comorbidities in bleeders [12], the perceived clinical relevance of this complication has recently prompted the addition of bleeding to the traditional triad of events (death, MI, and urgent revascularization) employed to evaluate the overall effect of antithrombotic drugs in patients with ACS undergoing PCI [13].
3. Use of blood transfusion Although blood transfusion may be a life-saving procedure for patients with hypovolemic shock, evidence of its general efficacy in ACS patients is not favorable [8]. Data from 3 large clinical trials totaling 24,112 patients with ACS were included in a meta-analysis to establish whether or not there was an association between blood transfusion and outcomes in patients with moderate to severe bleeding [14]. The need for transfusion was associated with an approximately 4-fold increased risk for 30-day mortality, even after adjustment for other predictive factors such as baseline and nadir hematocrit, the type of invasive procedures and comorbidities. Even though there are also contrasting data showing a favorable effect of blood transfusion on the rates of adverse outcomes [15], the intensive and liberal use of transfusions with the goal to maintain normal hemoglobin levels should be adopted with caution. Indeed, a Cochrane systematic review indicates that in surgical and medical patients needing red cell transfusion a restrictive transfusional regimen is associated with a 20% lower mortality and a 24% lower rates of cardiovascular events (myocardial infarction, arrhythmias, cardiac arrest, pulmonary edema, stroke and angina) [16]. Several pathophysiologic mechanisms may underlie the increased risks carried by transfusions, such as alterations in erythrocyte deformability, microvascular impairment, vasoconstriction, nitric oxide depletion in stored blood, alterations in oxygen affinity due to high 2,3-diphosphoglyceric acid levels and decrease in oxygen delivery to tissues [17]. These alterations may also explain the increased risk of postoperative complications and reduced survival after cardiac surgery when transfused red cells have been stored for prolonged periods [18]. A number of studies have documented the beneficial effect of leukocyte depletion (by means of filtration of transfused blood products) on the postoperative mortality in patients undergoing cardiac surgery [19,20]. For instance, in a randomized controlled trial [19], 7.8% of 305 patients receiving non-white cell (WBC)-reduced red cells died within 60 days after cardiac surgery, compared with 3.5% of 604 subjects receiving WBC-reduced cells. The postulated mechanisms of the benefits of leukoreduction in cardiac surgery include lower rates of postoperative infection, perhaps due to immunomodulatory effects of WBC in transfused blood, lack of alloimmunization against HLA antigens and of the systemic inflammatory response caused by neutrophils exposed to artificial surfaces in the extracorporeal circuit [21]. It must be emphasized again that the aforementioned advantages of leukoreduc-
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tion in the cardiac surgery setting can only be taken as a proxy of the advantages that transfused medical patients with ACS may obtain. 4. Prevention of bleeding Concerns on the increased mortality rate associated with major hemorrhage and the adverse effects of blood transfusion in patients with ACS emphasize the role of prevention, which should be tailored to the patient's individual risk of bleeding. Evaluation of this risk is based upon knowledge that there are comorbidities and/or patient features that increase this risk during antithrombotic therapy for ACS: older age (higher than 75 years), female sex, low body weight, renal insufficiency, severe hypertension, cerebrovascular disease, diabetes and alcoholism. Malignancy and previous gastrointestinal bleeding are also strong predictors of bleeding. There have been efforts to combine several risk factors in the attempt to develop bleeding risk scores meant to facilitate the choice and dosage of antithrombotic drugs for the medical treatment of ACS with or without PCI. For instance, a bleeding score validated in a large number of patients with ACS in the frame of CRUSADE [22] includes eight parameters as predictors of bleeding (hematocrit on admission, creatinine clearance, female sex, signs of congestive heart failure, peripheral vascular disease, diabetes, systolic blood pressure and heart rate on admission) (Table 1). According to CRUSADE, the risk of bleeding ranks from very low (score less than 20, predicted rate of major bleeding 3.1%), low (score between 21 and 30, predicted bleeding rate 5.5%), moderate (score 31–40, 8.6%) to high (score 41–50, 11.2%) and very high (score higher than 50, 19.5%) [22]. The relationships between different antithrombotic drugs, their dosage, the characteristics of the patient population, the clinical condition that led to the use of these drugs and the risk of hemorrhagic complications were recently reviewed in the frame of the American College of Chest Physicians (ACCP) guidelines [23]. The main conclusions were that unfractionated heparin is associated with less bleeding than low molecular weight heparins when administered as an adjunct to fibrinolytic therapy in ST-segment elevation myocardial infarction (data stemming from the SYNERGY trial) [24]. In unstable angina or non-STsegment elevation ACS, the anti-Xa inhibitor fondaparinux appears to cause less bleeding than low molecular weight or unfractionated heparin (OASIS-5 trial) [25]. The direct thrombin inhibitor bivalirudin is associated with a lower rate of bleeding than unfractionated heparin plus glycoprotein IIb/IIIa inhibitor (ACUITY [26] and HORIZONS-AMI [27] trials) (Table 2). The authors of the ACCP guidelines, after making these statements on the varying degrees of risk associated with different drugs in ACS, point out that between drug comparisons for the risk of bleeding are jeopardized by such uncontrolled variables as drug dosages and other characteristics and risk factors in the actually treated patients [23]. 5. Treatment of bleeding Table 3 summarizes the measures that should be considered for the general management of minor and major bleeding in patients with ACS treated with multiple antithrombotic drugs. In situations of minor bleeding not endangering life and organ functions, attempts should be made to avoid stopping antithrombotic drugs and to understand whether or not there are alterations of the hemostasis system by using simple exploratory laboratory tests. When bleeding is severe, antithrombotic drugs must be stopped but transfusional treatment should be avoided as long as possible. To this end, one should consider pharmacological approaches based upon drugs that potentiate hemostasis through various mechanisms. The hemostatic drugs that have been evaluated (mainly in cardiac surgery) to see whether or not they reduce blood loss and transfusional needs are the synthetic antifibrinolytic amino acids aminocaproic acid and tranexamic acid, the broadspectrum protease inhibitor aprotinin extracted from bovine lung, the synthetic derivative of the antidiuretic hormone desmopressin
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Fig. 1. Mechanism and points of action of drugs that potentiate the hemostatic mechanism. Abbreviations: DDAVP, desmopressin; rFVIIa, recombinant activated factor VII; TF, tissue factor; VWF, von Willebrand factor. The Roman numbers denote the corresponding coagulation factors, with the suffix a denoting the active enzymatic forms.
(DDAVP) and the activated form of coagulation factor VII produced by recombinant DNA technology (rFVIIa) [3,4] (Fig. 1). Aminocaproic acid (6-aminohexanoic acid) and tranexamic acid (4-aminomethyl cyclohexanecarboxylic acid) inhibit fibrinolysis by saturating the lysine-binding sites on the plasminogen molecule,
Table 1 Components of the CRUSADE bleeding score. Component
Range
Score
Baseline hematocrit (%)
b 31 31–33.9 34–36.9 37–39.9 ≥ 40 ≤ 15 N 15–30 N 30–60 N 60–90 N 90–120 N 120 ≤ 70 71–80 81–90 91–100 101–110 111–120 ≥ 121 Male Female No Yes No Yes No Yes ≤ 90 91–100 101–120 120–180 181–200 ≥ 201
9 7 3 2 0 39 35 28 17 7 0 0 1 3 6 8 10 11 0 8 0 7 0 6 0 6 10 8 5 1 3 5
Creatinine clearance (ml/min)
Heart rate (beats/min)
Sex Signs of heart failure Prior vascular disease Diabetes mellitus Systolic blood pressure (mmHg)
which are essential for binding of this precursor of the fibrinolytic enzyme plasmin to fibrin clots [28,29]. In cardiac surgery, both drugs reduce by approximately 30 to 40% the need for perioperative blood transfusion [30]. The main perceived risk of these drugs is thrombosis, owing to the inhibition of such an important antithrombotic system as fibrinolysis, even though a Cochrane systematic review does not support the views that thrombotic events are more frequent in treated patients [30]. Aprotinin is a broad-spectrum protease that inhibits mainly the fibrinolytic enzyme plasmin [31,32]. In cardiac surgery, the Cochrane review [30] summarized the results of as many as 61 trials and globally demonstrated a reduction by 30% of the need for allogeneic transfusion of red cells, platelets and fresh–frozen plasma, and a 60% reduction in the need for reoperation. However, the recent BART trial [33], carried out in 2331 patients undergoing complex cardiac operations at particularly high risk of excessive bleeding and randomized to receive aprotinin, tranexamic acid or aminocaproic acid, had to be interrupted because of a higher 30-day mortality in patients treated with aprotinin (6.0%), compared with rates of 3.9% in the tranexamic acid and 4.0% in the aminocaproic acid-treated patients [33]. The excess of deaths observed in aprotinin-treated patients were mainly due to atherothrombotic cardiovascular events. The BART trial also demonstrated that antifibrinolytic amino acids were slightly less effective than aprotinin in reducing blood loss and
Table 2 Rates of major bleeding in acute coronary syndromes according to different antithrombotic drugs. Trial
Drugs
Rate of major bleeding (%)
SYNERGY [24]
UHF enoxiparin Enoxiparin fondaparinux UHF/GPI bivalirudin UHF/GPI bivalirudin
7.6 9.1 5.0 3.1 11.8 9.1 10.8 6.8
OASIS-5 [25] ACUITY [26] HORIZON-AMI [27]
UHF denotes unfractionated heparin; GPI, glycoprotein IIb/IIIa inhibitors.
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Table 3 General approach to the management of minor and major bleeding associated with the use of antithrombotic drugs in patients with acute coronary syndromes. Minor bleeding – Avoid as much as possible to withdraw antithrombotic drugs – Measure global coagulation tests (prothrombin time, activated partial thromboplastin time and thrombin time) and complete blood count – Adopt conservative measures (see Table 2) – Watch evolution by assessing and monitoring vital signs and complete blood count Major bleeding – Withdraw antithrombotic drugs – Measure global coagulation tests (prothrombin time, activated partial thromboplastin time, thrombin time) and complete blood count – Consider red cell and platelet transfusions (see Table 2 for recommended dosages) – Consider administration of hemostatic drugs (first choice: antifibrinolytic amino acids; second choice: recombinant factor VIIa) (see Table 2 for recommended dosages)
transfusion requirements, but safer and much less expensive. These results have been strengthened by a recent meta-analysis by Henry et al. [34] of 49 trials involving 7439 cardiac surgery patients: the relative risk (RR) of more deaths after use of aprotinin than after tranexamic acid or aminocaproic acid was 1.43 (95% CI 0.98–2.08) and 1.49 (95% CI 0.98–2.28) respectively, and the reduction of transfusion requirements was similar for the three drugs 0.66 (95% CI 0.61–0.72) for aprotinin, 0.70 (95% CI 0.61–0.80) for tranexamic acid and 0.75 (95% CI 0.58–0.96) for aminocaproic acid. Hence, antifibrinolytic amino acids, which are safer and have a similar efficacy than aprotinin, they should be preferred to reduce blood loss and transfusion after cardiac surgery. However, it must be emphasized that randomized trials evaluating the efficacy of these agents in bleeding patients with ACS are lacking, so that cardiac surgery can only be considered a proxy of this medical situation. Desmopressin (DDAVP) is currently licensed only for the treatment of patients with mild to moderate hemophilia and von Willebrand disease [3,4]. In these congenital bleeding disorders the efficacy of desmopressin is well established, owing to its property to increase the plasma levels of factor VIII and of ultralarge von Willebrand factor multimers that are hyperactive in primary hemostasis [3,4]. This drug has also been used to reduce blood loss and transfusion requirements in cardiac surgery and in other medical and surgical situations associated with excessive bleeding [35,36]. According to a systematic review of 17 randomized double-blind, placebo-controlled trials including 1171 patients undergoing cardiac surgery [36], DDAVP significantly reduced postoperative blood loss by only 9%, and had no statistically significant effect on transfusion requirements [36]. However, a subgroup analysis showed that, although DDAVP was not efficacious when the 24-h postoperative blood loss in placebo-treated patients was in the lower or middle third of the distribution (687–1092 mL), blood losses were reduced by 34% when the 24-h blood loss in the placebo-treated patients was in the upper third of the distribution (N1092 mL) [36], suggesting that DDAVP may be clinically efficacious but only in patients at risk of excessive bleeding. However, two subsequent systemic reviews, that did not include a subgroup analysis on the effects of DDAVP as a function of the severity of blood loss in placebo-treated patients, found no demonstrable effect of the drug on transfusion requirements, need for re-thoracotomy or mortality [37,38]. Hence, it is difficult to propose DDAVP as first choice hemostatic agent.
Recombinant activated factor VII (FVIIa), produced by recombinant DNA technology, promotes hemostasis by binding to tissue factor exposed on the damaged vessel wall and in the extravascular space and generates small amounts of thrombin [39–41]. In turn, thrombin acts mainly through the generation of more thrombin on the platelet surface. Factor VIIa is also hemostatic through the inhibition of fibrinolysis, mediated by thrombin-induced activation of one of the principal inhibitors of fibrinolysis (TAFI, i.e., thrombin-activable fibrinolysis inhibitor) [42]. Recombinant FVIIa was initially developed to bypass the coagulation defect in patients with hemophilia A complicated by inhibitory anti-factor VIII antibodies, and is licensed for the treatment of bleeding episodes in these patients. The drug is also licensed for the control of bleeding in Glanzmann's thrombasthenia, a rare but severe defect of platelet function due to the deficiency or dysfunction of platelet glycoprotein IIb/IIIa. This inherited hemostatic defect is mimicked by the therapeutic use in ACS patients of inhibitors of this platelet receptor such as abciximab, tirofiban and eptifibatide. Recombinant FVIIa has been increasingly used off-label as a general hemostatic agent, and became an attractive option in patients bleeding for various etiologies, including several conditions associated with excessive blood loss due to the intake of antithrombotic drugs [43–45]. However, it must be emphasized that there is no randomized clinical trial showing its efficacy beside hemophilia and thrombasthenia, that the drug is very expensive and that the risk of thrombosis is looming large, particularly in ACS patients at high baseline risk of this complication. The hemostatic strategies that should be adopted for the management of bleeding in patients with ACS are summarized in Table 4. We emphasize that when there is a situation of excessive bleeding in these patients, before considering the use of hemostatic drugs and transfusional blood products, simple conservative measures should be implemented, such as the application of pressure to the bleeding site with or without the adoption of adjunctive local measures such as fibrin glues. When these measures fail, hemostatic drugs have the potential to prevent or stop bleeding and to avoid transfusion, but increase the likelihood of novel thrombotic events in patients who, like those with ACS, are at high baseline risk. It must be borne in mind that so far the available evidence on the clinical efficacy of the off-label use of hemostatic agents in ACS consists of case reports or small case series with no adequate control, and that the frequent parallel use in patients of other agents with a potentially favorable impact on hemostasis (such as fresh–frozen plasma and platelet concentrates) are confounding
Table 4 Possible strategies for treatment of minor and major bleeding in patients with acute coronary syndromes. Strategy
Principles of treatment
– Compression for minor bleeding, where site is accessible. – Fibrin glue application to bleeding site where accessible. Platelet transfusion – Only for severe bleeding or cases in which other measures fail and before invasive procedures. Dosage: one single donor apheresis unit (or 6–8 random donor units) is the standard dose for adult patients. – Use leukocyte-depleted platelets where available and possible, and repeat as appropriate until resolution of bleeding. Antifibrinolytic amino acids – Tranexamic acid: oral 10–25 mg/kg q8h; intravenous 10–15 mg/kg q8h. Aminocaproic acid: oral/intravenous 50–60 mg/kg q4h. Recombinant factor VIIa – Bolus injections: 80–100 µg/kg repeated 3 or more times. After bleeding stops, additional consolidation doses may help to decrease recurrence. Conservative measures
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Table 5 The pros and cons of various strategies to prevent or treat bleeding in patients with acute coronary syndromes. Product
Pros
Cons
Red cell concentrates Life saving in case of severe anemia, improvement of platelet function Plasma Platelet concentrates Antifibrinolytic amino acids Recombinant factor VIIa DDAVP
Transfusion-related side effects may adversely affect mortality and cardiovascular events Repletes both pro- and anticoagulants Transfusion-related side effects, fluid overload, very commonly underdosed Improve primary hemostasis: adequate thrombin production with levels Transfusion-related side effects 3 exceeding 50,000/mm Small volume, oral administration, low cost, proven efficacy and lack of No data from controlled trials on efficacy in ACS, theoretical risk of severe side effects in cardiac surgery thrombosis Small volume, data from uncontrolled studies and case reports High cost, no proven efficacy from controlled randomized trials in patients with ACS, theoretical risk of thrombosis Laboratory improvement of primary hemostasis, easy administration Efficacy in patients with ACS is not proven, risk of thrombosis
interpretation on the efficacy of these drugs. Table 5 shows the pro and cons of the different measures that can be used to stop bleeding in patients with ACS. 6. Conclusions Even though in ACS the balance is ultimately in favor of the use of antithrombotic agents, the risk of bleeding is looming large. The most important approach is prevention, which can be realized through a careful scrutiny of the pattern of risk factors in each patient. In spite of a high risk of bleeding, it is not recommended to withdraw the antithrombotic strategies and invasive procedures that are of proven efficacy in ACS. However, the combination of drugs and their dosages may be tailored and modified according to each patient and his/her category of risk. For instance, platelet glycoprotein IIb/IIIa inhibitors, often added to aspirin and clopidogrel in high-risk patients with ACS undergoing PCI, may be avoided. By the same token, double loading and maintenance doses of clopidogrel (600 and 150 mg daily), that are sometime used to circumvent poor responsiveness to this antiplatelet drug, should be avoided in the presence of a high risk of bleeding. In general, it is better to reduce dosages rather than to have to stop all antithrombotic treatments after the patient bled. If bleeding is life-threatening, blood transfusion should be considered. However, the concept that patients with coronary artery disease should be aggressively transfused owing to the putative adverse effects of anemia on their heart diseases has been challenged by the accumulating evidence that intensive transfusional regimens may increase mortality and cardiovascular events. Hemostatic drugs are definitely capable to reduce blood loss and transfusion requirements in cardiac surgery, and this favorable effect may be cautiously taken as a proxy of efficacy in ACS. Among them antifibrinolytic amino acids should be preferred for their higher safety and lower cost. However, it remains to be established whether or not these drugs are efficacious outside cardiac surgery, and particularly when bleeding occurs in patients with ACS. This question should be answered by controlled clinical trials, but we have no knowledge that these are being planned in ACS patients with major bleeding. Learning points • Acute coronary syndromes may be complicated by excessive bleeding, owing to the use of multiple antithrombotic drugs concomitantly with invasive procedures such as coronary angiography and percutaneous coronary intervention. • The risk of bleeding complications is proportional to the number and type of antithrombotic drugs, being smaller with aspirin alone and increasing stepwise with the number of drugs used. • Prevention is the most important goal, through the accurate evaluation of the risk of bleeding in each patient and by tailoring the number and dosages of antithrombotic drugs to the risk of bleeding.
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