Bleeding avoidance strategies among patients undergoing percutaneous coronary intervention

Corresponding Author:

Jonathan Byrne
King’s College Hospital, London, SE5 9RS, UK
Tel: +44 203 299 5945
E-mail: jonathan.byrne@nhs.net

Abstract

Keywords

ACS, acute coronary syndrome, bleeding, mortality, PCI, percutaneous coronary intervention, vascular access

This paper reviews the recent study by Marso et al., demonstrating that in a large national percutaneous coronary intervention (PCI) registry, the use of vascular closure devices (VCDs) and bivalirudin were associated with significantly lower bleeding rates, particularly if applied among patients considered to be at greatest risk of bleeding following PCI [1]. Bleeding is the most common noncardiac complication in patients undergoing PCI, and major bleeding independently predicts both increased in-hospital and 1-year mortality, with the predominant source being access-site related [2–11]. Adjuvant antithrombotic and antiplatelet drugs used during PCI are effective in preventing recurrent ischemia in patients with acute coronary syndromes (ACS), but are also associated with a higher bleeding risk [12]. A reduction in the incidence of ischemia following PCI has been achieved at the expense of major bleeding complications [13,14]. Elderly female patients and those undergoing emergent procedures and receiving intense antithrombotic regimens are at a higher risk of major bleeding [13]. In these subgroups, the risk of major bleeding can reach up to 5%, potentially negating any benefit that PCI might offer in this subgroup [14,15]. This study utilizes a clinical risk model to calculate periprocedural bleeding risk (previously developed and validated using the American College of Cardiology National Cardiovascular Data Registry [NCDR] CathPCI Registry^®) [16].

Study design, setting & patients

The investigators retrospectively analyzed nationally representative PCI data (NCDR CathPCI Registry) from over 1,522,000 patients at 955 US centers undergoing PCI over a 4-year period [1].

Exclusion criteria included a nonfemoral access site (radial or brachial), undergoing more than one PCI procedure during the same hospital episode, patients with incomplete data or missing information on bleeding.

Bleeding avoidance strategies consisted of VCD alone, bivalirudin alone or VCD plus bivalirudin. Patients who received manual compression hemostasis served as the reference group. Periprocedural bleeding (requiring blood transfusion or >3 g hemoglobin loss) was the main outcome measure.

Results

Of the 1,759,408 patients who underwent PCI in the study period, 236,473 were excluded. Overall bleeding occurred in 2% of patients. Bleeding was reported in 2.8% of patients who received manual compression, compared with 2.1% with VCD only, 1.6% with bivalirudin only and 0.9% receiving both strategies (p < 0.001). The observed bleeding rates in low-, intermediate- and high-risk groups were 0.72, 1.73 and 4.69%, respectively. In highrisk patients, manual compression resulted in an observed bleeding rate of 6.1%. With VCD alone, this was 4.6%, and with bivalirudin alone it was 3.8%. Use of both strategies resulted in a much lower rate of 2.8% (p < 0.001).

In this registry, the use of VCD and bivalirudin were associated with significantly lower bleeding rates, particularly in the high-risk population who were least likely to receive both strategies when compared with the low-risk group (14.4 vs 21%, respectively; p < 0.001).

Significance

Periprocedural bleeding remains the most common noncardiac complication of PCI, and independently predicts short- and long-term mortality. A meta-analysis of data from several large studies indicates a fivefold increase in the risk of death in patients with ACS who experience major bleeding [2,12,17].

The current study highlights the importance of applying clinically validated risk models to identify the risk of peri-PCI bleeding, and of adopting necessary bleeding avoidance strategies. It also suggests that clinical outcomes may be improved in patients where a targeted bleeding avoidance strategy is utilized. There are important caveats to the study, many of which are acknowledged by the authors. Although large, this is an observational study and can only be regarded as hypothesis-generating. Importantly, the use of adjunctive pharmacology, particularly GpIIb/IIIa inhibitors (GPIs), is not stated in the manuscript, despite this being a major driver of periprocedural bleeding. Potential confounders include local practice and differences in case mix between centers. Finally, although not recorded, the periprocedural use of other antithrombotics such as fondaparinux may also have had an effect on bleeding [8,18].

Adverse outcomes observed following periprocedural bleeding may also be related to transfusion itself. Important transfusion-related pathophysiological effects may explain the adverse effects [7,19], and recent data have demonstrated that red cells stored for prolonged periods have a direct effect on short- and long-term outcome [20].

Future perspective

▪ Other strategies to reduce periprocedural bleeding

Periprocedural bleeding following PCI can be broadly categorized into access-site and nonaccess- site bleeding. A number of patient- and procedure-related factors may increase the risk of bleeding. Broadly speaking, the main target areas for the avoidance of bleeding are vascular access and the use of adjunctive pharmacotherapy.

Vascular access: is there an advantage to trans-radial over femoral access?

More than two-thirds of bleeding occurrences are often attributed to femoral access site complications [5,10,21]. Randomized trials and registries have demonstrated that trans-radial PCI is associated with a lower risk of bleeding and need for blood transfusion when compared with femoral access, translating into a mortality benefit [11,22]. In this era of stringent antithrombotic and anticoagulant use, trans-radial access offers a major advantage by virtually eliminating access-site-related complications and reducing periprocedural bleeding. However, this is a more technically demanding procedure with a significant learning curve, which probably underlies its comparatively limited use.

Adjunctive pharmacotherapy

Antithrombotic and anticoagulant pharmacotherapy regiments have constantly been refined in order to decrease bleeding risk. Strategies that maintain the benefits of currently available antithrombotic therapies but result in less bleeding, are of distinct clinical relevance. Unfractionated when compared with lowmolecular- weight heparin reduces nonfatal outcomes in ACS with or without ST-segment elevation, but increases major bleeding [23,24]. Therefore, newer agents are required that are safer and work effectively across the whole spectrum of patients undergoing PCI [8,21].

Fondaparinux – a factor Xa inhibitor – reduces the risk of ischemic events in patients with ACS (non-ST-segment elevation myocardial infarction [STEMI]) undergoing PCI, and also substantially reduces major bleeding, leading to a reduction in mortality at 30 days [8].

Bivalirudin – a direct thrombin inhibitor – has been demonstrated to reduce both major and minor bleeding compared with GPIs, with similar efficacy following PCI in both elective and acute settings [9,25]. Elderly patients undergoing PCI following ACS exhibit significantly fewer bleeding complications when assigned to bivalirudin instead of a heparin plus GPI strategy [26]. In patients undergoing primary PCI for STEMI, assignment to bivalirudin as compared with heparin plus GPI resulted in significantly lower rates of major bleeding at 30 days and a mortality advantage at 1 year [27,28].

Vascular closure

Several VCDs have been developed over the last decade or so and have been variably used around the world. Despite their popularity and ease of use, their use has not generally been associated with a reduction in femoral accesssite complications and a number of studies have shown an increase in complications [29,30]. This study by Marso conversely suggests that their use may be associated with a reduction in bleeding in higher risk groups, an observation that certainly merits further study.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Executive summary

Background

▪ Bleeding remains the most common noncardiac periprocedural complication during percutaneous coronary intervention (PCI). Major bleeding is an independent predictor of short- and long-term mortality.

Methodology

▪ A retrospective observational study of nationally representative PCI population data from over 1,522,000 patients undergoing PCI procedures via femoral access, carried out in all 955 US centers over 4 years.

Results

▪ Periprocedural bleeding occurred in 2% of the cases. The use of bivalirudin with a vascular closure device was associated with a 3.8% absolute reduction in PCI-related bleeding in high-risk patients, who were paradoxically the least likely to receive both strategies.

Future perspective

▪ New antithrombin agents combined with radial access for PCI potentially offer an optimal strategy to significantly reduce bleeding following PCI.

References

Papers of special note have been highlighted as:

▪ of interest

▪▪ of considerable interest

1. Marso SP, Amin AP, House JA et al.: Association between use of bleeding avoidance strategies and risk of periprocedural bleeding among patients undergoing percutaneous coronary intervention. JAMA 303, 2156–2164 (2010).
2. Eikelboom JW, Mehta SR, Anand SS et al.: Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 114, 774–782 (2006).

▪▪ This powerful study of 34,146 patients with acute coronary syndromes (ACS) demonstrated a strong, consistent and dose-dependant relationship between bleeding and mortality. It led to greater awareness of prognostic importance of bleeding in ACS.

3. Moscucci M, Fox KA, Cannon CP et al.: Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur. Heart J. 24, 1815–1823 (2003).
4. Feit F, Voeltz MD, Attubato MJ et al.: Predictors and impact of major hemorrhage on mortality following percutaneous coronary intervention from the REPLACE-2 Trial. Am. J. Cardiol. 100, 1364–1369 (2007).
5. Kinnaird TD, Stabile E, Mintz GS et al.: Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions. Am. J. Cardiol. 92, 930–935 (2003).
6. Manoukian SV, Feit F, Mehran R et al.: Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY Trial. J. Am. Coll. Cardiol. 49, 1362–1368 (2007).
7. Rao SV, Eikelboom JA, Granger CB et al.: Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes. Eur. Heart J. 28, 1193–1204 (2007).
8. Yusuf S, Mehta SR, Chrolavicius S et al.: Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N. Engl. J. Med. 354, 1464–1476 (2006).

▪▪ Discusses the organization to Assess Strategies in Acute Ischemic Syndromes (OASIS)-5 study, which compared fondaparinux with enoxaparin in 20,078 patients with ACS. Fondaparinux preserves enoxaprin anti-ischemic benefits in the short term, but substantially reduces major bleeding and improves long-term mortality.

9. Lincoff AM, Kleiman NS, Kereiakes DJ et al.: Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA 292, 696–703 (2004).
10. Yatskar L, Selzer F, Feit F et al.: Access site hematoma requiring blood transfusion predicts mortality in patients undergoing percutaneous coronary intervention: data from the National Heart, Lung, and Blood Institute Dynamic Registry. Catheter Cardiovasc. Interv. 69, 961–966 (2007).
11. Chase AJ, Fretz EB, Warburton WP et al.: Association of the arterial access site at angioplasty with transfusion and mortality: the M.O.R.T.A.L study (Mortality Benefit of Reduced Transfusion After Percutaneous Coronary Intervention via the Arm or Leg). Heart 94, 1019–1025 (2008).

▪▪ Study utilizing analysis of three large registries of all comers to percutaneous coronary intervention (PCI), which demonstrated that trans-radial access was associated with halving transfusion rate and reduction in 30-day and 1-year mortality.

12. Yusuf S, Zhao F, Mehta SR et al.: Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N. Engl. J. Med. 345, 494–502 (2001).
13. Alexander KP, Chen AY, Roe MT et al.: Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes. JAMA 294, 3108–3116 (2005).
14. Avezum A, Makdisse M, Spencer F et al.: Impact of age on management and outcome of acute coronary syndrome: observations from the Global Registry of Acute Coronary Events (GRACE). Am. Heart J. 149, 67–73 (2005).
15. Goodman SG, Fitchett D, Armstrong PW et al.: Randomized evaluation of the safety and efficacy of enoxaparin versus unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. Circulation 107, 238–244 (2003).
16. Mehta SK, Frutkin AD, Lindsey JB et al.: Bleeding in patients undergoing percutaneous coronary intervention: the development of a clinical risk algorithm from the National Cardiovascular Data Registry. Circ. Cardiovasc. Interv. 2, 222–229 (2009).

▪ Study analyzed data from over 300,000 patients in American College of Cardiology National Cardiovascular Data Registry (NCDR) and identified baseline characteristics associated with bleeding, and developed a clinical algorithm to estimate bleeding risk (nine referred to in the current study).

17. Yusuf S, Flather M, Pogue J et al.: Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without initial ST elevation. OASIS (Organisation to Assess Strategies for Ischaemic Syndromes) Registry Investigators. Lancet 352, 507–514 (1998).
18. Yusuf S, Mehta SR, Chrolavicius S et al.: Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 295, 1519–1530 (2006).
19. Rao SV, Jollis JG, Harrington RA et al.: Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 292, 1555–1562 (2004).
20. Koch CG, Li L, Sessler DI et al.: Duration of red-cell storage and complications after cardiac surgery. N. Engl. J. Med. 358, 1229–1239 (2008).
21. Montalescot G, White HD, Gallo R et al.: Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N. Engl. J. Med. 355, 1006–1017 (2006).
22. Agostoni P, Biondi-Zoccai GG, de Benedictis ML et al.: Radial versus femoral approach for percutaneous coronary diagnostic and interventional procedures; systematic overview and meta-analysis of randomized trials. J. Am. Coll. Cardiol. 44, 349–356 (2004).

▪▪ Meta-analysis comparison of trans-radial and trans-femoral approaches to PCI. The former virtually eliminates local vascular complications.

23. Eikelboom JW, Quinlan DJ, Mehta SR et al.: Unfractionated and low-molecular-weight heparin as adjuncts to thrombolysis in aspirin-treated patients with ST-elevation acute myocardial infarction: a meta-analysis of the randomized trials. Circulation 112, 3855–3867 (2005).
24. Murphy SA, Gibson CM, Morrow DA et al.: Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a metaanalysis. Eur. Heart J. 28, 2077–2086 (2007).
25. Stone GW, McLaurin BT, Cox DA et al.: Bivalirudin for patients with acute coronary syndromes. N. Engl. J. Med. 355, 2203–2216 (2006).
26. Lopes RD, Alexander KP, Manoukian SV et al.: Advanced age, antithrombotic strategy, and bleeding in non-ST-segment elevation acute coronary syndromes: results from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J. Am. Coll. Cardiol. 53, 1021–1030 (2009).
27. Stone GW, Witzenbichler B, Guagliumi G et al.: Bivalirudin during primary PCI in acute myocardial infarction. N. Engl. J. Med. 358(21), 2218–2230 (2008).

▪▪ Randomized trial, Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONSAMI), that included 3602 patients with ST-segment elevation myocardial infarction undergoing primary PCI. Bivalirudin alone compared with heparin plus a GpIIb/IIIa inhibitor resulted in a significantly reduced rate of major bleeding at 30 days.

28. Parodi G, Antoniucci D, Nikolsky E et al.: Impact of bivalirudin therapy in high-risk patients with acute myocardial infarction: 1-year results from the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial. JACC Cardiovasc. Interv. 3, 796–802 (2010).
29. Nikolsky E, Mehran R, Halkin A et al.: Vascular complications associated with arteriotomy closure devices in patients undergoing percutaneous coronary procedures: a meta-analysis. J. Am. Coll. Cardiol. 44, 1200–1209 (2004).
30. Koreny M, Riedmuller E, Nikfardjam M et al.: Arterial puncture closing devices compared with standard manual compression after cardiac catheterization: systematic review and meta-analysis. JAMA 291, 350–357 (2004).