Anticoagulation after coronary stenting: a systemic review

Abstract

Introduction

Anticoagulant therapy is essential to prevent thromboembolism, especially in patients who are undergoing percutaneous coronary intervention (PCI).¹ Taking the effect of anticoagulant strategies into account, anticoagulant agents can be divided into two categories, one of which is anticoagulant agents, such as unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), fondaparinux and bivalirudin, which are mainly used in the perioperative period of a PCI to prevent ischemic events, including stent thrombosis (ST) and reinfarction, from occurring locally in the coronary artery. According to the recommended guidelines, UFH, LMWH and fondaparinux are usually administered intravenously or subcutaneously during a primary and elective PCI, and then should be discontinued after the PCI except in specific situations [e.g. left ventricular (LV) aneurysm and/or thrombus, atrial fibrillation (AF), prolonged bed rest]. Meanwhile, bivalirudin monotherapy is reasonable in preference to a combination of UFH and glycoprotein IIb/IIIa inhibitor (GPI) for patients who are undergoing PCI and are at a high risk of bleeding.^2,3 However, the superiority of bivalirudin monotherapy over heparin is still doubted in clinical practice; therefore, the aim of this review is to interpret the relevant data regarding to the efficacy of bivalirudin in a PCI.

The other strategy is oral anticoagulants, including vitamin K antagonists (VKAs) (e.g. warfarin) and nonvitamin K antagonist oral anticoagulants (NOACs) (e.g. dabigatran, apixaban and rivaroxaban). It is recommended that oral anticoagulants are combined with antiplatelet therapy to prevent systemic thromboembolic events. This review also intends to illuminate the indication of triple antithrombotic therapy and reduce the risk of bleeding events.

Post-PCI anticoagulation to prevent ST locally in the coronary artery

Current views of post-PCI anticoagulation

The administration of UFH for 48 hours or enoxaparin or fondaparinux for the duration of hospitalization (up to 8 days) is recommended for acute coronary syndrome (ACS) patients who choose an ischemia-guided strategy.³ Anticoagulant therapy is also recommended as a first-class primary PCI procedure for acute myocardial infarction (AMI) in American and European guidelines.^4,5 However, routine post-PCI anticoagulation has not yet been acknowledged in the guidelines, despite many hospitals routinely continuing to administer anticoagulation after a primary PCI according to the contemporary status. Madhavan et al. assessed the utility of routine post-PCI anticoagulation and its association with a 30-day outcome by analyzing sample data of Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, and found that patients who received (n = 869) and did not receive (n = 2063) routine post-PCI anticoagulation experienced similar rates of 30-day adverse ischemic and major bleeding.⁶ Recent studies merged the patient-level databases of two international, randomized and open-label primary PCI trials: EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) and HORIZONS-AMI. EUROMAX enrolled 2218 patients from 65 centers in 9 countries and HORIZONS-AMI enrolled 3602 patients from 123 sites in 11 countries, and the results showed that a post-PCI anticoagulation strategy did not reduce the 30-day rate of adverse ischemic events; on the contrary, it increased bleeding complications.⁷ Therefore, routine post-PCI anticoagulant therapy is not currently recommended to prevent ST after a successful primary PCI, unless there is a definite indication to do so, such as AF, mechanical valves or LV thrombus, to prevent venous thromboembolism or in patients requiring prolonged bed rest.

Application of bivalirudin during the perioperation

Bivalirudin, an analog of naturally produced hirudin, is a direct thrombin inhibitor, which is usually used to prevent ischemic events from occurring during and after a PCI. Its pharmacokinetics are characterized by the rapid onset of the effect and a short half-life of approximately 25 min after the infusion has ceased.⁸ Considering its effective but transient inhibition of thrombin, it is expected that the application of bivalirudin during the perioperation could not only avoid an ST and reinfarction, but also obviously reduce the risk of bleeding. The establishment of bivalirudin as an antithrombotic agent is based on a series of clinical trials, such as BAT (Bivalirudin Angioplasty Trial), CACHET (Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial) and REPLACE-1 (Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events-1).^9,10 The capability of bivalirudin to reduce ischemic and bleeding complications after stenting was demonstrated to be superior in these early-stage trials, but it has been controversial in recent studies. In the large-scale, multicenter HORIZONS-AMI study (n = 3602), the ST-segment elevation myocardial infarction (STEMI) patients without a post-PCI infusion in the bivalirudin arm experienced a significant reduction of 30-day mortality from cardiac causes, and all-cause mortality was mainly due to the lower rates of major bleeding at the expense of an increased rate of acute ST (<24 h) compared to heparin plus GPI.¹¹ Similarly, in the EUROMAX trial, while a prehospital administration of bivalirudin (n = 1102) with a low-dose post-PCI infusion improved the 30-day clinical outcomes with a reduction in the primary composite end point of death and major bleeding compared to the heparin group (n = 1116), the beneficial effects of bivalirudin on a marked reduction in major bleeding did not translate into a reduction of either 30-day or 1-year mortality. It is worth noting that the risk of acute ST within 24 hours in the bivalirudin group significantly increased.^12,13 Furthermore, the results of another single-center HEAT-PPCI (How Effective are Antithrombotic Therapies in Primary PCI) trial were completely different in that patients treated with bivalirudin without post-PCI infusion had an increased 30-day rate of ST and reinfarction compared to heparin alone without any difference in bleeding.¹⁴ The NAPLES III trial (Novel Approaches in Preventing or Limiting Event III) resulted in a similar conclusion.¹⁵ These are interesting studies that cast doubt on the positive impact of bivalirudin on bleeding and thus, influence clinical practice. In fact, the current European and ACC/AHA guidelines for revascularization give a limited recommendation (Table 1), mainly based on the results of the above-mentioned clinical trials.

Since discontinuing bivalirudin right after the PCI may result in an inadequate antithrombotic status, further investigation is needed to reveal whether higher doses of bivalirudin with pronged infusion could prevent acute ST, such as the BRIGHT (The Bivalirudin in Acute Myocardial Infarction vs. Heparin and GPI plus Heparin) trial, a large-scale, multicenter, randomized, open-label study. The outcome of the BRIGHT trial was that the administration of bivalirudin in AMI patients resulted in a decrease in net adverse clinical events at 30 days and 1 year compared to either UFH alone or UFH plus GPI. Incidents of bleeding were significantly reduced using bivalirudin compared to heparin, without any concomitant increase in ischemic events, including an early ST.¹⁶ The efficacy of full doses (1.75 mg/kg/h), low doses (0.25 mg/kg/h) or null post-PCI bivalirudin has been investigated in emerging studies of STEMI patients undergoing primary PCI, and the results show that a post-PCI full-dose bivalirudin infusion does not increase the risk of bleeding and tends to protect against an acute ST.¹⁷ In contrast to the previous trials without a bivalirudin infusion or with a low-dose infusion after a PCI, the above-mentioned trials mentioned may provide pivotal evidence that a higher dose of bivalirudin monotherapy with pronged infusion after stenting is safe and may be critical for avoiding an ST (Table 2).

A meta-analysis was undertaken focusing on the higher risk of bleeding complications and mortality in women than men during a PCI based on 9 trials that involved women being randomly chosen to undergo a PCI with bivalirudin (n = 3960) vs. heparin (n = 4050). The results showed that the bivalirudin group was at a reduced risk of net adverse clinical events (RR = 0.85; 95% CI 0.73–0.98; P = 0.03), mainly driven by a reduction in major bleeding (RR = 0.59; 95% CI 0.49–0.71; P < 0.001) compared with heparin at 30 days, although there was no difference in major adverse cardiovascular events (MACEs), and all-cause mortality was not demonstrated between both two groups either at 30 days or at 1 year, thereby suggesting that bivalirudin may be beneficial for women who are undergoing PCI.¹⁸

Post-PCI anticoagulation to prevent systemic thrombosis

Current studies related to an anticoagulation strategy after stenting

There have been two randomized trials which involved patients requiring long-time anticoagulation after stenting being assigned to triple therapy vs. dual therapy. WOEST (What is the Optimal antiplatelet and anticoagulant therapy in patients with oral anticoagulation and coronary Stenting) was one of these trials, and the primary aim was to assess the intention to treat any bleeding episodes within 1 year of a PCI.¹⁹ Five hundred and seventy-three patients were enrolled from 15 centers in Belgium and the Netherlands. Two hundred and seventy-nine of them were assigned double therapy and 284 were assigned triple therapy based on 1-year data. Bleeding events were recorded in 19.4% of the patients who received VKA and clopidogrel and in 44.4% of those who received VKA, clopidogrel and aspirin for a whole year (P < 0.0001). Meanwhile, the combined endpoint of death, MI, stroke, target-vessel revascularization and ST were no different between the two antithrombotic regimens (P = 0.025). These results suggested that dual therapy with VKA and clopidogrel may be safer and more efficient than triple therapy.²⁰ The other trial was ISAR-TRIPLE (The Intracoronary Stenting and Antithrombotic Regimen) which involved the testing of a 6-week vs. 6-month clopidogrel treatment regimen in patients with concomitant aspirin and oral anticoagulant therapy following a drug-eluting stenting with the aim of evaluating whether shortening the duration of clopidogrel therapy from 6 months to 6 weeks after implanting a drug eluting stent (DES) was responsible for a superior net clinical outcome in patients receiving concomitant aspirin and OAC. The primary endpoint was a combination of death, myocardial infarction, definite ST, stroke or TIMI major bleeding at 9 months. A total of 614 patients who underwent DES implantation at 3 European centers and received concomitant aspirin and OAC were randomized to either 6-week clopidogrel therapy (n = 307) or 6-month clopidogrel therapy (n = 307). The primary endpoint occurred in 30 patients (9.8%) in the 6-week group compared with 27 patients (8.8%) in the 6-month group (hazard ratio [HR]: 1.14; 95% CI: 0.68 to 1.91; P = 0.63), which suggested that 6 weeks of triple therapy was not superior to 6 months in terms of the net clinical outcome.²¹

A recent meta-analysis of seven randomized trials involving ACS patients showed that, the combination of an NOAC and aspirin reduced the incidence of MACE (HR and 95% confidence interval 0.70; 0.59–0.84) compared to aspirin alone, but significantly increased clinical bleeding (HR: 1.79; 1.54–2.09). Compared to dual antiplatelet therapy (DAPT) with aspirin and clopidogrel, adding an NOAC decreased modestly the incidence of MACE (HR: 0.87; 0.80–0.95), but more than doubled the bleeding (HR: 2.34; 2.06–2.66).²² Therefore, since the optimal combination and duration of anticoagulant therapy in AF or venous thromboembolism (VTE) patients after stenting is still unclear, physicians should balance ischemic and bleeding risk when choosing the combination and duration of anticoagulant therapy.

Indication and duration of oral anticoagulation after stenting recommended in the guidelines

It is widely known that it is necessary for most patients undergoing stenting after a PCI to receive DAPT, including aspirin and a P2Y12 inhibitor, for at least 1 year. However, the use of oral anticoagulation is recommended in addition to DAPT if patients suffer from some other comorbidity after stenting, such as AF with a CHA₂DS₂-VASc score ≥2, recent venous thromboembolism, LV thrombus or mechanical valve prosthesis, and this is called triple therapy by ESC and ACC/AHA guidelines.^3,4

The duration of combined anticoagulation and antiplatelet therapy in AF patients after stenting depends on: (i) the status of illness before stenting (ACS or stable CAD), (ii) stent type, (iii) risk of bleeding (based on the HAS-BLED score) and (iv) risk of systemic thromboembolic events (according to the CHA₂DS₂-VASc score). Taking these views into account, triple therapy should be administered for as short a period as possible, namely, 1 month for stable CAD and no longer than 6 months for ACS after stenting to prevent recurrent coronary and cerebral ischemic events. Subsequently, OAC and single antiplatelet therapy should be administered for up to 12 months. A similar duration of anticoagulation should be considered for patients after stenting with a mechanical valve prosthesis or moderate-to-severe mitral stenosis according to an AF strategy and VKA therapy (INR 2.0–3.0 or higher) is recommended to prevent a stroke in these settings.²³

According to a recent meta-analysis, the rate of LV thrombus reaches up to 2.7% after STEMI, and LV thrombus remains a relatively frequent complication.²⁴ Once diagnosed, LV thrombi require oral anticoagulant therapy with vitamin K antagonists for 3 to 6 months. However, considering the risk of bleeding involved in triple therapy after stenting, repeated ultrasound imaging of the left ventricle after 3 months of therapy may facilitate the discontinuation of anticoagulation earlier than 6 months, if there is not further evidence of thrombus, particularly if the apical wall motion has recovered.^5,25 Meanwhile, at least 3 months of anticoagulant treatment is suggested by guidelines for patients with recent or historical recurrent deep venous thrombosis or a pulmonary embolism.²⁶

Current status of NOACs after stenting

Regardless of the DAPT after stenting, both VKA and NOACs are effective for the prevention of strokes in AF. Four pivotal studies that included a meta-analysis of 42 411 patients receiving a NOAC and 29 272 receiving warfarin have been conducted to assess the relative efficacy and safety of NOACs compared to VKA [RE-LY (The Randomized Evaluation of Long-Term Anticoagulation Therapy), ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), ARISTOTLE (The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial) and ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48)]. The results showed that NOACs significantly reduced strokes or systemic embolic events by 19% compared to warfarin (RR 0.81, 95% CI 0.73–0.91; P < 0.0001), mainly based on a reduction of hemorrhagic strokes (0.49, 0.38–0.64; P < 0.0001). NOACs also significantly reduced all-cause mortality (0.90, 0.85–0.95; P = 0.0003) and intracranial hemorrhage (0.48, 0.39–0.59; P < 0.0001).²⁷ Thus, when oral anticoagulation is initiated in a patient with AF, a NOAC (apixaban, dabigatran, edoxaban or rivaroxaban) is recommended in preference to a VKA based on the patient's eligibility.²³ Research related to stenting in nonvalvular atrial fibrillation (NVAF) patients treated with NOACs vs. VKA is still limited. The exploratory, open-label, multicenter, randomized PIONEER AF-PCI study was the first randomized comparison of VKA vs. novel oral anticoagulant therapy (rivaroxaban) in patients with NVAF receiving antiplatelet therapy after PCI stenting.²⁸ Although the trial has been completed, the results have not yet been published. Meanwhile, other clinical trials are still ongoing, including the RE-DUAL PCI trial (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With NVAF Undergoing PCI), the AUGUSTUS trial and the EVOLVE AF PCI trial.^29,30 These large-scale trials aim to assess the efficacy and safety of an anticoagulation regimen with NOACs vs. VKA in combination with antiplatelet agents, and the results are expected to illustrate the optimal combination and duration of anticoagulant therapy in NVAF patients after stenting. The efficacy and safety of NOACs in VTE patients has already been demonstrated by many clinical trials; therefore, NOACs can be viewed as an alternative to the standard treatment in this setting.^26,31

The aim of the RE-ALIGN trial was to evaluate the use of dabigatran to prevent thromboembolic complications in patients with mechanical heart valves; however, this trial was terminated prematurely because of the increased rate of thromboembolisms and bleeding complications compared to the warfarin group.³² Furthermore, since patients with a severe heart-valve disorder were excluded from all the classical trials of NOACs, all NOACs (apixaban, dabigatran, edoxaban and rivaroxaban) are not recommended for patients with mechanical heart valves or moderate-to-severe mitral stenosis.^33–36 Also, since the efficacy and safety of NOACs have not been evaluated in patients after stenting with LV thrombus, they cannot be recommended for use in this context.

Prevention of bleeding risk in triple antithrombotic therapy

The addition of DAPT to OACs after stenting results in at least a 2- to 3-fold increase in bleeding complications compared to OACs alone³⁷; therefore, certain points should be highlighted to diminish the risk of bleeding, the first of which is the application of the HAS-BLED score [Hypertension, Abnormal renal and liver function (1 point each), Stroke, Bleeding history or predisposition, Labile INR, Elderly (65 years), Drugs and alcohol (1 point each)]. The 2015 ESC guidelines for the management of NSTE-ACS indicates that, if the HAS-BLED scores of NSTE-ACS patients with NVAF are 0–2 points, triple therapy should be administered in the first 6 months and then adjusted to OAC along with a single antiplatelet drug for a further 6 months. If the HAS-BLED scores are more than 2 points, triple therapy should only be administered for the first 4 weeks and then adjusted to dual therapy. Second, proton pump inhibitors can also be used for patients receiving triple antithrombotic therapy who have a history of gastrointestinal bleeding or some other high risk of bleeding.³⁸ Thirdly, it is also worth noting that the use of prasugrel or ticagrelor as part of triple therapy should be avoided in AF patients after stenting.^23,39,40 Fourthly, the lowest tested dose for stroke prevention (i.e. dabigatran 110 mg twice a day, rivaroxaban 15 mg once a day, apixaban 2.5 mg twice a day) should be applied for patients treated with NOACs. Fifthly, according to the practical guide of European Heart Rhythm Association, new generation DES or bare metal stent is recommended to shorten the duration of the triple therapy, especially for patients with a high risk of bleeding. In addition, some risk score models such as the TIMI-AF can also assist in predicting poor composite outcome and guide the selection of anticoagulant therapy with a NOAC or VKA.⁴¹

Conclusion

It is acknowledged that anticoagulant therapy can improve the prognosis of patients after stenting by reducing the risk of coronary and systemic thromboembolic events. For post-PCI anticoagulation did not reduce ischemic events and may increase bleeding complications. Therefore, during the perioperation, anticoagulant therapy using UFH, LMWH and fondaparinux should be discontinued after PCI unless there is a compelling reason to continue such therapy.

According to recent guidelines, the use of bivalirudin monotherapy is preferential to using a combination of UFH and a GPI for patients undergoing a PCI who are at a high risk of bleeding especially women. Meanwhile, considering the short half-life and the increased risk of acute ST observed in some clinical trials, a higher dose of bivalirudin with pronged infusion after stenting is recommended to avoid an ST. Until now, the superiority of bivalirudin compared with UFH monotherapy is still controversial and needs more evidence from large-scale clinical trials, especially in terms of a radial approach for a PCI.

Long-term antithrombotic treatment is recommended for patients after stenting with some other comorbidity such as AF, VTE, LV thrombus or mechanical valve prosthesis. In this process, triple therapy is necessary for at least 1 month, despite the obvious increase in the risk of bleeding. Thus, it is vital for physicians to balance the benefits of oral anticoagulant therapy and the risk of bleeding. Type of CAD, type of stent, risk of bleeding and systemic thromboembolic events should be taken into account. In case of NVAF, NOAC is a certainly good choice for reducing bleeding events as well as mortality; thus, it is recommended for NVAF patients in preference to a VKA. In a word, an individualized anticoagulation treatment regimen based on an assessment of the bleeding risk is extremely important for patients after stenting.

Conflict of interest statement

The authors have no potential conflict of interests.

References