Managing Antiplatelet Therapy and Anticoagulants in Patients with Coronary Artery Disease and Atrial Fibrillation
Zubair Shah, MD, Reza Masoomi MD, Peter Tadros, MD
Division of Cardiovascular Diseases, Mid America Cardiology, University of Kansas Hospital and Medical Center, Kansas City, KS.
Oral anticoagulation (OAC) is essential in patients with atrial fibrillation (AF). Interestingly coronary artery disease coexists in 20–30% of these patients.1,2 Balancing the risk of bleeding and thromboembolism is very important for the management of patients on OAC, especially than when such patients require percutaneous coronary intervention (PCI). Lack of data and clear societal guidelines for peri-procedural and post-procedural management of anticoagulated patients has resulted in diverse clinical practices among clinicians, hospitals, and countries. Furthermore with expanding number of available oral antiplatelet and anticoagulant agents, the uncertainty regarding optimal combination therapy in this growing pool of the patients with overlapping clinical indications is also growing. Given the high proportion of patients with atherothrombosis and requiring OAC for conditions particularly like AF, it is important that physicians are aware of the clinical implications and management of these overlapping syndromes.
In this article we discuss; this evolving dilemma of peri-procedural and post-procedural management of anticoagulated patient’s, burden of the disease, available data, risk factors that could identify high risk patients and propose a well-balanced management strategy.
Key Words : Lariat, Embolic Stroke, Anticoagulant Therapy.
Correspondence to: Dr. Peter N. Tadros,Director, Lynn H. Kindred, MD, Cardiac Catheterization Laboratories.Mid America Cardiology,University of Kansas Hospital and Medical Center, Kansas City, KS3901 Rainbow Boulevard, MS 4023Kansas City, KS 66160.
Long-term oral anticoagulation (OAC) is the cornerstone in the treatment of patients with atrial fibrillation (AF) at moderate to high risk of stroke, those with prosthetic heart valves, cardiogenic thromboembolism, recent deep vein thrombosis or pulmonary embolism. Approximately 70–80% of all patients in AF have an indication for continuous OAC, and coronary artery disease coexists in 20–30% of these patients.1,2 Balancing the risk of bleeding and thromboembolism is crucial in the management of patients on OAC, and this is never more apparent than when such patients require percutaneous coronary intervention (PCI). The periprocedural management of anticoagulated patients is very important, but clinical practice varies widely between clinicians, hospitals, and countries, driven by a lack of data on which to draw guidance. Furthermore as the number of available oral antiplatelet and anticoagulant agents continue to grow, so does the uncertainty regarding optimal combination therapy in this growing pool of the patients with overlapping clinical indications. Given the high proportion of patients with atherothrombosis and requiring OAC for conditions particularly like AF, it is important that physicians are aware of the clinical implications and management of these overlapping syndromes.
Burden Of The Atrial Fibrillation, Valvular Heart Disease And Venous Thromboembolism Disease
The prevalence of atrial fibrillation (AF) in the United States is approximately 6 million patients and is on the rise.3 More than 17 million patients have coronary artery disease (CAD), and over 6 and 8 million Americans, respectively, have suffered a stroke or have peripheral arterial disease.4 The prevalence of AF in patients with established atherothrombosis (11.7%) or risk factors for atherothrombosis (6.2%) is substantially higher compared with the general population (2.3%).5,6 Another challenging patient population is those with valvular heart disease who underwent mechanical valve replacement. Approximately 90000 valve substitutes are now implanted in the United States and 280 000 worldwide each year; approximately one fourth of the US valve replacements are mechanical valves requiring long term OAC.7 Venous thromboembolism (VTE)
causes significant morbidity and mortality with an estimated annual
incidence of 900,000 patients with clinically evident VTE in the
U.S., resulting in an estimated 300,000 deaths from PE.8 Keeping in
mind the burden of various diseases requiring long term OAC, it is estimated that 5–7% of patients undergoing percutaneous coronary
interventions (PCI) have indications for chronic oral anticoagulant
therapy .9,10
Table 1. Recommended antithrombotic strategies following coronary artery stenting in patients with atrial fibrillation at moderate-to-high thrombo-embolic risk (in whom oral anticoagulation therapy is required) by European Society of Cardiology Working Group on Thrombosis, endorsed by the European Heart Rhythm Association (EHRA) and the European Association of Percutaneous Cardiovascular Interventions (EAPCI)
| Haemorrhagic Risk |
Clinical Setting |
Stent Implanted |
Recommendation |
| Low or intermediate |
Elective |
Bare metal |
1 month: triple therapy of warfarin(INR 2.0 - 2.5) + aspirin ≤ 100 mg/day + clopidogrel 75 mg/day
Lifelong: warfarin (INR 2.0 - 3.0) alone |
|
Elective |
Drug eluting |
3 ( -olimus group) to 6 (paclitaxel) months: triple therapy of warfarin (INR 2.0 - 2.5) + aspirin ≤ 100 mg/day + clopidogrel 75mg/day
Up to 12 months: combination of warfarin (INR 2.0 - 2.5) + clopidogrel 75mg/day ( or aspirin 100 mg/day)a
Lifelong: warfarin (INR 2.0 - 3.0) alone |
|
ACS |
Bare metal/ drug eluting |
6 months: triple therapy of warfarin (INR 2.0 - 2.5) + aspirin ≤ 100 mg/day + clopidogrel 75mg/day
Up to 12 months: combination of warfarin (INR 2.0 - 2.5) + clopidogrel 75mg/day ( or aspirin 100 mg/day)a
Lifelong:warfarin (INR 2.0 - 3.0) alone |
| High |
Elective |
Bare metalb |
2 - 4 weeks: triple therapy of warfarin (INR 2.0 - 2.5) + aspirin ≤ 100 mg/ day + clopidogrel 75 mg/day
Lifelong:warfarin (INR 2.0 - 3.0) alone |
|
ACS |
Bare metalb |
4 weeks: triple therapy of warfarin (INR 2.0 - 2.5) + aspirin ≤ 100 mg/day + clopidogrel 75 mg/day
up to 12 months: combination of warfarin (INR 2.0 - 2.5) + clopidogrel 75mg/day ( or aspirin 100 mg/day); mg/day);a
Lifelong:warfarin (INR 2.0 - 3.0) alone |
INR international normalized ratio; acute cornary syndrome acombination of warfarin (INR 2.0 - 2.5) + clopidogrel 75mg/day may be considered as a alternative bDrug eluting sents should be avoided
Understanding The Problem
The mechanisms of thrombus formation differ between that associated with thromboembolic diseases like AF and that of
coronary artery disease and stent thrombosis. Plasma factors (i.e.,
coagulation factors) are more important in the development of
thromboembolic events during AF and cellular factors (i.e., platelets)
are more important in the pathophysiology of atherothrombotic
events.11 Consequently, oral anticoagulant therapies are mainstay
of treatment for stroke prevention in atrial fibrillation (AF), aswell
as prevention of pulmonary embolism in the recent deep vein thrombosis or pulmonary embolism and antiplatelet agents are of
greater benefit in the prevention of ischemic events, including stent
thrombosis, in patients undergoing PCI.
Table 2. Risk factors associated with an increased risk for stroke/ thromboembolism,68 peri -procedural bleeding68 and stent thrombosis.69
| Thromboembolism/
Stroke |
Stent thrombosis |
Peri-pocedural
bleeding |
| Diabetes mellitus. |
1. Patient-related factors relating to increased
thrombogenecity.
Smoking, Diabetes mellitus, Chronic
kidney disease, Acute coronary syndrome
presentation, High post-treatment platelet
reactivity, Premature discontinuation or
cessation of dual antiplatelet therapy. |
Advanced age
(<75years). |
| Previous stroke,
transient ischemic
attack, or embolism |
2. Surgical procedures (unrelated to the PCI)
Diffuse coronary artery disease with long
stented segments, Small vessel disease,
Bifurcation disease, Thrombus-containing
lesions, Significant inflow or outflow lesions
proximal, or distal to the stented segment. |
Female gender. |
| Heart failure or
moderate–severe
left ventricular
dysfunction on
echocardiography
(e.g. ejection fraction
≤40%) |
3. Stent-related factors
Poor stent expansion,
Edge dissections limiting inflowor outflow,
Delayed or absent endothelialization of stent
struts, Hypersensitivity/inflammatoryand/ or
thromboticreactions to DES polymers , Strut
fractures,
Late malposition/aneurysm formation,
Development of neoatherosclerosis within
stents with new plaque rupture. |
Renal failure. |
| Vascular disease. |
|
Uncontrolled
hypertension. |
| Hypertension. |
Years |
Low body weight.
Patients (n) |
| Female gender. |
|
History of bleeding. |
| Renal failure. |
2006 |
Right heart
catheterization. |
| Mitral stenosis or
prosthetic heart valve. |
2008 |
Anemia. |
|
|
Use of GPIIb-IIIa
antagonists. |
|
|
Triple therapy. |
AF is the most common cardiac arrhythmia and is associated
with a small but significant incidence of stroke and systemic
thromboembolism.12 It is well established that oral anticoagulants
reduce the incidence of stroke and systemic embolism in these
patients.13 A meta- analysis of 29 trials showed that warfarin
reduced stroke by 64% as compared with placebo and by 39% as
compared with aspirin in patients with non-valvular AF14 (Figure 1).
Furthermore several trials including ACTIVE-W have confirmed
the superiority of warfarin in reducing embolic events over dual
antiplatelet therapy (DAPT) with aspirin and clopidogrel in patients
with both paroxysmal and sustained AF and at least 1 additional
stroke risk factor15 (Figure 2).
Figure 1. Reveals relative effects of antithrombotic therapies on all types of strokes from randomized trials in patients with atrial fibrillation. Horizontal lines represent 95% CIs around point estimates. A. Adjusted-dose warfarin compared with placebo or no treatment in 6 randomized trials.
Figure 2. Depicts that compared with clopidogrel plus aspirin, oral anticoagulation therapy reduced all strokes. (RR 1.72, 95% CI 1.24–.37; p=0.01) indicating that oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation at high risk of stroke, especially in those already taking oral anticoagulation therapy.
As a result, the ACC/AHA guidelines recommend oral
anticoagulant therapy with warfarin for those patients with at least
1 additional risk factor for stroke and suggest the use of aspirin only
for those at low risk for stroke such as patients without risk factors.12
Dual antiplatelet therapy (DAPT) is the standard of care to reduce
recurrent ischemic events after acute coronary syndrome (ACS) and
to prevent stent thrombosis after percutaneous coronary intervention
(PCI). Furthermore dual antiplatelet therapy has also been proven
to be superior in terms of safety and efficacy when compared with
anticoagulation with Warfarin following coronary stenting. Data
from Stent Antithrombotic Regimen Study (STARS) trial, in
which 1653 patients who had successful placement of the stent
were randomly assigned to one of three regimens: aspirin alone (557 patients), aspirin and warfarin(550 patients), and dual antiplatelet
therapy (DAPT) with aspirin and ticlopidine (546patients),
revealed that DAPT reduced the occurrence of death, target lesion
revascularization, stent thrombosis, and recurrent MI at 30 days from
3.6% with aspirin alone and 2.7% for aspirin and warfarin compared
to only 0.5% for aspirin and ticlopidine16Figure 3. Because
clopidogrel, a second-generation thienopyridine, has fewer adverse
effects than ticlopidine, such as thrombotic thrombocytopenic
purpura and severe neutropenia, it rapidly became the thienopyridine
of choice.17,18 Current ACC/AHA guidelines recommend DAPT in
patients with an STEMI for at least 1 year for BMS and DES. In
patients with unstable angina or NSTEMI receiving a BMS, DAPT
should be given for at least 1 month and preferably for 1 year.19,20 In
patients who receive an elective DES, the current recommendations
are for one year of DAPT.
Figure 3. 1653 patients who had successful placement of the stent were randomly assigned to one of three regimens:aspirin alone (557 patients), aspirin and warfarin(550 patients), or aspirin and ticlopidine (546patients). The figure shows cumulative Incidence of the primary end point in the Three Treatment Groups. DAPT reduced the occurrence of death, target lesion revascularization, stent thrombosis, and recurrent MI at 30 days from 3.6% with aspirin alone and 2.7% for aspirin and warfarin to 0.5% for aspirin and ticlopidine.
Three antithrombotic drug combinations have been used most in
practice: triple therapy (oral anticoagulation and dual antiplatelet
therapy with aspirin and clopidogrel), oral anticoagulation, and 1
antiplatelet agent (aspirin or clopidogrel), or rarely, DAPT alone
without oral anticoagulants. Although there are wide variations
in type and duration of therapy in practice, triple therapy is the
most common treatment regimen in this setting. Several studies
demonstrate that the risk of bleeding rises with an increased number
of antithrombotic agents. In one study of 21,443 elderly patients
followed on average for 22 months after an acute MI, bleeding
was 1.7 times more frequent with DAPT and 1.9 times more
frequent with aspirin plus warfarin when compared with aspirin
monotherapy.21 Similarly, in a nationwide registry of 40,812 patients
with acute MI in Denmark, the risk of bleeding was 2.6% for aspirin,
4.6% for clopidogrel, 4.3% for DAPT, 5.1% for aspirin plus an oral
anticoagulant, 12.3% for clopidogrel plus an oral anticoagulant,
and 12.0% for triple therapy over a mean follow-up of 16 months22Figure 4. Hence patients taking combination of oral anticoagulants
with aspirin and clopidogrel (“triple therapy”) pose a significant
dilemma for the cardiologist because of the increased risk of major bleeding.
Figure 4. Reveals adjusted risk of non-fatal and fatal bleeding in 40,812 patients treated with antithrombotic drugs after first myocardial infarction HR=hazard ratio. Aspirin monotherapy is used as the reference. The risk of bleeding was 2.6% for aspirin, 4.6% for clopidogrel, 4.3% for DAPT, 5.1% for aspirin plus an oral anticoagulant, 12.3% for clopidogrel plus an oral anticoagulant, and 12.0% for triple therapy over a mean follow-up of 16 months.
In one study among patients on triple therapy with aspirin,
clopidogrel, and warfarin, major bleeding occurred in 4.7%, and
approximately 50% of these patients died within 6 months.23 In a
meta-analysis involving 13 retrospective studies Figure 5 and
registries assessing antithrombotic regimens in patients with AF
undergoing PCI risk of major bleeding was 1.5% at 30 days and 5.2%
at 1 year with triple AT (aspirin + warfarin + clopidogrel/ticlopidine).
Dual antiplatelet therapy (aspirin + clopidogrel/ticlopidine) was
associated with 2.4% annual risk of major bleeding.24 Similarly, in
another meta-analysis involving 9 randomized controlled trials
Figure 5B, patients with triple antithrombotic regimen had
significant reduction in ischemic stroke (odds ratio [OR] is 0.29,
95% confidence interval [CI] is from 0.15 to 0.58; and P = 0.0004) as
compared with dual antiplatelet therapy. While there was a two-fold
increased risk of major bleeding associated with triple antithrombotic
regime (OR 2.00, 95% CI 1.41 to 2.83; and P < 0.0001). The overall
incidence of death (OR 1.20, 95% CI 0.63 to 2.27, and P = 0.56)
and myocardial infarction (OR 0.84, 95% CI 0.57 to 1.23; and P
= 0.38) was comparable between the two regimens.25 Both studies
confirm the cardiovascular benefits of triple antithrombotic regimen
by reducing ischemic stroke risk, but also demonstrated its increased
risk of major bleeding
Figure 5A. Reveals results of the meta-analysis involving 13 retrospective studies and registries assessing antithrombotic regimens in patients with AF undergoing PCI, risk of major bleeding was 1.5% at 30 days and 5.2% at 1 year with triple AT (aspirin + warfarin + clopidogrel/ticlopidine). Dual antiplatelet therapy (aspirin + clopidogrel/ticlopidine) was associated with 2.4% annual risk of major bleeding.
Figure 5B. Shows meta-analysis involving 9 randomized controlled trials. (a) Patients with triple antithrombotic regimen had significant reduction in ischemic stroke (odds ratio [OR] is 0.29, 95% confidence interval [CI] is from 0.15 to 0.58; and P = 0.0004) as compared with dual antiplatelet therapy.(b) While there was a two-fold increased risk of major bleeding associated with triple antithrombotic regime (OR 2.00, 95% CI 1.41 to 2.83; and P < 0.0001).(c) The overall incidence of death (OR 1.20, 95% CI 0.63 to 2.27, and P = 0.56) and myocardial infarction (OR 0.84, 95% CI 0.57 to 1.23; and P = 0.38) was comparable between the two regimens
Major bleeding is a serious complication that is associated with
increased morbidity and mortality particularly when it occurs shortly
after a stent procedure. Despite different bleeding definitions, both
access site and non-access site bleeding has been observed across
all the major trials in patients undergoing PCI. In fact, in one of a
major meta-analysis using combined dataset from the REPLACE-2
(Randomized Evaluation in PCI Linking Angiomax to Reduced
Clinical Events), Acute Catheterization and Urgent Intervention
Triage Strategy (ACUITY), and HORIZONS-AMI (Harmonizing
Outcomes with Revascularization and Stents in Acute Myocardial
Infarction) trials in 17,393 PCI patients, non-access site bleeding
after PCI was found to be common, representing approximately
two-thirds of all TIMI bleeding events, and was found to be
associated with a 4-fold increase in 1-year mortality.26 Furthermore, similar results have been found in other studies indicating a strong
relationship between early bleeding and 1 year mortality. Results
from a major meta-analysis that included 5,384 patients from 4
randomized placebo-controlled trials: ISAR-REACT, SWEET,
SMART-2, and REACT-2, revealed that the 30-day occurrence
of bleeding independently predicted 1-year mortality by a Cox
proportional hazards model, indicating a strong relationship between
the 30-day frequency of bleeding and 1-year mortality after PCI
27fig 6.
Figure 6. Depicts. Kaplan-Meier curves of 1-year mortality among 5,384 patients from 4 randomized bn vmplacebo-controlled trials. The 1-year mortality was 14.1% (n = 30) among patients in whom bleeding occurred within the 30 days after PCI versus 3.3% (n = 167) among patients who had no bleeding within the 30 days (OR 4.75, 95% CI 3.34 to 6.76, p < 0.001).
Bleeding severity also has been found to be directly related to mortality. In a meta-analysis involving about 26500 patients from
the multicenter international GUSTO IIb, the Platelet Glycoprotein
IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin
Therapy (PURSUIT), and the Platelet IIb/IIIa Antagonism for
the Reduction of Acute Coronary Syndrome Events in a Global
Organization Network (PARAGON) A and B trials were studied.
The study demonstrated a relationship between bleeding severity
and worsening 30 day mortality.28 Interestingly, the studies aimed
to investigate the long-term prognosis of patients with in-hospital
major bleeding after primary PCI also show significantly increased
3-year rates of morbidity and mortality29,30fig 7.
Figure 7. Results of the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial involving 3,345 patients with primary PCI. The rates of mortality and MACE were significantly higher in patients with in-hospital major bleeding (IHMB) within each time interval. The deleterious effect of major bleeding was observed within 1 month, between 1 month and 1 year, and between 1 and 3 years. IHMB was an independent predictor of mortality (hazard ratio: 2.80; 95% confidence interval: 1.89 to 4.16, p < 0.0001) at 3-year follow up.
Managing the patients with AF requiring oral anticoagulants with
aspirin and clopidogrel needs a thoughtful balancing act between
risk of stroke or systemic embolism, risk of stent thrombosis and
recurrent ischemic events as well as risk of bleeding.
Arguably, the 3 key issues appear to be:
1. Whether or not to interrupt OAC for the procedure
2. The choice of long term antithrombotic therapy that follows PCI
3. How best to modify the procedure to ensure optimal safety
Whether Or Not To Interrupt Oac For The Procedure
Current guidelines offer limited guidance on long-term OAC
during the peri-PCI period. Strategies like temporary replacement of
warfarin by dual antiplatelet drug therapy and temporary adjustment
of warfarin dosing to reach a perioperative INR of 1.5–2.0 have been
proven to result in more adverse effects and inadequate for PCI or
stroke prevention in AF respectively.31,32,33 This view is supported by
data showing that non-use of OAC markedly increases mortality in
patients with AF after acute myocardial infarction.34,35,36 The most
common practice is to offer “bridging” with either unfractionated
or low molecular weight heparin (LMWH) to cover the temporary
discontinuation of OAC, if the risk of thromboembolism is considered
high. While this practice makes sense and appears to be logical based
on the competing pathophysiologies, this approach is based on
circumstantial evidence and there are no large randomized trials to support the recommendation. Furthermore, studies have shown that
patients with ACS and on home warfarin are significantly less likely
to undergo coronary angiography and PCI and their waiting times
for these procedures are longer than in patients not on warfarin.37
The general perception that warfarin should be discontinued a few
days prior to PCI and the periprocedural INR level should fall below
therapeutic range (2.0) may contribute to these delays.
Interestingly, studies show that the incidence of bleeding or
thrombotic complications is not related to peri-procedural INR
levels, and propensity score analyses suggested that the bridging
therapy with either unfractionated heparin or LWMH, to cover
the temporary discontinuation of OAC increases the risks of periprocedural
bleeding and access site complications.34,38,39 Supporting
this view, recent findings suggest that uninterrupted anticoagulation with warfarin may be a better alternative to heparin bridging in
catheter interventions with a favorable balance between bleeding
and thrombotic complications.60,61,62 Data from a major prospective
multicenter European registry (Atrial Fibrillation undergoing
Coronary Artery Stenting-AFCAS Registry) that recruited 963 patients with AF undergoing coronary stenting to compare the safety
of uninterrupted anticoagulation (UAC), indicate that UAC does
not increase perioperative complications during coronary stenting and is a simple and cost-effective alternative to conventional heparin
bridging.
Furthermore, studies have indicated advantages of PCI with UAC
that includes prevention of the transient pro-thrombotic state due
to proteins C and S suppression caused due to warfarin reinitiation,
minimal wide and long lasting fluctuation in INR following warfarin
interruption and effect of warfarin can be easily overcome by FFP or
activated clotting factors II, VII,IX and X.40,41,42
In the European Society of Cardiology (ESC) guidelines for
the management of valvular heart disease, continuation of OAC at
modified doses is recommended for the majority of patients who
undergo cardiac catheterization.43 Similarly in the consensus paper
of the Working Group on Thrombosis of the ESC, endorsed by the
European Heart Rhythm Association and European Association
of Percutaneous Cardiovascular Interventions, the UAC strategy is
recommended as the preferred strategy for AF patients at moderate
to high risk of thromboembolism.44 For patients admitted with
acute coronary syndrome, the risk of bleeding vs. thromboembolism
becomes more complex, as these patients often require bivalirudin (a
direct thrombin inhibitor) or glycoprotein IIb/IIIa inhibitors (GPI).
The consensus document suggests stopping the OAC on admission
in this circumstance. Exception to this may be patients at a very high
risk of thromboembolism, such as those with mechanical mitral valves
or recurrent venous thromboembolism, where uninterrupted OAC
may be preferable to the potential risk of bleeding with interruption and heparin bridging.44
Choice Of Long Term Antithrombotic Therapy That Follows PCI
Acute coronary syndrome patients presenting with acute STelevation
myocardial infarction (STEMI) are increasingly managed
with primary PCI with additional combined antithrombotic
therapy regimes.19,20 Those presenting with non-ST-elevation acute
myocardial infarction (NSTEMI) are also managed with combined
antithrombotic and anti-platelet therapy, as an early invasive
revascularization strategy, is often employed based on guideline
recommendations.19,20
The long-term results of stent usage have been blighted by the
dual problem of in stent restenosis (ISR) and stent thrombosis.
In particular, the increasing use of drug-eluting stents (DES) to
minimize ISR necessitates long-term dual antiplatelet therapy with
aspirin plus a thienopyridine (at present most frequently clopidogrel)
to reduce the risk of early and late stent thrombosis. Current ACC/
AHA guidelines recommend DAPT in patients with an STEMI for
at least 1 year for DES and BMS.19,20
As noted before, the results from ACTIVE-W trials demonstrated
that combined aspirin– clopidogrel therapy cannot replace OAC in
stroke prevention in patients with AF.15 Several observational studies
on clinical practice support this conclusion also in patients with AF
after coronary stenting.34,35 Likewise OAC alone is insufficient to
prevent stent thrombosis45,46,47,48 making management of patients
with Afib patients requiring stent very complicated. At present, in
patients on OAC therapy, the additional use of dual antiplatelet therapy (triple therapy) seems to be the best option to prevent stent
thrombosis and thromboembolism. Data from CRUSADE Registry
indicates that Triple Therapy is the commonest regimen used in the
setting of atrial fibrillation patients requiring PCI.49 Similarly data
from Society for Cardiac Angiography and Interventions survey
(2011) reveal that 86% of interventionists prefer Triple Therapy for
1 month followed by warfarin and aspirin in case of bare-metal stent
and 47.4% recommend at least 6 months of Triple Therapy after
DES implantation.
As per consensus paper of the Working Group on Thrombosis
of the ESC, endorsed by the European Heart Rhythm Association
and European Association of Percutaneous Cardiovascular
Interventions,44 in case of elective PCI Clopidogrel 75 mg daily
should be given in combination with OAC plus aspirin 75–100 mg
daily for a minimum of 1 month after implantation of a BMS, but
longer with a DES (at least 6 months) and clopidogrel 75 mg daily
(or alternatively aspirin 75–100 mg daily, plus gastric protection with
a PPI) may be continued depending on the bleeding and thrombotic
risks of the individual patient. In case of the AF patients presenting
with Non-ST elevation ACS like NSTEMI and unstable angina
with or without PCI and at moderate to high risk of stroke it is
recommended to continue/give anticoagulation therapy in addition
to dual antiplatelet therapy with aspirin plus clopidogrel. However
in the acute setting, patients are often given aspirin, clopidogrel,
heparin (whether UFH or an LMWH, enoxaparin) or bivalirudin
and with some frequency a GPIIa/IIIb inhibitor (GPI). Given the
risk of bleeding with such combination antithrombotic therapies, it
is recommended to stop OAC therapy, and administer antithrombins
or GPIs only if INR ≤ 2. As per consensus paper, in the setting of
acute STEMI with primary PCI and AF, it is recommended that
patients should be given aspirin, clopidogrel, and heparin (UFH).
When patients have a high thrombus load, GPIs may be given as a
‘bail out’ option. As an alternative to heparin plus GPI, bivalirudin
might be used and has a superiority in bleeding risk as demonstrated
in the ACUITY and HORIZONS-AMI trials. Given the risk of
bleeding with such combination antithrombotic therapies, it may be
prudent to stop OAC therapy. Ideally, GPIs would not be considered
if except only in a ‘bail out’ option. Detailed recommendations from
consensus paper of the Working Group on Thrombosis of the ESC,
endorsed by the European Heart Rhythm Association and European
Association of Percutaneous Cardiovascular Interventions are
depicted in the Table-1.
Dual Therapy (Warfarin+ Clopidogrel ) Vs. Triple Therapy
Results from the single center WOEST trial involving 573 patients
who underwent PCI with a mean follow up of 1 year clearly show
that use of dual therapy (Warfarin and clopidogrel without aspirin)
was associated with a significant reduction in bleeding complications
with no increase in the rate of thrombotic events were observed50.
Furthermore use of triple therapy was associated with higher
mortality and morbidity Figure 8. Similar observations were made
in previous smaller studies51. Although data on the efficiency and
safety of warfarin plus clopidogrel combination are limited, but this
combination may be an alternative in patients with high bleeding risk
and/or absent risk factors for stent thrombosis. Future multi-center
trials will need to confirm these results.
Figure 8. Results of the WOEST (The What is the optimal antiplatelet and anticoagulant therapy in patients with oral anticoagulation and coronary Stenting) study, an open-label, randomized, controlled trial done at 15 sites in the Netherlands and Belgium involving patients taking oral anticoagulants who underwent PCI. 573 patients were enrolled and 1-year data were available for 279 (98·2%) patients assigned double therapy and 284 (98·3%) assigned triple therapy. (A). Incidence of the primary endpoint (any bleeding), bleeding episodes were seen in 54 (19·4%) patients receiving double therapy and in 126 (44·4%) receiving triple therapy (hazard ratio [HR] 0·36, 95% CI 0·26–0·50, p<0·0001).
Modifying The Procedure And Bleeding Avoidance Strategies To Ensure Optimal Safety
For optimal outcome, a delicate balance is needed between
the prevention of thromboembolism, against recurrent cardiac
ischemia or stent thrombosis, and bleeding risk, to individualize
treatment options thus avoiding regimented common protocol.
Following considerations could be used while managing a patient on
anticoagulation requiring PCI.
(A) Identify The High Risk Patient
Thromboembolism, stent thrombosis and peri-procedural bleeding
are all described as complex phenomenon and dependent on several
independent predictors.68,69 (Table-2) Identification of the AF patients
undergoing PCI who are at high risk for thromboembolism, stent
thrombosis and peri-procedural bleeding is very important for the
optimal outcome. Interestingly Faxon et al identifies patients with AF
at moderate to high risk of stroke (CHADS-2 score≥1) undergoing
PCI into three groups based on the risk for stent thrombosis (ST)
and bleeding.67 Low ST and low bleeding risk group, high ST and
low bleeding risk group and high ST and high bleeding risk group.
The management plan from each group is depicted in Figure 9.
Figure 9. Recommendations for the combination and duration of triple therapy in patients with atrial fibrillation and a coronary stent (BMS or DES) with moderate/high stroke risk (CHADS2≥1. BMS indicates bare metal stent; DES, drug-eluting stent; OAC, warfarin; AP, antiplatelet agent; and triple therapy, aspirin, clopidogrel, and warfarin. In patients at high risk for atherothrombotic events including stent thrombosis, continued single antiplatelet therapy with warfarin should be considered after 12 months. The authors used the following average crude estimates of risk for each adverse outcome listed below (low and high) to be: ● Stroke risk (CHADS2_1) on warfarin average 1.5%(1.0% for CHADS2_1–7% for CHADS2_5–6) per year (or adjusted stroke rates from 1.95%/y to _12.5%/y).● Stent thrombosis (first year) on DAPT_1.5% (1–5%) but 5- to 36-fold higher for premature discontinuation within the first month, and 2.5- to 5-fold if between 1 and 6 months. On DAPT the risk is greatest in the first month.● Major bleeding requiring hospitalization on triple therapy_6–15%/y; warfarin and 1 antiplatelet agent_6–12%/y; and on either DAPT or warfarin alone 2.5–4%/y. The rate is highest within the first 30 days after the procedure.
(B) Choosing The Right Stent And Procedure
Recommendations from consensus paper of the Working Group
on Thrombosis of the ESC, endorsed by the European Heart
Rhythm Association and European Association of Percutaneous
Cardiovascular Interventions,44 clearly state that the use of DES
of first and second generation, due to the prolonged need of dual
antiplatelet therapy, should be avoided in patients with an indication
for long-term OAC and high bleeding risk. However DES is
recommended in the patients with high risk of stent restensois and
where a significant benefit is expected DES when compared with
BMS. Furthermore, as more studies emerge suggesting shorter
duration of DAPT therapy is safe and effective in reducing stent
thrombosis with second generation drug eluting stents, cardiologists
will be able to reduce their patient exposure to either dual therapy
or triple therapy. Reduction in the need for DAPT to 3-6 months
for 2nd generation DES will make DES a more accessible option in
even higher risk patients. Finally, in the extremely high risk bleeding
patient, balloon angioplasty can also be considered when the
angiographic result after balloon angioplasty is acceptable. In some
cases also coronary artery bypass graft (CABG) might be favored
over PCI if the patient is a reasonable surgical candidate otherwise.
(C) Wise Selection Of Access Site
Several independent studies indicate that vascular access site
selection may have a great impact on bleeding complications. Metaanalyses
of randomized trials and registry studies clearly reveals
that radial artery access is associated with a reduced risk of access
site bleeding and other vascular complications.52,53,54,55 Furthermore
femoral access was an independent predictor (hazard ratio of 9.9)
of access site complications in 523 warfarin-treated patients.55 On
the basis of current evidence, a radial approach should be always
considered in anticoagulated patients, since haemostasis is rarely an
issue with this access site.
(D) Avoidance Of Newer Anti-Platelet Agents Like Prasugrel And
Ticagrelor In Triple Therapy
Results from TRITON–TIMI 38 and PLATO trials, reveal
higher rates of bleeding with newer anti-platelet agents prasugrel
and ticagrelor respectively.56,57,58 Therefore avoidance of newer antiplatelet
agents like prasugrel and ticagrelor in the patients on OAC
in the setting of ACS or requiring PCI is reasonable if a strategy of triple therapy is being pursued. Use of the newer antiplatelet therapy
in setting of dual therapy with warfarin or novel oral anticoagulants
are still being investigated. Please see below.
(E) Gastric Acid Suppression With PPIs
Gastric protection with proton pump inhibitors (PPIs) is
considered useful in patients on triple therapy and those prone to
develop gastrointestinal bleeding (elderly, patients with a history of
ulcer disease or prior gastrointestinal bleeding).59
Several studies indicate that the GPI use is associated with a 3–13-
fold risk of early major bleeding in warfarin-treated patients who
undergo revascularization in the form of PCI.60,61,62 In general, GPIs
seem to increase major bleeding events irrespective of peri-procedural
INR levels and should be used with some caution in this patient
group and probably avoided if use is not indicated due to massive
intraluminal thrombi. Furthermore, GPIs add little benefit in terms
of reduction of ischemic events in patients with stable angina and
troponin-negative ACS.63,64
Results from HORIZONS-AMI, and ACUITY trials reveal
superiority of bivalirudin usage in the setting of primary PCI and
non-ST-elevation (NSTE) ACS over combination of heparin plus
GPI in terms of lesser morbidity and mortality. Furthermore data
from studies support reduced both access site and non-access site
bleeding with bivalirudin usage compared to heparin plus GPIs.65,66
Although data on bivalirudin in AF patients, especially in the setting
of concomitant anticoagulation with an OAC is lacking based on the
current available date it is likely to be a safer and effective option in
the setting of acute coronary syndromes.
Currently several planned trials are undergoing in this field.
PIONEER AF-PCI is a 3 arm study involving 2100 patients
randomized to (a) Rivaroxiban 15mg PO daily and clopidogrel
75mg PO daily (b) Initial period of rivaroxaban 2.5mg PO BID and
dual antiplatelet therapy followed by rivaroxaban 15mg PO daily
and low dose aspirin.(c) Initial period of dose-adjusted warfarin and
dual antiplatelet therapy followed by dose-adjusted warfarin and low
dose aspirin. RE-DUAL PCI (“Randomized Evaluation of Dual
Therapy with Dabigatran vs. Triple Therapy Strategy with Warfarin
in Patients with NVAF that have undergone PCI with Stenting”),
is designed to evaluate the efficacy and safety of Dabigatran in
patients with nonvalvular atrial fibrillation (NVAF) who have
undergone PCI. MUSCA 2 trail will compaire dual antiplatelet
therapy with triple antiplatelet therapy in patients with non-valvular
atrial fibrillation undergoing PCI who are at low to moderate risk
of stroke (CHADS-2 ≤ 2). The ISAR-TRIPLE is a randomized,
open-label trial that examines the restriction of clopidogrel therapy
from 6 months to 6 weeks after DES implantation in the setting of
concomitant aspirin and oral anticoagulant. Patients are randomized
in a 1:1 fashion to either 6-week or 6-month clopidogrel therapy.
The primary end point is a composite of death, myocardial infarction,
definite stent thrombosis, stroke, or major bleeding. The result of
these trials will be critical in assessing safety and efficacy of treating
these complex patients with competing indications for their disease
treatments.
Balancing the risk of bleeding, thromboembolism and the risk for acute and late stent thrombosis in the patient who has a clear
indication for oral anticoagulation and has undergone percutaneous
coronary intervention, continues to remain a complex and difficult
dilemma for clinicians. The need to address competing indications
is further magnified in the setting of acute coronary syndromes.
Risk stratification of patients, utilization of direct thrombin
inhibitors, avoidance of GPIs, carefully choosing POBS, BMS,
and second generation DES are critical in reducing bleeding
complications. Limiting the length of exposure to DAPT in the
setting of anticoagulation is also a mainstay of reducing risk. Dual
therapy (single non-aspirin anti-platelet therapy coupled with
anticoagulation, warfarin or a NOAC) may be a viable and safer
alternative without compromising risk or long term stent outcomes.
Further trials will hopefully answer whether this strategy and the
concept of uninterrupted anticoagulation will be ideal approaches to
treating these complex patients.
