Review in depth 247

Bleeding complications in patients undergoing percutaneous coronary interventions: current status and perspective Gjin Ndrepepa and Adnan Kastrati Bleeding complications are among the most common complications of percutaneous coronary intervention (PCI) procedures. A multitude of studies carried out over the last decade have confirmed that bleeding complications after PCI have a negative impact on patients’ outcome (dissatisfaction, morbidity, and mortality) and hospital indices (length of stay and costs). Apart from better recognition and classification of bleeding, recent research has helped to device several risk stratification tools that have markedly improved prediction of peri-PCI bleeding. Moreover, parallel with the recognition of the deleterious effects of peri-PCI bleeding, several strategies (pre-PCI risk stratification for bleeding, the use of bivalirudin as an antithrombotic/anticoagulant strategy, the radial artery route for vascular access and vascular closure devices) that aim to reduce peri-PCI bleeding were developed and used. Their application has markedly reduced the incidence of bleeding and improved the clinical outcome. In this review, we focus primarily

on the bleeding complications occurring during PCI procedures. Specifically, we summarize recent research on the need for a consensus in bleeding definition, incidence of bleeding events, and their impact on outcome, factors associated with increased risk and risk stratification for bleeding, putative mechanisms through which bleeding impact on outcome, and bleedingavoidance strategies to be used in the setting of PCI c 2014 Wolters procedures. Coron Artery Dis 25:247–257 Kluwer Health | Lippincott Williams & Wilkins.

Introduction

(TIMI) [4] and Global Use of Strategies to Open Occluded Arteries (GUSTO) [5] definitions are among the first developed and most commonly used bleeding definitions. The TIMI definition is laboratory based and uses decreases in hemoglobin concentration, hematocrit, or intracranial bleeding site to classify bleeding as major, minor, or minimal. The GUSTO classification was based on clinical events and stratifies bleeding into severe or life-threatening, moderate, or mild. The TIMI and GUSTO classifications were developed to stratify bleeding events in patients receiving thrombolytic therapy and their applicability in recent trials involving PCI and current antithrombotic therapy has been questioned. These classifications are restrictive and may underestimate the severity of bleeding or its association with mortality. For example, a retroperitoneal bleed with a decrease in hemoglobin of 40 g/l is considered dangerous because of an increased risk of mortality; yet, it is classified only as TIMI minor bleeding. Because of these limitations, several study-specific bleeding classifications were developed and used in the PCI trials and registries. An analysis by Steinhubl et al. [3] showed that nine of 13 analyzed trials designed specific bleeding definition criteria, other than TIMI or GUSTO classifications. These classifications are more inclusive and targeted to PCI-borne bleeding as they include, among others, PCI-specific events such as access-site hematomas, access-site surgical repair, and retroperitoneal bleeds.

Roughly one million percutaneous coronary interventions (PCIs) are performed yearly in the USA [1]. Potent antithrombotic therapy has markedly reduced the peri-PCI ischemic complications, but it has increased the rates of bleeding. Bleeding complications are among the most common complications of PCI procedures and account for 12% of 30-day PCI-related mortality [2]. In the last decade, considerable efforts have been made to better recognize, classify, investigate impact on outcome, risk stratify, treat, and avoid peri-PCI bleeding complications. Experts in the field of coronary interventions consider peri-PCI bleeding complications as frequent, dangerous, and costly and, to some extent, predictable and avoidable. In this review, we focus primarily on the bleeding complications occurring in the setting of PCI procedures. Consequently, coronary artery bypass graft (CABG) surgery-related bleeding, bleeding complications occurring in the setting of conservative therapy in patients with acute coronary syndromes (ACS), or chronic post-PCI antiplatelet therapy are not covered. Bleeding definition

Several definitions have been developed to diagnose bleeding or to scale its severity. The existence of several definitions represents a major obstacle for the recognition of the true frequency of bleeding across various studies [3]. The Thrombolysis in Myocardial Infarction c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-6928

Coronary Artery Disease 2014, 25:247–257 Keywords: bleeding, morbidity, mortality, percutaneous coronary intervention German Heart Center, Technical University, Munich, Germany Correspondence to Gjin Ndrepepa, MD, German Heart Center, Lazarettstrasse 36, 80636 Munich, Germany Tel: + 49 89 12181535; fax: + 49 89 12184053; e-mail: [email protected]

DOI: 10.1097/MCA.0000000000000096

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Coronary Artery Disease 2014, Vol 25 No 3

They have improved the detection and stratification of peri-PCI bleeding but have also led to inconsistencies and uncertainties in assessing and reporting bleeding across various studies. To avoid negative consequences caused by multiple bleeding criteria, the Bleeding Academic Research Consortium (BARC) proposed a standardized bleeding definition through the use of a hierarchical approach of describing the grade of bleeding severity in patients receiving antithrombotic therapy [6]. The proposed BARC classification consisted of six classes, from class 0 (no bleeding) to class 5 (fatal bleeding). Details of the BARC classification are shown in Table 1. The BARC definition was validated in 12 459 patients undergoing PCI in the setting of six Intracoronary Stenting And Antithrombotic Regimen (ISAR) trials [7]. Bleeding events according to the BARC classification occurred in 1233 patients (9.9%). Bleeding of BARC class 2 or higher occurred in 679 patients (5.4%). These frequencies were significantly higher than major bleeding frequencies defined according to TIMI (0.9%) or the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events II (REPLACE)-2 trial (3.9%) criteria. A BARC class 2 or higher was associated with a 2.72-fold increase in the adjusted risk for 1-year mortality. BARC-defined bleeding significantly increased the c-statistic of the multivariable model, showing that bleeding provides prognostic information that is independent of and supplementary to that provided by cardiovascular risk factors and relevant clinical variables. Although the BARC criteria appeared to be slightly more sensitive than TIMI or REPLACE-2 criteria for the prediction of 1-year mortality, this was achieved at the cost of a lower specificity [7]. There is a progressive increase in the risk of 1-year mortality with increasing severity of bleeding (Fig. 1) [8]. The BARC criteria offer a balanced combination of laboratory and clinically based metric in bleeding definition. Moreover, the BARC criteria offer a detailed hierarchical system of quantification of bleeding severity that correlates closely to the risk of death. However, the main role of BARC criteria is not to substitute for other existing bleeding definitions but to serve as a unified metric to allow comprehensive and consistent reporting of bleeding and comparison of bleeding rates in future studies. Incidence of peri-PCI bleeding and impact on outcome

The incidence of peri-PCI major bleeding has been reported to vary from 2.2 to 14% [9]. Information on periPCI bleeding was derived from registries and randomized trials. The Global Registry Of Acute Coronary Events (GRACE) showed that PCI is an independent correlate of major bleeding among patients with ACS [10]. Kinnaird et al. [11] were among the first to report the incidence, predictors, and prognostic implications of bleeding and blood transfusion following PCI. In a series of 10 974 nonselected consecutive patients undergoing

Bleeding classification according to the Bleeding Academic Research Consortium

Table 1

Type

Characteristics

0 1

No bleeding Bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical therapy by the patient without consulting a healthcare professional Any overt, actionable sign of hemorrhage (e.g. more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fulfill the criteria for type 3, 4, or 5 but does fulfill at least one of the following criteria: (1) requiring nonsurgical, medical intervention by a healthcare professional, (2) leading to hospitalization or increased level of care, or (3) prompting evaluation Overt bleeding plus hemoglobin decrease of 3 to 50). The discriminatory tests (c-statistic) showed that the CRUSADE bleeding score showed a good ability to discriminate between patients who did versus those who did not have a major bleeding event. Although treatments that increase the risk of bleeding (invasive care or antithrombotic drugs) were excluded, the majority of patients in the CRUSADE registry underwent an initial invasive strategy [24]. Randomized trials were also used to identify predictive factors for bleeding and devise risk stratification risk scores for patients undergoing PCI. The ACUITY trial identified age, female sex, diabetes, hypertension, renal insufficiency, anemia, no previous PCI, cardiac biomarker elevation, ST-segment deviation of at least 1 mm, and treatment with heparin plus GPIs versus bivalirudin monotherapy as independent correlates for bleeding risk [25]. An analysis of the REPLACE-2 trial identified baseline (older age, female sex, impaired renal function, and anemia) and periprocedural (treatment with heparin plus GPIs, prolonged procedure duration, provisional use of GPIs, increased time-to-sheath removal, length of intensive care unit stay, and the use of intra-aortic balloon pump) as independent correlates of major bleeding [16]. Baseline and procedural variables from the REPLACE-2 and REPLACE-1 trials were used to develop a risk score for bleeding in patients undergoing PCI through the femoral approach.

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Bleeding and coronary interventions Ndrepepa and Kastrati 251

The analysis identified seven independent correlates of increased risk for major bleeding: age above 55 years, female sex, estimated glomerular filtration rate less than 60 ml/min/1.73 m2, pre-existing anemia, use of low-molecular weight heparin within 48 h before PCI, and use of GPIs and intra-aortic balloon pump. The risk of major bleeding varied from 1.0% in patients without risk factors to 5.4% in high-risk patients (score Z 10) [26]. In the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors trial, the rate of non-CABG-related TIMI major bleeding by sheath size was 1.5% for 4 or 5-F, 1.6% for 6-F, 3.3% for 7-F, and 3.8% for 8-F or higher. After adjustment, femoral access site (used in 94.9% of cases), larger sheath size, and delayed sheath removal were independent correlates of major bleeding and need for blood transfusion [27]. In a pooled analysis of REPLACE-2, ACUITY, and HORIZONS-AMI trials, Mehran et al. [28] developed a risk score to predict non-CABG-related TIMI major bleeding and evaluated the impact of various types of bleeding on 1-year mortality. The risk score was derived by assigning the weighted integers to each of the following variables: serum creatinine, age, sex, presentation, white blood cell count, cigarette smoking, and randomized treatment. The TIMI major bleeding rates increased from 0.4% among patients in the lowest risk group to 5.8% among those in the highest risk group. TIMI major bleeding and the myocardial infarction within 30 days were associated independently with increased risk of subsequent mortality. TIMI major bleeding showed the strongest association with 1-year mortality, followed by blood transfusion without TIMI bleed, TIMI minor bleeding requiring blood transfusion, and TIMI minor bleeding not requiring blood transfusion. Isolated hematomas were not predictive of mortality [28]. The Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With the Guidelines (ACTION Registry–GWTG) database was also used to develop an in-hospital major bleeding risk model in patients with STEMI and non-STEMI. The 12 baseline variables associated with major bleeding were heart rate, hemoglobin, female sex, serum creatinine, age, ECG changes, heart failure or shock, diabetes, peripheral artery disease, body weight, systolic blood pressure, and warfarin use. The risk score for major bleeding corresponded well with observed bleeding: very low risk (3.9%), low risk (7.3%), moderate risk (16.1%), high risk (29.0%), and very high risk (39.8%). The model showed a good ability to discriminate between patients who did and those who did not have a major bleeding event [29]. These studies identified a plethora of non-modifiable (baseline demographic and clinical variables) and modifiable (pharmacologic drug regimens and procedural

variables) factors that increase the risk of peri-PCI bleeding [25]. The list of predisposing factors may be incomplete because of the exclusion from several trials of several high-risk conditions (history of bleeding or stroke, malignancies, or advanced renal disease). Moreover, the impact of genetic predisposition to bleeding [30] was not considered. Common to all peri-PCI bleeding risk stratification scoring models is the fact that all of them had a good discriminatory power that was within the range of clinical utility in terms of the prediction of periPCI bleeding. Recognition of these factors underlies the basis for the use of bleeding-avoidance strategies in patients undergoing PCI. Predisposing factors for bleeding are summarized in Fig. 2. Peri-PCI bleeding in women

Multiple previous studies have shown that women are more likely than men to experience bleeding complications during PCI. Bleeding complications during PCI in women have been reviewed recently [31]. Data from the large CathPCI Registry with 570 777 patients showed that women had an almost two-fold increase in the adjusted risk for bleeding compared with men and that women remain at a higher risk for bleeding even after the use of bleeding-avoidance strategies [32]. As compared with men, women undergoing PCI are older, have a smaller body, lower creatinine clearance, and more comorbidities, and are more likely to receive less recommended therapies [31]. Although at the time of PCI women may have a worse cardiovascular risk profile including many conditions that predispose for bleeding, the actual reasons for the increased risk for bleeding in women remain unknown. Our group assessed peri-PCI bleeding complications and their association with mortality in 3351 women and 3351 men, matched for age, body mass index, and type of antithrombotic therapy. The 30-day incidence of any bleeding (15.5 vs. 10.6%) and BARC class bleeding of 2 or higher (9.4 vs. 6.5%) was significantly higher in women than in men. After adjustment, female sex remained an independent correlate of any bleeding (OR = 1.61) and of access-site bleeding (OR = 2.00) but not of non-accesssite (OR = 1.18, P = 0.205) bleeding. Bleeding was associated independently with 1-year mortality (HR = 2.18), with no bleeding-by-sex interaction [33]. By showing that women are at a higher risk for access-site bleeding than men, this study may point to the local anatomic differences at the access site as a reason for the increased risk of bleeding in women. The common femoral artery in women was found to be shorter and of a smaller diameter compared with that in men [34]. Consequently, the zone of safe vascular puncture may be smaller and catheter manipulation may be more difficult in women compared with men, which may lead to increased susceptibility for vascular complications in women [34]. Moreover, because of lower body weight,

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252 Coronary Artery Disease 2014, Vol 25 No 3

Fig. 2

Baseline factors

Procedural factors

- Older age - Impaired renal function - Lower body weight - History of bleeding/stroke - Hypocoagulative states - Genetic factors

- Female sex - Anemia - Diabetes - Arterial hypertension - ST-segment changes - Neoplasms

Pharmacologic nterventions - Unfractionated heparin vs. enoxaparin - Unfractionated heparin vs. bivalirudin - Glyocoprotein IIb/llla inhibitors - Adenosine diphosphate receptor antagonists

- Femoral artery access - Large sheaths - Complex procedure - Prolonged procedure - Intra-aortic pump - Increased time-to-shealth removal

Increased bleeding risk

Cerebral location Torrential bleeding

Immediate effect

Anemia

Hemodynamic effects

Hypovolemia Hypotension Increased O2 demand Decreased O2 supply

Neuro endocrine activation

Catecholamines Angiotensin Endothelin-1 P-selectin Erythropoietin VCAM-1

Blood transfusion

Antithrombotic drug discontinuation

2,3-diphosphoglycerate and nitric oxide depletion Proinflammatory state Prothrombotic state Blood viscosity Electrolyte disturbances

Thrombotic events

Increased morbidity/mortality

Predisposing factors for peri-PCI bleeding and putative mechanisms linking bleeding with morbidity or mortality. PCI, percutaneous coronary intervention; VCAM-1, vascular cell adhesion molecule-1.

circulating lipid profile, and lower glomerular filtration rate, women may be at a higher risk of drug overdosing during PCI [31]. It has been reported that drug overdosing accounts for 25% of the bleeding risk in women [35]. Despite increased bleeding risk in women compared with men, bleeding-avoidance strategies are remarkably successful in reducing bleeding in women [32]. Access-site and non-access-site bleeding

The impact of bleeding site on mortality after PCI has been addressed recently [8,36]. In a recent study that included a combined data set from the REPLACE-2, ACUITY, and HORIZONS-AMI trials with 17 393 patients, mostly undergoing PCI through femoral access, the 30-day incidence of TIMI major/minor bleeds was 5.3%. Of all bleeds, 61.4% were of the non-access site. Non-access-site bleeding was associated with more than a two-fold increase in the risk for 1-year mortality (HR =

3.94) compared with access-site bleeding (HR = 1.82). As compared with heparin plus a GPI, bivalirudin reduced both access-site and not-access-site bleeding by B40% [36]. In an analysis of 14 180 patients undergoing PCI through the femoral approach in the setting of seven ISAR trials, bleeding events according to the BARC criteria occurred in 1510 patients (10.6%). Bleeding at the access and non-access site occurred in 905 patients (6.4%) and 605 patients (4.2%), respectively. One-year mortality was 2.5% among patients with no bleeding, 4.5% among patients with access-site bleeding, and 10.0% among patients with non-access-site bleeding (Fig. 3). The inclusion of non-access-site bleeding but not of access-site bleeding in the multivariable model improved the discriminatory power of the model for mortality prediction. Compared with unfractionated heparin, bivalirudin significantly reduced the risk for access-site bleeding (42% reduction) and was associated with a

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Bleeding and coronary interventions Ndrepepa and Kastrati 253

Upregulation of cellular adhesion molecules, P-selectin, and vascular cell adhesion molecule-1 potentially occurring in the setting of severe bleeding causing hemorrhagic shock may occur. A prothrombotic state may predispose to adverse cardiovascular events, especially in patients with ACS [37].

Fig. 3

Probability of mortality (%)

20.0

OR = 2.09 (1.43−3.07) for NASB vs. ASB

15.0 10.0%

10.0

4.5%

5.0

0.0 0

2

4

Patients at risk

6 Months

8

10

12

NAS bleeding

605

567

558

552

545

538

525

AS bleeding

905

876

866

860

846

839

813

Kaplan–Meier curves of 1-year mortality in patients with access-site bleeding (ASB) and non-access-site bleeding (NASB) [8]. OR, odds ratio.

strong trend toward less non-access-site bleeding as well (18% reduction) [8]. Mechanisms of bleeding impact on outcome

Mechanisms through which bleeding or blood transfusion may lead to adverse events have been reviewed recently [37]. A bleeding–mortality causal relationship has been difficult to establish as both conditions seem to have very similar predictive factors. Thus, the occurrence of bleeding simply may unmask a group of patients with a worse cardiovascular risk profile who are at a higher risk for bleeding and mortality [38]. The association of even minor bleeding with adverse outcomes seems to support this opinion [17]. Apart from being a sign of poor health, bleeding itself may increase the risk of morbidity and mortality after PCI (Fig. 2). Bleeding occurring in strategic locations (intracerebral) or the torrential nature of bleeding may lead to death irrespective of other cardiac conditions, if untreated. Bleeding, if massive, may cause hypovolemia, hypotension, anemia, reduction in the oxygen-carrying capacity of blood, and predisposing to tissue ischemia. Bleeding may also induce an endogeneous neurohormonal response, leading to increased circulating levels of catecholamines, angiotensin, and endothelin-1, which may negatively impact on tissue perfusion accentuating myocardial ischemia and myocardial damage, especially in patients presenting with ACS. Major bleeds may require invasive monitoring, reparative surgery, endoscopic procedures, anesthesia, or other therapeutic measures, which in itself poses a risk [9,39,40]. Bleeding may promote a prothrombotic state. Increased synthesis and release of erythropoietin in response to anemia may induce plasminogen activator inhibitor-1.

Blood transfusion used to correct anemia in the setting of ACS almost tripled the risk of 30-day mortality [41]. Poor outcomes after transfusion may be related to the fact that transfusion is indicated in patients with major bleeding or profound (baseline or bleeding induced) anemia, conditions that portend a poor prognosis. Depletion of 2,3diphosphoglycerate – an effector that facilitates oxygen release from hemoglobin at the tissue level – in packed red cells may impair oxygen delivery at the tissue level [42]. Nitric oxide-depleted packed red cells at the time of capillary passage may serve as a sink for nitric oxide, leading to a reduction in the nitric oxide concentration at the capillary endothelium surface [43]. As nitric oxide is crucial for microvascular function, its reduced level may lead to microvascular dysfunction, vasoconstriction, and platelet activation. All these factors may promote tissue ischemia, especially in patients with ACS undergoing PCI. Finally, blood transfusion may exert other deleterious effects through increased prothrombotic state, increased inflammatory burden, and fluid overload, electrolyte imbalance, and increased blood viscosity [9,37,39]. Data from the GRACE registry showed an increased rate of aspirin, thienopyridine, and heparin discontinuation in patients with major bleeding and increased rates of in-hospital mortality among those who discontinued these drugs [38]. Discontinuation of antithrombotic therapy because of major bleeding after PCI has also been associated with increased rates of ischemia, myocardial infarction, stent thrombosis, and repeat procedures. Thus, in the ACUITY trial, stent thrombosis was observed in 3.4% of patients with bleeding, but only in 0.6% among patients without bleeding [13].

Bleeding-avoidance strategies in patients undergoing PCI

According to the current American College of Cardiology/ American Heart Association PCI guidelines [44], all patients should be evaluated for the risk of bleeding complications before PCI (class I, level of evidence C). The application of bleeding-avoidance strategies – a term coined by Marso et al. [45] – has markedly reduced the incidence of peri-PCI bleeding in men and women [32]. Bleeding-avoidance strategies in patients undergoing PCI have been reviewed recently by Dauerman et al. [46]. Briefly, bleeding-avoidance strategies may be categorized into two components: risk evaluation for bleeding and application of pharmacological, procedural, and device interventions aiming at reduction of bleeding.

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Careful assessment of risk for bleeding could be crucial for risk stratification of patients undergoing PCI. The risk assessment may start by weighing the risk/benefit aspects of PCI itself. As shown earlier in this material, several risk stratification schemes and algorithms have been devised and, unanimously, all of them have shown a graded increase in the bleeding rates with the increase in the categories of risk. Nevertheless, a patient risk–treatment paradox has been reported, whereby patients at greatest risk of bleeding were least likely to receive a bleedingavoidance strategy [45]. Fortunately, this paradox seems to have been attenuated recently through the incorporation of individualized bleeding risk estimates into clinical practice and rational increase in the use of bivalirudin in patients with an intermediate to a high risk for bleeding [47]. The selection of the type and dose of peri-PCI antithrombotic drugs impacts on the risk of bleeding. The use of bivalirudin as a peri-PCI antithrombotic/ anticoagulant strategy represents the most important component of pharmacological bleeding-avoidance strategies. Bivalirudin reduces the rates of peri-PCI bleeding significantly across patients in all categories of cardiovascular risk while maintaining the efficacy in protecting against ischemic complications [18]. In some trials, parallel with the reduction in the incidence of major bleeding, a reduction in early and late mortality was observed [19]. Concerns about its antithrombotic efficacy, lack of agents to reverse its antithrombotic effects (if indicated), and its costs may limit the use of bivalirudin in the setting of bleeding-avoidance strategies. Although many procedural measures such as the use of small sheaths, fluoroscopic, or ultrasound-guided femoral artery puncture or earlier sheath removal have been reported to reduce the incidence of bleeding, especially at the access site, the use of the radial artery for vascular access during PCI procedures has attracted the greatest attention. Recent guidelines have issued a class IIa (level of evidence: A) for the use of the radial artery route during PCI [44]. The advantages and disadvantages of the use of the radial artery for vascular access during PCI have been reviewed recently [48]. The use of the radial artery for vascular access is associated with lower rates of major vascular complications, major bleeding, hospital stay, reduced resource use, and cardiac mortality, especially in patients with STEMI [49–51]. The Study of Access site For Enhancement of PCI for Women (SAFE-PCI for Women) tested the safety and effectiveness of radial-access PCI in women. The trial planned to randomize 1787 women undergoing elective PCI, urgent PCI, or diagnostic catheterization with possible PCI to either a radial or a femoral vascular access approach. The primary efficacy endpoint was bleeding (BARC classes 2, 3 or 5) or vascular complications requiring intervention within 72 h after procedure or at hospital discharge. After

1120 patients were recruited, the study was prematurely interrupted by the Data and Safety Monitoring Board because the primary efficacy event rate was markedly lower than expected. In the PCI group, bleeding and complication rates were 1.2% in the radial group versus 2.9% in the femoral group (P = 0.12). In the entire cohort of randomized patients, bleeding and complication rates were 0.6 versus 1.7% (P = 0.03) among patients assigned to radial or femoral artery approaches. Radial-to-femoral access crossover occurred in 6.1% of radial-access-treated patients. The overall procedural failure rate was 6.7% in the radial group and 1.9% in the femoral group (P < 0.001). Although prematurely interrupted, the trial suggested that the radial artery may be a preferred strategy for women with the understanding that a proportion of patients may need bailout to femoral access [52]. Although associated with a favorable efficacy and safety profile compared with the femoral approach, the radial artery route is not the panacea for abolition of bleeding or other vascular complications. Although rare, if left without treatment, large forearm hematomas or compartment syndrome may occur. The non-access-site bleeding is not expected to be affected by vascular route. The use of the radial artery for vascular access in the elderly and in women seems to be technically demanding. The radial route may be not appropriate for complex or procedures requiring large-size equipment. Finally, concerns have been raised about the impact of the inability to obtain access, arterial spasm, radial artery occlusion, nerve damage, greater radiation, impact of learning curve, noninclusion in trained programs, and long-term consequences such as availability for repeat use or use as a bypass graft [48,53]. The use of vascular closure devices in the setting of bleeding-avoidance strategies remains controversial. Earlier studies have shown an overall higher risk of vascular complications with the use of vascular closure devices compared with manual compression [54]. Concerns, however, have been raised about the quality of devices and the effect of learning curve in earlier studies. Failed attempts to implant vascular closure devices may increase the risk of vascular complications. In a recent analysis of 9853 patients, the vascular closure device failure rate was 2.3% and it was associated with 4.8-fold increase in the risk for vascular complications compared with successful implantation [55]. A more recent meta-analysis of 31 randomized studies with 7528 patients randomized to vascular closure devices or manual/mechanical compression concluded that the use of vascular closure devices significantly shortened time to hemostasis, but it was associated with an increased risk of infection, lower limb ischemia, or need for vascular surgery [56]. The rates of groin hematoma or bleeding were not significantly reduced. In the CathPCI registry, vascular closure devices and bivalirudin were associated with significantly lower bleeding rates, particularly among high-risk patients.

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Bleeding and coronary interventions Ndrepepa and Kastrati 255

Bleeding events were reported in 2.8% of patients who received manual compression, compared with 2.1, 1.6, and 0.9% of patients receiving vascular closure devices, bivalirudin, and both strategies [45]. Despite these favorable results, the current guidelines remain restrictive on the use of vascular closure devices. Specifically, they issued a class IIa recommendation (level of evidence: B), for the use of vascular closure devices for the purposes of achieving faster hemostasis and earlier ambulation, and a class III recommendation (level of evidence: B), which is no recommendation of these devices for the purpose of decreasing vascular complications [44]. The ongoing randomized Instrumental Sealing of Arterial Puncture Site Closure Device Versus Manual Compression Trial (ISAR-CLOSURE), estimated to enroll 4500 patients, will investigate the impact of vascular closure devices on access-site complications after coronary angiography. The study design is shown in Fig. 4. Avoiding bleeding in patients undergoing PCI while on oral anticoagulant therapy remains challenging. In the setting of the What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing (WOEST) trial, bleeding episodes were reported in 44.4% of patients on triple therapy (clopidogrel plus aspirin) and 19.4% of patients in the double therapy (clopidogrel) arm (a 64% reduction in the hazard for bleeding). Thus, a strategy of using clopidogrel without aspirin was associated with a significant decrease in the bleeding complications without an increase in the rate of thrombotic events [57].

Fig. 4

ISAR-CLOSURE

Patients undergoing diagnostic coronary angiography via common femoral artery puncture n = 4500

FemoSeal VCD

EXOSEAL VCD

Manual compression

Follow-up: Duplex ultrasonography prior to hospital discharge Clinical follow-up at 30 days

ISAR-CLOSURE study design. VCD, vascular closure device. ISAR-CLOSURE, Instrumental Sealing of Arterial Puncture Site Closure Device Versus Manual Compression Trial.

Concluding remarks and unresolved issues

Recent research has markedly improved our understanding of peri-PCI bleeding complications on several aspects. First, recent studies involving millions of PCI procedures provided confirmatory information on the negative impact of bleeding on clinical outcome including an increased risk of mortality. Second, recent research has offered several risk-stratification tools that have markedly improved the prediction of peri-PCI bleeding events. Third, a consensus document aiming at standardization of bleeding definitions for cardiovascular trials has been proposed and validated. Although its applicability in clinical practice remains to be seen, the BARC document may serve as a unified metric to allow consistent reporting of bleeding and allow a comparison of bleeding rates in future clinical investigations. Fourth, recent research has provided further support for the beneficial effects of bleeding-avoidance strategies not only in reducing the frequency of bleeding but also in improving clinical outcome. Despite these achievements, several unresolved issues remain. Although the association between bleeding and mortality is strong, causality in the bleeding–mortality relationship remains unproven. Mechanisms relating bleeding with outcome still remain hypothetical at least in part because of not being a primary focus of recent research. The strategies of continuation, dose adjustment, drug switching, or discontinuation of antiplatelet therapy in patients with peri-PCI bleeding remain largely unknown. Several aspects of the efficacy/safety relationship of bleeding-avoidance strategies remain unsatisfactorily investigated. Application or selection of the most beneficial bleeding-avoidance strategy commensurate to patients’ bleeding risk remains a task for future studies. In particular, cost-effectiveness of bleeding-avoidance strategies needs further investigation. Decision-analytic models have shown that substituting bivalirudin for unfractionated heparin alone may be not cost-effective in more than 90% of patients at low and moderate risk of bleeding and that bivalirudin is reasonably cost-effective for only a small proportion of patients at a higher risk of bleeding when undergoing PCI [58]. It has also been estimated that specially designed equipment for radial artery access is associated with incremental costs of US$ 55–75 per procedure compared with the femoral artery approach [46]. Although a strategy of clopidogrel alone seems to significantly reduce the risk of peri-PCI bleeding in patients on oral anticoagulant therapy [57], more investigation is needed to define the most optimal peri-PCI antiplatelet therapy in these patients. The efficacy and safety of new drugs to be used as peri-PCI antithrombotic/ anticoagulant therapy remain to be tested.

Acknowledgements Conflicts of interest

Dr Kastrati has received payment for lectures including service on speakers bureaus from Abbott, Astra-Zeneca,

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Biosensors, Biotronik, Daiichi Sankyo, MSD and The Medicines. Ndrepepa has no conflicts of interest.

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