Impact of Bleeding Complications on Outcomes After Percutaneous Coronary Interventions

John P. Vavalle, MD; Sunil V Rao, MD

Interv Cardiol. 2009;1(1):51-62.

Bleeding Definitions Used in PCI Trials & Registries

One of the obstacles to fully understanding the impact of bleeding after PCI is the inconsistency in definitions used to define a bleeding event. A number of definitions used to scale the severity of bleeding events have been developed and the reported bleeding rate incidence has been shown to be highly dependent upon the definitions used.^[10] Steinhubl et al. analyzed bleeding data from 13 large trials evaluating antithrombotic drugs in acute coronary syndrome (ACS) in over 178,000 patients. They concluded that it is ‘undoubtedly true’ that variations in definitions used to define major bleeding have led to differences in reported rates.^[11]

Bleeding Definitions Used in Clinical Trials

Two commonly used definitions in the past were the Thrombolysis In Myocardial Infarction (TIMI) and Global Use of Strategies to Open Occluded Arteries (GUSTO) bleeding definitions ( Table 1 ).^[12,13] The TIMI scale uses decreases in hemoglobin or hematocrit and intracranial hemorrhage to classify bleeding as minimal, minor or major. The GUSTO scale defines clinical events that stratify bleeding episodes into mild, moderate or severe. While some studies have used either the GUSTO or TIMI definition, others have used both, and yet others have combined selected elements of both scales. Furthermore, some studies have developed their own criteria to define bleeding events, such as in the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events II (REPLACE-2), the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY), the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), and the Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention Patients (STEEPLE) trials.^[7,8,14,15] In the 13 trials analyzed by Steinhubl, nine of them used their own definitions, other than TIMI or GUSTO.^[11]

Table 2 provides a listing of some of the bleeding definitions used in PCI clinical trials and registries. This table illustrates the wide spectrum of bleeding definitions used and demonstrates why bleeding rates can vary so widely based solely on the definitions applied. Very broad definitions will capture a larger number of bleeding events compared with very narrow definitions and will lead to a higher reported incidence of bleeding events. Even within a single clinical trial, bleeding rates may vary depending on the definitions used. For instance, in the REPLACE-2 study, bleeding episodes were reported using the TIMI and REPLACE-2 definitions. This study compared bivalirudin with provisional glycoprotein (GP)IIb/IIIa inhibitor (GPI) versus heparin with planned GPIIb/IIIa in patients undergoing elective or urgent PCI. When the TIMI definitions are used, no difference in TIMI major bleeding is noted between the two arms (0.9 vs 0.6%; p = 0.30); however, when the REPLACE-2 definitions are applied there is significantly less major bleeding in the bivalirudin group (4.1 vs 2.4%; p = < 0.001).^[7]

Another example of this is found in the STEEPLE trial, comparing two different doses of intravenous enoxaparin with unfractionated heparin (UFH) in patients undergoing PCI. Using the STEEPLE major bleeding definition, there is significantly more bleeding in the UFH group than in either enoxaparin group. If one uses the TIMI major bleeding definition, there is no difference between any of the groups. Furthermore, if one applies the GUSTO moderate or severe definitions, there is a difference in bleeding rates between the UFH group and the low-dose enoxaparin group, but no difference between the enoxaparin groups or between the UFH group and high-dose enoxaparin group.^[8]

Bleeding Definitions Used in Registries

Another confounder in delineating an accurate rate of bleeding complications comes from the variations in the source data. For example, clinical trial data that report bleeding rates are very different from registry data for several reasons. First, registry data can more accurately represent a ‘real world’ demographic of patients, and often include patients with more comorbidities who are often not candidates for clinical trials. Second, the way in which bleeding events are captured in clinical trials differs from how these events are noted in registries. In clinical trials, patients are often prospectively evaluated for bleeding events by study coordinators or clinicians, while bleeding events reported from registry data are often found through retrospective chart review. Owing to this difference in identifying bleedings, the rate of bleedings in registries are usually based on data elements that are readily identifiable from chart review such as transfusions or surgical interventions.^[16] Therefore, variation in patient populations, data capture and definitions all likely lead to differences in sensitivity of detecting bleeding events.

Kinnard et al. reported a three-hospital registry experience on 10,974 patients undergoing PCI from 1991 to 2000 on the incidence and predictors of bleeding after PCI. They used the TIMI bleeding definition and noted major bleeding in 5.4% and minor bleeding in 12.7%, with a blood transfusion given to 5.4% of patients. The majority of bleeding events in both the major and minor bleeding groups were related to vascular access-site hematomas. They also reported the independent risk factors for bleeding, after adjustment for confounders: age, procedural hypotension, intra-aortic balloon pump use, chronic renal insufficiency, systemic hypertension history, and the use of abciximab, which were all independently associated with in-hospital bleeding events.^[17]

The National Heart, Lung, and Blood Institute (NHLBI) Dynamic Registry included a cohort of 6656 patients undergoing PCI enrolled at multiple centers, of which 97% had femoral access. Access-site hematomas requiring blood transfusions occurred in 1.8% of these patients. Older age, lower BMI, female sex, history of renal, cerebrovascular, peripheral vascular or pulmonary disease, and hypertension were significantly associated with hemorrhage.^[4]

The Global Registry of Acute Coronary Events (GRACE) analyzed data from 24,045 patients with ACS and found the overall major bleeding rate to be 3.9%. Right-heart catheter and PCI were independently associated with an increased risk of bleeding. Among the patients in the registry who had PCI, female sex, advanced age and renal insufficiency were associated with increased bleeding risk. Among all major bleeds recorded in this registry, nearly a quarter (23.8%) of them were vascular access site bleeds.^[16]

Data from over 300,000 patients undergoing PCI from the National Cardiovascular Data Registry have been used to develop a risk model to predict the risk of in-hospital bleeding after PCI. Bleeding was defined as transfusion, a drop in hemoglobin greater than 3 g/dl, or an access-site hematoma greater than 10, 5 or 2 cm in the femoral, brachial or radial site, respectively ( Table 2 ). With this definition, the incidence of bleeding was relatively low (2.5%). Significant predictors of bleeding included female sex, age, renal insufficiency, prior PCI, cardiogenic shock, emergent/urgent PCI and chronic obstructive pulmonary disease.^[18]

As outlined above, the reported incidence of bleeding depends highly on several factors: the data source (clinical trial vs registry), the patients, concomitant medical and procedural strategies (e.g., antithrombotic regimens, vascular access site), and the bleeding definition used. Despite these differences, there are some consistencies across studies. In patients undergoing PCI, the primary site of bleeding is the vascular access site. Older patients, females and patients with renal insufficiency are consistently identified as being at high risk for bleeding complications. These data are valuable in determining strategies to reduce bleeding risk, as will be discussed later.

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Cite this: Impact of Bleeding Complications on Outcomes After Percutaneous Coronary Interventions - Medscape - Oct 01, 2009.

Abstract and Introduction
Bleeding Definitions Used in PCI Trials & Registries
Impact of Bleeding on Outcomes
Potential Mechanisms Underlying the Association Between Bleeding & Outcomes
Strategies to Reduce Bleeding Risk
Procedural Methods
Future Perspective
Conclusion
References
Executive Summary

Table 1. TIMI and GUSTO Bleeding Definitions
TIMI bleeding definitions ¹³
Major	Intracranial hemorrhage ≥ 5 g/dl decrease in the hemoglobin concentration ≥ 15% absolute decrease in hematocrit
Minor	Observed blood loss: ≥ 3 g/dl decrease in the hemoglobin concentration ≥ 10% decrease in the hematocrit No observed blood loss: ≥ 4 g/dl decrease in the hemoglobin concentration ≥ 12% decrease in the hematocrit
Minimal	Any clinically overt sign of hemorrhage associated with a <3 g/dl decrease in the hemoglobin concentration or < 9% decrease in the hematocrit
GUSTO bleeding definitions ¹³
Severe or life-threatening	Intracranial hemorrhage Bleeding that causes hemodynamic compromise and requires intervention
Moderate	Bleeding that requires blood transfusion but does not lead to hemodynamic instability
Mild	Bleeding that does not meet criteria for severe or moderate bleeding

GUSTO: Global Use of Strategies to Open Occluded Arteries; TIMI: Thrombolysis In Myocardial Infarction.

Table 2. Bleeding Definitions Used in Percutaneous Coronary Intervention Clinical Trials and Registries
Trial	Patient Population	Agents	Bleeding Definition	Ref.
Bleeding definitions used in PCI trials
EASY	Transradial PCI-ACS	Clopidogrel + abciximab	REPLACE-2	¹⁹
TARGET	PCI-elective	Abciximab vs tirofiban	TIMI	⁵³
PCI-CURE Bivalirudin angioplasty study	PCI-ACS PCI-ACS	ASA + UFH/LMWH ± clopidogrel Bivalirudin vs heparin	CURE bleeding, major bleeding, life-threatening, fatal bleeding, decrease in hemoglobin ≥ 5 g/dl, significant hypotension, symptomatic intracranial bleeding, transfusion ≥ 4 units, non-life-threatening, minor, any bleeding that led to interruption of study medication, blood transfusion of 2 or more units ‘Major hemorrhage’, overt bleeding with a decrease in hemoglobin of ≥ 3 g/dl, need for transfusion, intracranial hemorrhage, retroperitoneal bleeding	⁵⁴ ^38,55
REPLACE-2	PCI-elective	Bivalirudin + provisional GPIIb/IIIa inhibitor vs heparin + planned GPIIb/IIIa inhibitor	REPLACE-2 ‘major bleeding’, intracranial, intraocular or retroperitoneal hemorrhage, clinically overt blood loss resulting in a decrease in hemoglobin > 3 g/dl, any decrease in hemoglobin > 4 g/dl, transfusion of ≥ 2 units PRBCs or whole blood	⁷
STEEPLE	PCI-elective	UFH vs enoxaparin 0.5 mg/kg vs enoxaparin 0.75 mg/kg	Major bleeding, fatal bleeding, retroperitoneal, intracranial or intraocular bleeding, hemodynamic compromise requiring specific treatment, bleeding requiring surgical or endoscopic intervention, clinically overt bleeding requiring ≥ 1 unit PRBC or a drop > 3 g/dl, minor bleeding, gross hematuria, prolonged epistaxis, gastrointestinal hemorrhage, hemoptysis, subconjunctival hemorrhage, hematoma > 5 cm or causing hospitalization, overt bleeding with 2–3 g/dl requiring protamine	⁸
ACUITY	PCI-ACS	UFH/LMWH + GPIIb/IIIa inhibitor vs bivalirudin + GPIIb/IIIa inhibitor vs bivaluridin	Major bleeding, intracranial or intraocular bleeding, access-site hemorrhage requiring intervention, ≥ 5 cm diameter hematoma, drop in hemoglobin ≥ 4 g/dl without source, drop in hemoglobin ≥ 3 g/dl with source, reoperation for bleeding, use of any blood products	¹⁴
EPIC	PCI-elective and ACS	Abciximab bolus vs abciximab bolus + infusion vs placebo	TIMI	⁵⁶
EPILOG	PCI-elective	Abciximab/standard dose UFH vs abciximab/low-dose UFH vs UFH	TIMI	⁵⁷
RESTORE ESPRIT	PCI-ACS PCI-elective	Tirofiban/UFH vs UFH Eptifibatide/UFH vs UFH	TIMI and major bleeding, decrease in hemoglobin > 5 g/dl, transfusion > 2 units, associated with surgery, intracranial bleeding, retroperitoneal bleeding TIMI and GUSTO	⁵⁸ ⁵⁹
HELVETICA	PCI-ACS	i.v./sc. hirudin vs iv. hirudin vs UFH	Major bleeding, overt bleeding and decrease in hemoglobin ≥ 2 g/dl, or requiring transfusion of >2 units of whole blood or packed cells, intracranial bleeding, retroperitoneal bleeding, bleeding in major joint, minor bleeding, overt bleeding that did not meet above criteria	⁶⁰
Bleeding definitions used in PCI registries
Kinnard et al. (2003)	10,974 patients who underwent PCI	Variable	TIMI, clinical bleeding, large hematoma ≥ 4 cm, gastrointestinal bleed, retroperitoneal bleed	¹⁷
Steinberg et al. (2008)	1205 patients undergoing elective PCI at a single center	ASA + clopidogrel + UFH/GPIIb/IIIa or bivalirudin	TIMI	⁶¹
Yan et al. (2007)	4360 patients undergoing PCI at a single center	Variable	Major bleeding, drop in hemoglobin >3 g/dl, blood transfusion	⁶²
NHLBI Dynamic Registry Global Registry of Acute Coronary Events	6656 patients undergoing PCI at multiple centers 24,045 patients with ACS	Variable Variable	Access-site hematoma requiring transfusion, access-site hematoma requiring procedural or surgical intervention Major bleeding, life-threatening bleeding requiring ≥ 2 units blood, decrease in hematocrit ≥ 10%, death, intracranial bleed	⁴ ¹⁶
CathPCI Registry of the National Cardiovascular Data Registry (not yet in PubMed)	302,152 patients undergoing PCI	Variable	Transfusion, drop in hemoglobin >3 g/dl, hematoma, >10 cm femoral access, >5 cm brachial access, >2 cm radial access

ACS: Acute coronary syndrome; ASA: Acetyl salicylic acid; GP: Glycoprotein; GUSTO: Global Use of Strategies to Open Occluded Arteries; HgB: Hemoglobin; iv.: Intravenous; LMWH: Low-molecular-weight heparin; NHLBI: National Heart, Lung, and Blood Institute; PCI: Percutaneous coronary intervention; PRBC: Peripheral red blood cell; sc.: Subcutaneous; TIMI: Thrombolysis In Myocardial Infarction. UFH: Unfractionated heparin.

Table 3. ACUITY Trial Primary Outcome Results
Individual end points	UFH or enoxaparin plus GPIIb/IIIa (n = 4603 [%])	Bivalirudin plus GPIIb/IIIa (n = 4604 [%])	p-value	p-value Bivalirudin alone (n = 4612 [%])	p-value
Death from any cause	62 (1.3)	70 (1.5)	0.48	74 (1.6)	0.31
Myocardial infarction	227 (4.9)	229 (5.0)	0.93	248 (5.4)	0.33
Unplanned revascularization	105. (2.3)	123 (2.7)	0.23	110 (2.4)	0.74
Major bleeding (not related to CABG)	262 (5.7)	243 (5.3)	< 0.001	139 (3.0)	< 0.001

ACUITY: Acute Catheterization and Urgent Intervention Triage Strategy; CABG: Coronary artery bypass graft; GP: Glycoprotein; UFH: Unfractionated heparin.

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