Impact of Major Bleeding Post-percutaneous Coronary Intervention
Major bleeding events following a PCI are associated with adverse outcomes such as increased mortality and major adverse cardiovascular events (MACE).17–19 Major bleeding complications account for 12.1 % of all in-hospital mortality after PCI in the National Cardiovascular Data Registry.20
The risk of bleeding following PCI in a patient is increased if the patient is older, has a more acute presentation, has renal failure, heart failure or is haemodynamically compromised.21,22 These factors all predict a poorer outcome in themselves. Does bleeding post- PCI independently predict poor outcome or is it a marker for other comorbidity? Previous studies, which did not account for the higher incidence of these comorbidities in patients who bled, could overestimate the impact of bleeding in the future. Indeed, following an analysis of the Global Registry of Acute Coronary Events (GRACE) data, which took account of the comorbidity, then eliminated the significance of the effect of bleeding, the authors concluded that the comorbidities associated with major bleeding accounted for the higher mortality observed.23 Our recent meta-analysis1 of 42 studies including over 500,000 patients, reported that studies that did not adjust for the incidence of confounding comorbidity in patients that bled demonstrated that major bleeding conferred a sixfold increased risk of death, which reduced to threefold once baseline covariates were adjusted for. It is therefore important to consider the confounding influence of comorbidities on the long-term impact of peri-procedural bleeding.
Different definitions of major bleeding will also have a differential impact on mortality and MACE outcomes, for example the REPLACE-2 (OR 6.69, 95 % confidence interval [CI] 2.26–19.81), STEEPLE (OR 6.59, 95 % CI 3.89–11.16) and BARC (OR 5.40, 95 % CI 1.74–16.74) had the worst prognostic impacts on mortality while HORIZONS-AMI (OR 1.51, 95 % CI 1.11–2.05) had the least impact in a recent meta-analysis.1
Mechanism of Effect
Why does bleeding have such a profound effect on outcome following PCI? Clearly in the acute setting, a GI or intracranial haemorrhage can cause fatal blood loss. Blood loss can occur from the access site, e.g. the femoral artery, or away from the access site, such as intra-cranially or in the contralateral retroperitoneal space. GI haemorrhage after PCI for acute myocardial infarction is associated independently with a prolonged hospital stay and greater mortality in-hospital and at 6-month mortality.24 Access-site-related bleeding, such as major femoral bleeding complications requiring transfusion, are also independently associated with increased 30-day mortality.25 When we compare non-access site, or systemic, bleeding with such access site bleeding, both are associated with increased 1-year mortality, although non-access site bleeding confers poorer prognosis and is associated with a twofold greater impact on 1-year mortality compared with access-site-related bleeding.26
Peri-procedural mortality directly due to the acute haemorrhage does not explain why the adverse outcomes are observed up to a year after the PCI. Bleeding complications may affect the long-term prognosis via several distinct mechanisms. The premature discontinuation of anti-platelet medications may increase the risk of stent thrombosis, itself an independent predictor of long-term outcome.27 Erythropoietin production is stimulated in an anaemic state following blood loss. This could contribute to a pro-thrombotic state beyond the acute phase through platelet activation and induction of plasminogen activator inhibitor-1 (PAI-1) and thus worsen prognosis.28–30 Treatment with erythropoietin in patients following STEMI has been shown to increase the composite end point of death, MI, stroke and stent thrombosis.31 Blood transfusions themselves have an adverse impact on mortality. This has been demonstrated independently of the bleeding and haematocrit 30 days after the event32,33 and with use of other blood products, such as plasma or platelets, which may be necessary following a major haemorrhage.34 For example, our recent meta-analysis of 2,258,711 patients undergoing PCI with 54,000 transfusion events demonstrated that blood transfusion was independently associated with an increase in mortality (OR 3.02, 95 % CI 2.16–4.21) and MACE (OR 3.15, 95 % CI 2.59–3.82) with similar observations recorded in studies that adjusted for baseline hematocrit, anaemia and bleeding.35 Potential mechanisms through which the long-term adverse outcome of transfusion may be mediated are thought to include, the prothrombotic effects of CD40 ligand released by platelets and inhibition of endogenous fibrinolytic systems.28,36 Furthermore, during storage, significant changes in the deformability of red blood cells, as well as changes in their shape, may predispose to ‘plugging’ of transfused cells at the microvascular level, leading to tissue ischaemia. Therefore, the adverse outcomes associated with a bleeding event are likely to relate to the site of the bleed and the acute haemorrhagic event itself, as well as the therapeutic interventions undertaken following the bleeding event, such as discontinuation of anti-platelet therapy, reversal of anticoagulants and receipt of blood transfusions.