Incidence and predictors of bleeding complications

Selective coronary angiography as a diagnostic method followed by percutaneous coronary intervention (PCI) as a therapeutic method has become routine practice for patients with acute coronary syndrome (ACS) as well as for patients with stable forms of ischemic heart disease. As a result of the more widespread application of selec tive coronary angiography and PCI in general practice, a greater number of older people and patients with serious comorbidities are receiving this procedure. Owing to the development of new techniques for cardiac catheteri zation and the continual production of new generations of highly eff ective antiplatelet drugs, the care of patients with ACS has improved, resulting in reductions in rates of death due to ischemic events as well as periprocedural ischemic complications, ischemic stroke, and heart failure [1,2]. All of these actions lead to an increased risk of bleeding complications in these patients which is signifi cantly associated with worse short-term and longterm prognoses [3]. As a result of these fi ndings, bleeding complications, which have been disregarded for quite some time, have become a highly signifi cant medical and economic problem. If it is ex pected that more attention will be focused on this issue in the future, this attention should concurrently lead to a special eff ort of creating one standard bleeding compli cation classifi cation which is necessary for unambiguous comparison of outcomes from clinical trials evaluating treatment strategies in ACS.


Introduction
Selective coronary angiography as a diagnostic method followed by percutaneous coronary intervention (PCI) as a therapeutic method has become routine practice for patients with acute coronary syndrome (ACS) as well as for patients with stable forms of ischemic heart disease. As a result of the more widespread application of selec tive coronary angiography and PCI in general practice, a greater number of older people and patients with serious comorbidities are receiving this procedure. Owing to the development of new techniques for cardiac catheteri zation and the continual production of new generations of highly eff ective antiplatelet drugs, the care of patients with ACS has improved, resulting in reductions in rates of death due to ischemic events as well as periprocedural ischemic complications, ischemic stroke, and heart failure [1,2]. All of these actions lead to an increased risk of bleeding complications in these patients which is signifi cantly associated with worse short-term and longterm prognoses [3]. As a result of these fi ndings, bleeding complications, which have been disregarded for quite some time, have become a highly signifi cant medical and economic problem. If it is ex pected that more attention will be focused on this issue in the future, this attention should concurrently lead to a special eff ort of creating one standard bleeding compli cation classifi cation which is necessary for unambiguous comparison of outcomes from clinical trials evaluating treatment strategies in ACS.

Incidence and predictors of bleeding complications
Th e incidence of bleeding complications in trials with patients with ACS varies, ranging from 2.0% to 17.6% [3][4][5][6][7][8]. Th ese varying results come from trials examining diff erent demographic data, access sites, cardiac catheterization techniques, and pharmacotherapy regimes and from randomized studies in which specifi c defi ned groups of patients are included and which do not refl ect the real-world clinical experience. Several factors associated with an increased risk of periprocedural bleeding have been identifi ed. Th ese factors are age, gender, body weight, renal insuffi ciency, and the techniques used in invasive procedures [9]. Older age is a strong independent risk factor for major bleeding during hospitalization, and this risk factor increases by approximately 30% per decade of age [10]. Additionally, women and patients with renal insuffi ciency were found to exhibit a higher risk of hemorrhage and the risk rate is also associated with the use of invasive techniques and the sheath size [11]. Because these risk factors have been identifi ed, the scale for predicting the risk for the development of major bleeding complications in patients with ACS has been evaluated on the basis of results from the ACUITY (Acute Catheterization and Urgent Interven tion Triage strategy) and the HORIZONS-AMI (Harmonizing Out comes with Revascularization and Stents in Acute Myo cardial Infarction) trials. Th is simple integer-based scoring system calculates individual risk scores by using six independent measurements of factors that have been identifi ed to be associated with an increased risk of bleeding compli cations (gender, age, serum creatinine, white blood cell count, anemia, and presentation), combined with the type of anticoagulation therapy applied (heparin + inhibitors of GP IIb/IIIa versus bivalirudin monotherapy). Four categories of bleeding are then defi ned according to the total integer score: low (<10), moderate (10 to 14), high (15 to 19), and very high (>20) [12]. It is hoped that this simple scoring system for identifying patients at increased risk of bleeding can be used as a tool for individualization of the treatment strategy for each patient, similar to an easily applied scale for predicting the risk of bleeding versus thrombotic events which has begun to be used in general practice in patients with atrial fi brillation, leading to a recommen dation of optimal therapy: HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile International Normalized Ratio, Elderly, Drugs/alcohol concomitantly) score and CHA2DS2-VASc (Congestive heart failure, Hyperten sion, Age of at least 75 years, Diabetes mellitus, Stroke, Vascular disease, Age of 65 to 74 years, Sex category) score [13].

New antiplatelet and anticoagulant therapy
Simultaneously with the development of the technique of coronary artery stenting, great advances have been made in relation to the arsenal of antithrombotic agents reducing ischemic events. A substantial proportion of patients (especially when the average age of patients undergoing PCI increases) is indicated concurrently for chronic anticoagulant and dual antiplatelet therapy. In all of these cases, the question about safety of these new agents and their combination arises.
In a group of thienopyridines, which typically are added to acetylsalicylate acid, clopidogrel is considered the gold standard and is widely used in general practice and as a reference drug in trials examining new antiplatelet drugs. Newly introduced P2Y12 antagonists, prasugrel and ticagrelor, promise to be more eff ective in reducing ischemic events in patients with ACS [14]. So far, the most important trials in which both of these drugs were separately compared with clopidogrel have been the TRITON-TIMI 38 trial (prasugrel versus clopidogrel) [15] and the PLATO trial (ticagrelol versus clopidogrel) [16]. Signifi cant reductions were found in the total number of ischemic events in both trials comparing new antiplatelet drugs with clopidogrel [17,18]. When focused on the safety of these drugs, TRITON showed a signifi cantly increased number of bleeding complications for patients receiving prasugrel [15]. For ticagrelor in the PLATO trial, the total rate of major bleeding was similar in the two groups -PLATO major bleeding (11.6% versus 11.2%, P = 0.43), TIMI major bleeding (7.9% versus 7.7%, P = 0.56), and GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) severe bleeding (2.9% versus 3.1%, P = 0.22) -as were procedure-related bleeding rate and incidence of fatal bleeding. At 30-day follow-up, there was an increased number of major non-coronary artery bypass graftrelated bleeding in the ticagrelor group. Th ere were no diff erences in major bleeding rates between ticagrelor and clopidogrel in a group of patients presumed to be at higher risk of bleeding (age of at least 75 years, weight of less than 60 kg, chronic kidney disease, aspirin dose of greater than 325 mg on the day of randomization, prerandomi zation clopidogrel administration, or clopidogrel loading dose) [16]. Nevertheless, the benefi t of both of these new drugs seems to exceed the consequential risk, and according to the new European Society of Cardiology guidelines, they should preferably be used in all patients with ACS (with clearly defi ned contraindications) [19,20]. Of course, additional random ized trials clarifying an optimal dose and focusing mainly on the high-risk group of patients are needed, and head-to-head trials directly comparing both of these agents are necessary.
It is even more complicated when it comes to the problem of concomitant antiplatelet and oral anticoagulant (OAC) therapy. Th e risk of bleeding for those who use triple therapy (OAC + aspirin + clopidogrel) is signifi cantly higher [21,22]. Th erefore, it is very diffi cult to fi nd an optimal balance between benefi t and safety in any combinations of drugs aff ecting hemostasis. According to current guidelines, triple therapy is recommended for all patients indicated for anticoagulant therapy and concurrently receiving intracoronary stent, with diff erent recommended lengths of this triple-therapy period (according to ACS presented and type of stent used), followed by a period of combined therapy of OAC and a single antiplatelet drug [13]. However, all of these recommendations come from a consensus of experts on the basis of a limited amount of evidence [23]. A new perspective on this topic may result from the recently published multicenter randomized WOEST (What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing) trial, which compared triple therapy (OAC + aspirin + clopidogrel) and dual therapy (OAC + clopidogrel). Th e results of this trial showed no diff erence in the number of ischemic events but did show a signifi cantly reduced number of bleeding complications in a group of patients receiving dual therapy (OAC + clopido grel) [24]. Th ese results may lead to new recommen da tions in the near future.
In the era of new antiplatelet drugs, new anticoagulants have also been introduced in the last decade. Novel oral anticoagulants, direct thrombin inhibitors (for example, dabigatran), and oral direct factor Xa inhibitors (for example, rivaroxaban and apixaban) have been tested in several clinical trials (RELY, ROCKET-AF, AVERROES, and ARISTOTLE) [25][26][27][28], and data from these trials did not show worse results in the incidence of ischemic events compared with warfarin and in some cases showed even better safety [13]. Th ese results are promising for further general use of new oral anticoagulants, but more data and experience are still necessary. Data for the use of new anticoagulants in triple therapy (thus in combination with dual antiplatelet therapy) are still insuffi cient.

Technique of cardiac catheterization
Since cardiac catheterization started to be performed in practice in the early 1980s, great developments have been made in terms of equipment and techniques. Initially, the size of the catheter sheath used was 12F, whereas sizes of 5F or even smaller are currently employed. Th e size of the catheter is known to be one of the risk factors for bleeding complications [29,30]. At the beginning of the cardiac catheterization era, all procedures were performed via a femoral approach (puncture of the femoral artery). However, owing to the reduction in sheath size in the last decade and the minimization of other tools and instruments, a radial approach now can be used and slowly is becoming a routine technique practiced worldwide [31][32][33]. Several trials have compared the advantages and disadvantages of the two approaches, mostly in the form of retrospective trials. A radial approach is usually more comfortable for patients and appears to be safer and to reduce bleeding complications. A metaanalysis of 10 randomized controlled studies comparing the association of diff erent types of complications with the use of these two puncture sites showed that there are no diff erences in the rates of death and severe bleeding complications and that there is a signifi cantly lower incidence of local minor bleeding complications associated with radial access [34]. Th e lack of relevant independent data led to the need for a large randomized trial. Between 2006 and 2010, RIVAL (Radial versus Femoral access for coronary intervention), a randomized, parallel, multicenter trial, was carried out. Th e results showed that the rate of primary outcomes (the composite of death, myocardial infarction, stroke, and non-coronary artery bypass graft-related major bleeding at 30 days) did not diff er between patients in the radial access group and those in the femoral access group (3.7% in the radial access group compared with 4.0% in the femoral access group), but there was an increased number of cases of access-site bleeding in the femoral access group (42 of 3,507 patients in the radial group compared with 106 of 3,514 in the femoral group exhibited a large hematoma; hazard ratio (HR) 0.40, 95% CI 0.28 to 0.57, P <0.0001). When the primary outcomes associated with a subgroup of procedures performed at highly experienced radial access centers were compared, a signifi cant benefi t was detected for patients in the radial access group. In summary, this study showed that both femoral and radial access appear to be safe and eff ective, and an improvement was observed when the radial approach was used in association with bleeding complications related to the access site. Furthermore, it showed that specifi c technical skills and a more experienced team can lead to greater benefi ts from radial access [35].

Classifi cation of bleeding complications
Th e fi rst formal approach for classifying the severity of bleeding as a complication related to treatment with antithrombotic drugs in patients with ACS was developed during the Th rombolysis In Myocardial Infarction (TIMI) trial in 1988 [36]. Th e TIMI classifi cation was based mainly on laboratory criteria. TIMI major bleeding was defi ned as bleeding associated with a decrease in hemoglobin of greater than 50.0 g/L (or 15% in hemato crit) or intracranial bleeding. TIMI minor bleeding was defi ned as any bleeding (for example, hematuria, hemate mesis, melena, retroperitoneal bleeding, or hematoma) with a hemoglobin loss of greater than 30 g/L (or at least 10% in hematocrit). Criteria for major bleeding were extended to hemorrhagic death and cardiac tamponade [37]. Th is classifi cation, sometimes modifi ed, has been widely applied in many trials despite its limitations resulting from the preference of laboratory values over clinical outcomes. However, the second widespread classi fi cation scheme for bleeding complications estab lished in the GUSTO trial in 1993 relies mainly on clinical data [38]. GUSTO investigators determined severe bleed ing to be intracranial bleeding or any bleeding that compromises hemodynamic state and that requires treat ment. Moderate bleeding is defi ned as any bleeding that does not lead to hemodynamic compromise but that requires transfusion. Mild bleeding does not need any specifi c treatment. Th e TIMI and GUSTO classifi cations have been subsequently applied in a wide range of trials, but owing to their limitations (the use of pure laboratory versus pure clinical data), they are applied mostly in combination with variable modifi cations or with only selected elements of these classifi cations. A slightly modifi ed GUSTO scale was used in the ASSENT-3 [39], HERO-2 [40], and PARAGON-A [41] and PARAGON-B [42] trials, and combinations of the TIMI and GUSTO classifi cations were applied in the SYNERGY [43] and PURSUIT [44] trials. Many other studies (CURE, ACUITY, OASIS-5, REPLACE-2, OASIS-6, HORIZONS-AMI, CURRENT-OASIS-7, PLATO, and GRACE [16,[45][46][47][48][49][50][51][52]) established their own classifi cations for evaluating hemor rhagic complications (Table 1). Some of these classifi cations aim toward using an increased number of reported details, whereas others prefer simplicity (GRACE). Th ey also show large diff erences on the basis of suspicious events and outcomes.
According to the diff erent defi nitions employed, it is very diffi cult for clinicians and experts to come to accurate conclusions regarding the outcomes from diff er ent trials and, thus, to evaluate the safety of new techniques and antitrombotic drugs. When data from two randomized studies were compared and analyzed to determine the association between TIMI and GUSTO bleeding and 30-day and 6-month death/myocardial infarction, a stepwise increase was observed in the adjusted hazard of 30-day death/myocardial infarction using GUSTO and TIMI classifi cations separately. However, in a model including both defi nitions, the risk of GUSTO bleeding persisted whereas TIMI bleeding did not [53]. In light of these fi ndings, it is more than clear that one unifi ed classifi cation for bleeding complications is necessary in the future.

Eff orts to standardize the classifi cation of bleeding complications
In light of variability in the data and the diffi culty of interpreting general outcomes from the available studies, there is a tendency toward standardizing the defi nition of bleeding. However, it is diffi cult to do so because of demographic diff erences and the varying outcomes expected. Classifi cation evaluating in-hospital mortality in patients with ACS requiring rescue PCI would be focused more on severe and life-threatening complications. On the other hand, classifi cation for subsequent follow-up should cover wider range of bleeding complications (including superfi cial bleeding as petechia and easy bruising). Th is classifi cation must be practical, easy to implement, and meaningful for clinical outcomes and have appropriate sensitivity, specifi city, reproducibility, and consistency across health-care systems [54]. One of the fi rst attempts to create a new classifi cation for bleeding events was introduced in 2007 and was termed the BloodScore classifi cation, which is based on point scores for each type of bleeding complication [55]. As defi ned, this classifi cation covers a wide spectrum of bleeding events (from nuisance bleeding to severe, lifethreatening complications) and can be easily applied and compared in trials. On the other hand, it does not refl ect any eff ect on the hemodynamic impact or need for treatment, and this may represent a limitation for general use.
In light of the need for a new general classifi cation for bleeding complications, a group of experts convened in April 2008 and developed a new strategy for assessing the severity of bleeding associated with ACS by using existing data from previous trials. Th e Academic Bleeding Consensus (ABC) Multidisciplinary Working Group, a group of clinical researchers and representatives from the health-care and pharmaceutical industries, established a con sensus statement that recommended evaluating specifi c data in each trial and divided the evaluated data into three categories (each assigned a diff erent color): essential (red), recommended (orange), and optional (green) ( Table 2). Th e collection and reporting data rely mainly on clinical and laboratory elements, the time and site of bleeding, the direct consequences of bleeding, and the outcomes after hemorrhage. Advantages of this method include the independent collection of all relevant data associated with bleeding complications, not infl uenced by the primary endpoint of each trial; the potential to compare clinical trials post hoc; and the fact that it can be used to construct a new standard bleeding defi nition [56]. To decrease the diff erences between prior defi ni tions of bleeding, this complicated evalu ation is most likely necessary, but its complexity and the associated inconvenience for users could be limitations to its wide application in clinical practice.
Th e attempt to develop a standardized classifi cation for bleeding complications in patients undergoing invasive procedures continued. In 2011, the Bleeding Academic Research Consortium (BARC), a group of independent experts, summarized all of the available evidence and data from clinical trials and evaluated new standardized bleeding defi nitions for cardiovascular clinical trials. Five main types of bleeding were defi ned, scaled from 0 to 5, beginning with type 0, corresponding to no evidence of bleeding, and ending with type 5, indicating fatal bleeding (Table 3). Several categories include subgroups specifying each type of bleeding. Bleeding associated with surgical revascularization appears to be crucial to include but was not included in previous bleeding classifi cations but may have a great infl uence on outcomes in many clinical trials. Th is classifi cation was constructed to capture bleeding events that are important and meaningful for patients and clinical outcomes but to remain simple, broadly applicable, and easy to use. Th ese character istics make this recent classifi cation promising for use in routine clinical practice. Th e authors note that it is necessary to verify the accuracy and usefulness of this new classifi cation in clinical trials and therefore appeal to all researchers to report bleeding events according to the BARC defi nition [57]. Bleeding events that did not meet the criteria for a major bleed and required transfusion of more than one unit of blood or modifi cation of the drug regiment

Bleeding and prognosis
Despite the variation in incidence across studies, a strong association with a worse short-term as well as long-term prognosis was found for patients exhibiting bleeding complications [3, [58][59][60]. In 2006, the data from a group of 34,146 ACS patients enrolled in the OASIS Registry, OASIS-2, and CURE studies were analyzed to examine the association between bleeding and death or ischemic events. Patients with bleeding complications presented a 5-fold higher incidence of death during the fi rst 30 days and a 1.5-fold higher incidence of death between 30 days and 6 months after an invasive procedure. An association was found between the severity of bleeding and an increased risk of death [3]. Also, the type of bleeding, in the context of location (access and non-access bleeding), may signifi cantly aff ect the prognosis. Th e data analysis from the REPLACE-2, ACUITY, and HORIZONS-AMI trials found increased total 1-year mortality for patients presenting bleeding complications, but the risk was signifi cantly higher when manifested as non-access bleed ing compared with access-site bleeding (HR 2.27, 95% CI 1.42 to 3.64, P <0.0007) [61]. Th e reason for the worse outcomes in patients exhibiting bleeding was not completely explained. It is assumed that bleeding leads to hemodynamic compromise, decreasing tissue oxygenation (for example, because of anemia or hypotension) and consequently activating adaptive mechanisms, which may trigger a chain of other adverse complications [62] (Figure 1). Anti platelet and anticoagulant drugs are often interrupted or at least reduced with an increased risk of subsequent ischemic events. Finally, blood transfusion administration is assumed to have protrombotic eff ects and therefore infl uence the higher mortality rate [63].

Management
Th e management of bleeding complications ideally should be focused mainly on preventive measures, especially in high-risk patients. For each patient, the therapy should be personally tailored according to the bleeding risk score. Th ese recommendations demonstrate the impor tance of an individual approach to each of the many steps associated with the treatment of patients with ACS, particularly patients with stable forms of ischemic heart disease [64]. Firstly, the real benefi t versus the risk from an invasive procedure should be considered thoroughly. For risk score assess ment, the scoring method described in the 'Incidence and predictors of bleeding complications' section may be used [12]. In regard to the invasive procedure itself, a radial approach and a smaller sheath size are assumed to be associated with a lower risk of bleeding complication and therefore should be preferred, when available, for patients with a higher risk of bleeding [29]. Th e same decrease in the rate of bleeding complications may be achieved with the use of specifi c closure devices. Th ere are several types of vascular closure devices. Th e most often used active closure devices (for example, Angio-Seal (St Jude Medical, Minnetonka, Minnesota) or Perclose A-T (Abbott Vascular, Abbott Laboratories, Abbott Park, IL, USA)) were part of the several studies comparing standard manual compression with these devices [65].
Th ese studies showed decrease in incidence of access-site bleeding when special vascular closure devices were used (similar to decrease achieved using radial access). Independent randomized trials are necessary, but these devices should be thoroughly considered for patients exhibiting a higher risk of bleeding [68]. To avoid gastrointestinal bleeding, proton pump inhibitors should be used for patients with a history of gastrointestinal bleeding, especially when dual antiplatelet therapy is necessary, and rehydratation therapy needs to be emphasized for patients with renal insuffi ciency. Th e administration of a specifi c drug and its dosage for anticoagulant and antitrombotic therapy are other important criteria that require a highly individual perspective [69]. According to evidence-based medical data from large randomized trials (SYNERGY, OASIS-, ACUITY, and HORIZONS-AMI), the guidelines of the American College of Chest Physicians noted that there is a decrease in the risk of bleeding complications when using unfractionated heparin rather than low-molecularweight heparin (LMWH) in patients with ST-elevation myocardial infarction receiving fi brinolytic therapy, whereas in patients with non-ST-elevation ACS and unstable angina pectoris, fondaparinux appears to be safer than LMWH, and bivalirudin (a direct thrombin inhibitor) is associated with a lower bleeding risk than GPIIb/IIIa inhibitors in combination with heparin [70].
In the era of new antitrombotic drugs, data from large randomized trials and the guidelines arising from them should provide clues for treatment, and the optimal Chest tube output of at least 2 L within a 24-hour period If a CABG-related bleed is not adjudicated as at least a type 3 severity event, it will be classifi ed as 'not a bleeding event' Type 5: fatal bleeding Type 5a Probable fatal bleeding: no autopsy or imaging confi rmation, but clinically suspicious Type 5b Defi nite fatal bleeding: overt bleeding or autopsy or imaging confi rmation Platelet transfusions should be recorded and reported but are not included in these defi nitions until further information is obtained about the relationship to outcomes. a Corrected for transfusion (1 unit of packed red blood cells or 1 unit of whole blood = 1 g/dL hemoglobin). b Only allogeneic transfusions are considered transfusions for Bleeding Academic Research Consortium (BARC) type 4 bleeding. Cell saver products will not be counted. CABG, coronary artery bypass graft.
therapy should be considered according to individual risk stratifi cation [19,20,71]. Once bleeding complications have occurred, the specifi c treatment is always determined on the basis of a combination of several factors: (a) the severity of bleeding, associated with hemodynamic compromise of the patient; (b) the possibility of applying specifi c, local treatment; and (c) the need for anticoagulant or antiplatelet therapy versus the risk of discontinuous treatment. Local minor bleeding usually does not require any specifi c treatment, and manual compression may be suffi cient, without a need for a change in the established therapy. For more severe bleeding, the applied treatment will be individually determined while the patient is closely monitored. If the patient is hemodynamically unstable, antiplatelet and anticoagulant therapy should preferably be interrupted until the bleeding is under control and its administration is safe again, despite the higher risk of ischemic events [62,72]. In the context of blood transfusion, the administration should be considered carefully [73]. According to recent guidelines for ACS, blood transfusion is recommended only in case of compromised hemodynamical status or hematocrit of less than 25% or hemoglobin level of less than 7 g/dL [19].

Conclusions
As percutaneous diagnostic coronary angiography and coronary intervention have become widespread and more eff ective therapeutically and with the development of new antiplatelet drugs, it may be stated that we have almost reached the boundary regarding the reduction of ischemic events as complications of these methods. Now is the time to focus on and improve the safety of these procedures. Th e reduction of bleeding complications associated with invasive procedures in cardiology, which is of both short-and long-term prognostic value, should be the next step and should become a point of interest for all clinical physicians as well as for researchers.