Triple Antithrombotic Therapy – Rates of Vascular Events and Bleeding
The combination of all three antithrombotic agents after PCI might be expected to minimise the risk of both stroke and stent thrombosis but it would also be expected to increase bleeding rates. Data from the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association guidelines (CRUSADE) registry showed that approximately one-third of patients with ACS who were established on OAC at hospital admission had their OAC discontinued when DAPT was started following PCI.29 It seems likely that this practice related to concerns regarding the risk of bleeding with triple therapy. In the absence of randomised trials in this area, information regarding clinical outcomes for patients who have received triple therapy come from observational studies. A recent meta-analysis of nine studies, which included 1,996 patients requiring OAC who underwent PCI, compared clinical outcomes in those who received triple therapy with those who received DAPT.30 In this analysis, triple therapy was associated with a lower rate of cardiac death, MI, stent thrombosis or target lesion revascularisation (odds ratio [OR] 0.60; 95 % confidence interval [CI] 0.42–0.86; p=0.005) and all-cause mortality (OR 0.59; 95 % CI 0.39–0.90; p=0.01) compared with DAPT. Major bleeding in the first six months after PCI, however, was significantly more common (4.1 versus 1.9 %; p=0.04) in patients who received triple therapy than DAPT (OR 2.12; 95 % CI 1.05–4.29).
In registries of patients who received triple therapy after PCI, the rate of major bleeding or need for blood transfusion ranged from approximately 5 % early after PCI to more than 10 % at 12 months.1–4 In a nationwide Danish registry of 11,480 patients with AF who were admitted for MI or PCI between 2001 and 2009, bleeding requiring hospital admission was significantly more frequent (14.2 events per 100 person-years) in patients who received triple therapy than in patients who received DAPT or OAC plus either aspirin or clopidogrel (9.7 versus 7.0 versus 6.9 events per 100 person-years, respectively).31 Furthermore, the bleeding risk was front-loaded with a hospital admission rate higher than 20 % in the first 90 days after PCI in patients who received triple therapy. In the post hoc analysis of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) study, the rate of major bleeding after PCI for acute MI during the index hospital admission was 17.1 % in patients treated with triple therapy compared with 6.5 % in patients who received DAPT (p<0.0001).32 Major bleeding or the need for blood transfusion after PCI is associated with increased mortality.33 Minor bleeding complicates clinical management and may lead to discontinuation of OAC or DAPT with consequent loss of their protective effect against thrombotic vascular events.5,7 It is desirable to limit the duration of triple therapy as much as possible, particularly in patients who are at high risk of bleeding. In patients who require OAC, this can only be achieved by curtailing the period of DAPT.
Limiting the Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention
BMS use affords the opportunity to limit the duration of triple therapy to one month after PCI in patients who require OAC. However, there are well-founded reasons why DES use might be preferable to BMS use in some patients who require OAC. The use of DES more than halves the requirement for repeat revascularisation compared with BMS use. Minimising the requirement for repeat invasive procedures is particularly desirable in patients who are taking OAC. Those patients who are at high risk of restenosis are likely to benefit most from DES use.
Several randomised controlled trials have now been published, which compared clinical outcomes in patients who received limited duration or standard duration DAPT after PCI using DES. In the REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation (RESET) trial, 2,117 patients who underwent PCI using the Endeavor® zotarolimus eluting stent (ZES) (Medtronic Inc, Minneapolis, Minnesota, US) were randomly assigned to receive either three months or 12 months DAPT after the procedure.34 The primary endpoint of cardiovascular death, MI, stent thrombosis, target vessel revascularisation (TVR) or bleeding at one-year occurred in 4.7 % patients in each group (p<0.0001 for non-inferiority of three months compared with 12 months DAPT). The rates of death, MI or stent thrombosis were 0.8 versus 1.3 % (p=0.48) and of stent thrombosis were 0.2 versus 0.3 % (p=0.65), respectively, in patients who received three months compared with 12 months DAPT. There were no cases of stent thrombosis after three months in the limited duration DAPT group. The Optimized duration of Clopidogrel Therapy Following Treatment with the Zotarolimus-Eluting Stent in Real- World Clinical Practice (OPTIMIZE) trial was of similar design, involving the random allocation of more than 3,000 patients undergoing PCI with ZES to receive either three months or 12 months DAPT.35 At one-year the rate of the primary endpoint (a composite of all-cause mortality, MI, stroke and major bleeding) was 6.0 % in the three- month DAPT group compared with 5.8 % in the 12-month DAPT group (p=0.002 for non- inferiority of three months versus 12 months DAPT). One-year rates of major adverse cardiac events were similar between groups (8.3 versus 7.4 %, respectively; hazard ratio [HR] 1.12; 95 % CI 0.87–1.45). Nor were there significant differences between groups in the rates of the primary net clinical benefit endpoint, major adverse cardiac events or stent thrombosis that occurred between three and 12 months.
The Resolute ZES (Medtronic Inc, Minneapolis, Minnesota, US) has CE Mark approval for only one month of DAPT following deployment. This was granted after analysis of a cohort of 4,896 patients who received this stent showed that the rate of stent thrombosis was very low (0.11 %) among the 903 patients whose DAPT was interrupted more than one month (and less than 12 months) following PCI.36 This rate was no higher than the 0.84 % rate of stent thrombosis observed among the 3,827 patients whose DAPT was uninterrupted, and it was significantly lower than the rate of 3.61 % in the 166 patients whose DAPT was interrupted within one month of stent deployment (p<0.001). In this cohort, DAPT was interrupted for >14 days in 874 patients. All six cases of stent thrombosis occurred in the 122 patients whose DAPT was interrupted within the first month of therapy while there were no cases of stent thrombosis among the 752 patients whose DAPT was interrupted between one and 12 months after PCI. The rate of cardiac death or target vessel MI was 6.84 % among patients whose DAPT was interrupted for >14 days within one month of PCI, 1.41 % when DAPT was interrupted for >14 days between one and 12 months after PCI and 4.08 % in the 4,071 patients whose DAPT was not interrupted for >14 days.
Is Dual Antiplatelet Therapy Necessary After Percutaneous Coronary Intervention in Patients Taking Oral Anticoagulation?
The question of whether or not DAPT (and thereby triple antithrombotic therapy in patients who require OAC) is needed at all following PCI was investigated in the What is the Optimal antiplatElet therapy in patients with oral anticoagulation and coronary StenTing (WOEST) trial.37 In this trial, 573 patients who were receiving OAC with a VKA and who underwent PCI were randomly assigned to clopidogrel and OAC or to triple therapy. The primary endpoint of any bleeding event within one year of PCI occurred significantly less frequently in patients in the clopidogrel and OAC group compared with the triple therapy group (19.4 versus 44.4 %; HR 0.36 [95 % CI 0.26–0.50]; p<0.0001). The secondary endpoint, a composite of death, MI, stent thrombosis, stroke or TVR, was also significantly reduced in patients taking clopidogrel and OAC compared with triple therapy (11.1 versus 17.6 %; HR 0.60 [95 % CI 0.38–0.94]; p=0.025). The omission of aspirin therefore led to a greater than 50 % reduction in bleeding without a detectable increase in adverse cardiovascular events. These results suggest that triple therapy may be unnecessary following PCI for patients who are treated with OAC.
Before applying the findings of the WOEST trial to routine clinical practice, several observations should be made about its methodology and results. The trial medication was administered in open label fashion, which might have introduced bias into the results. Most of the bleeding episodes were ‘minor’ or ‘moderate’ in severity depending upon the bleeding event classification used. There were relatively low rates of radial artery access and proton pump inhibitor use, which might have mitigated against lower bleeding rates. Importantly, the WOEST trial was not adequately powered to demonstrate non-inferiority for the composite secondary endpoint of cardiovascular events. On the other hand, the bleeding events committee were blinded to treatment allocation; the difference in bleeding events between groups was accounted for by lower rates in the clopidogrel and OAC group of overt haemorrhage causing a drop in haemoglobin concentration of 3–5 g/dL or a drop in haemoglobin concentration of >4 g/dL without overt haemorrhage (Thrombolysis In Myocardial Infarction [TIMI] minor bleeding) and by a lower rate of blood transfusions (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries [GUSTO] study moderate bleeding), events well worth avoiding; and there was no trend towards higher rates of stent thrombosis in patients who received clopidogrel and OAC compared with triple therapy, with rates of any stent thrombosis of 1.4 versus 3.2 %, definite stent thrombosis 0.4 versus 1.1 %, probable stent thrombosis 0 versus 0.7 % and possible stent thrombosis 1.1 versus 1.4 %, respectively. Indeed, the significantly lower rate of cardiovascular events in the clopidogrel and OAC group makes it unlikely that a clinically meaningful excess of cardiovascular events arises from omitting aspirin after PCI in patients who are taking clopidogrel and OAC. Furthermore, these findings are consistent with an analysis of 12,165 patients with AF hospitalised for MI or PCI in the Danish registry referred to earlier in which one-year rates of cardiovascular events and all-cause mortality were compared in patients who received different antithrombotic regimens.38 Rates of MI or cardiovascular death, stroke and all-cause mortality were similar in patients who were treated with the combination of clopidogrel and OAC with a VKA compared with triple therapy. By contrast, the ischaemic stroke rate was significantly higher in patients who were treated with DAPT (aspirin and clopidogrel) and all-cause mortality was significantly higher in patients who were treated with DAPT or with aspirin and OAC. Taken together, these data suggest that clopidogrel and OAC is at least as effective and as safe as triple therapy.