INCLUSION CRITERIA
- Adults > 18 years of age (Male or Female).
- Active or history of NVAF or flutter on anticoagulation.
- Percutaneous coronary intervention with stenting (DES)
RESULTS :
In our study the majority of the subjects were males with the male to
female ratio of 1.6:1.The mean age was 61\(\pm\)4.2 years. The risk
factors included diabetes (65%), hypertension (58%), dyslipidaemia(
57%) and smoking (32%). The most common cardiac presentation in the
patients was unstable angina 61patients followed by Non ST elevation MI
(NSTEMI) 25 patients , ST elevation MI(STEMI) 8 patients and stable
angina in 6 patients. Echocardiography revealed normal Left Ventricular
(LV) function in 47 patients , mild LV dysfunction in 31 patients ,
moderate in 12 patients and severe LV dysfunction in 10 patients.
The mean CHA2DS2VASc score was 2.46\(\pm 1.32\). Patients presenting
with persistent AF were 53 patients, paroxysmal AF 35 patients and
permanent AF in 12 patients. The patient were treated for single vessel
disease in 51 cases , double vessel in 38 cases and triple vessel
disease was noted in 11 patients.
The patients were started on triple therapy ( dual antiplatelet and
anticoagulant ) in 95 % cases with DAPT only seen in 5 % cases.
Amongst the anticoagulant therapy most of the patients were initiated on
NOACs 85 % with a few on VKA(Acitrom) 15 %. None of the patients were
started on warfarin. The bleeding manifestation were measured using BARC
definitions which showed majority of the cases 78 in BARC 0 , 14 in BARC
1 , 6 in BARC 2 and 2 in BARC 3. No cases were reported in BARC 4 and 5
group.
A number of patients who presented with STEMI (8 patients) , unstable
angina (10 patients), were initially loaded with ticagrelor but with the
advent of AF post loading dose, they were later shifted to clopidogrel
the next day in view of the initiation of anticoagulation as well . Only
1 patient was loaded with prasugrel outside which was shifted to
clopidogrel as per the same protocol.
The patients were followed up at 1 month , 3 months, 6 months and one
year for adjustment of antiplatelet, anticoagulation medicines and their
dosage.
The study analyzed the 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 best well-balanced management strategy of
antiplatelets and anticoagulation in patients with PCI and AF.
In our study of patients with AF and ACS, we came across these
scenarios. The management of the patients with antiplatelets,
anticoagulants and their dosage differed in the groups with changes at
initiation and follow up.
- Recent ACS ( STEMI) with recent AF
- Recent ACS ( NSTEMI) with recent AF
- Recent ACS ( STEMI/ NSTEMI) with old AF on anticoagulation
DISCUSSION ;
AF is associated with a small but significant incidence of stroke and
systemic thromboembolism.3 Oral anticoagulants (NOACs)
reduce the incidence of stroke and systemic embolism in these
patients.4 A meta- analysis of 29 trials on use of
antithrombotic therapy to prevent stroke in patients who have
nonvalvular atrial fibrillation. showed that anticogulation reduced
stroke by 64% as compared with placebo and by 39% as compared with
aspirin in patients with non-valvular AF5.
Furthermore several trials including ACTIVE-W have confirmed the
superiority of anticoagulation 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 factor6 As a result, the ACC/AHA guidelines
recommended oral anticoagulant therapy for those patients with at least
1 additional risk factor for stroke and suggested the use of aspirin
only for those at low risk for stroke such as patients without risk
factors.3
Three antithrombotic drug combinations have been used most in practice
in patients with AF and PCI: 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, initially triple
therapy is the most common treatment regimen in this setting.
Antiplatelets other than clopidogrel like prasugrel and ticagrelor have
been sparingly used in combination with anticoagulants due to increased
chance of bleeding events.
A study of 21,443 elderly patients on bleeding complications associated
with combinations of aspirin, thienopyridine derivatives, and warfarin
in elderly patients following acute myocardial infarction, when 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.7Similarly, 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
months8.
Thus the literature suggests that 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. Though the bleeding risk is higher as noted in
various studies still triple therapy (TT) was the commonest regimen used
in the setting of atrial fibrillation patients requiring PCI (Data from
CRUSADE Registry).9 Similarly data from Society for
Cardiac Angiography and Interventions survey (2011) revealed 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.
According to guidelines DAPT alone is inferior to warfarin for
prevention of thromboembolic events in patients with atrial
fibrillation.10Various trials addressed this issue of
dual Therapy (Warfarin+ Clopidogrel) Vs. Triple Therapy. The 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 observed11.
Furthermore use of triple therapy was associated with higher mortality
and morbidity 12. 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. The study did conclude
that anticoagulants and clopidogrel was associated with significant
reduction in major bleeding and no increase in thrombotic events
compared to triple therapy with anticoagulation, aspirin and
clopidogrel.12
In the past these patients received a (TT) for 3-12 months. This TT has
never been studied for efficacy; however, the rate of bleeding
complications in comparison to a simple OAC or DAPT is significantly
higher. Registries and smaller trials showed that DAPT with an OAC plus
a platelet inhibitor may be sufficient to prevent stroke and stent
thromboses/myocardial infarctions.
In the past anticoagulation was limited to vitamin K antagonists (VKA),
but with the recent addition of NOAC in the treatment regimen of AF, the
combination of antiplatelets and anticoagulants has become more wide
range.
These questions were investigated in various prospective and randomized
studies involving all four non-vitamin K oral anticoagulants (NOAC)
approved for stroke prevention in AF. The NOACs were tested against
vitamin K antagonists (VKA) involving single antiplatelet therapy
without using DAPT. The trials with rivaroxaban (PIONEER AF-PCI) ,
dabigatran (RE-DUAL PCI) , apixaban (AUGUSTUS) and edoxaban (ENTRUST-AF
PCI) are instrumental in determining the management. The current status
is that a NOAC plus a single antiplatelet agent, mostly clopidogrel, is
superior to TT with VKA with respect to bleeding complications without
any obvious disadvantage due to increases in stroke cases or cardiac
ischemia. The international guidelines already permit treatment without
TT in cases where the bleeding risk is prevalent. In this situation it
is recommended to prescribe a NOAC plus a single antiplatelet therapy.
Thus, TT no longer seems to be indicated for most patients with AF and
after ACS or PCI with exception of patients in high risk category like
left main PCI, multivessel stenting PCI, Diabetes and multiple stents.
NOVEL ORAL ANTICOAGULANTS
NOAC has become widely adopted since initial approval. They represent a
class of drugs that have two unique mechanisms of action; both directly
inhibit a single coagulation factor with the distinction between
individual types of agents occurring based on the coagulation factor
that is inhibited. Apixaban, edoxaban and rivaroxaban each inhibit
factor Xa, whereas the direct thrombin inhibitor dabigatran inhibits
factor IIa (thrombin).
The introduction and rise of NOAC were in response to numerous
limitations and challenges with the pre-existing therapy of vitamin K
antagonists (VKA), which requires frequent monitoring and has numerous
drug and dietary interactions. NOAC provides a potent and a predictable
therapeutic effect with comparatively minimal routine laboratory
monitoring required.
Multiple risk prediction scores have been introduced to assist in the
assessment and stratification of bleeding risk. The hypertension,
abnormal renal/liver function, stroke, bleeding history or
predisposition, labile international normalised ratio, elderly, drugs/
alcohol concomitantly (HAS-BLED) score is among the most commonly used
scores for bleeding risk stratification and is used to assess bleeding
risk in patients with AF. A patient with a HAS-BLED score ≥3 is
considered to be at high-risk for bleeding.13 The use
of the HAS-BLED score specifically for patients on concomitant DAPT
however has not been validated. The PREdicting bleeding Complications In
patients undergoing Stent implantation and subsequent (PRECISE)-DAPT
score was introduced to assess bleeding risk for patients on DAPT. A
longer duration of DAPT is associated with significantly increased
bleeding in patients at high PRECISE-DAPT risk
(score≥25).14 Data support an ischemic benefit of DAPT
only in patients with a PRECISE-DAPT score <25.16) Both
bleeding risk prediction models have utility for predicting future
significant bleeding events in patients taking an oral anticoagulants
(OAC) and undergoing PCI.15
An overview of the pivotal NOAC trials in patients with non-valvular AF
are summarized in Table 1. In the Randomized Evaluation of Long-term
anticoagulant therapy (RE-LY) trial, dabigatran was compared to warfarin
in 18,113 patients with results first published in
2009.16 In 2011, results were published from the
pivotal Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared
with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in
AF (ROCKET-AF) trial of 14,246 patients comparing rivaroxaban to
warfarin.17 The Apixaban for Reduction in Stroke and
Other Thromboembolic Events in AF (ARISTOTLE) trial compared apixaban to
warfarin and assessed outcomes in 18,201 patients.18Effective Anticoagulation with Factor Xa Next Generation in AF
(ENGAGE-AF) compared edoxaban to warfarin in 21,105 patients with
results reported in 2013.19
As discussed earlier the PIONEER AF-PCI trial and the RE-DUAL trial both
compared a NOAC plus single antiplatelet therapy with triple therapy
with a VKA plus DAPT. Both pivotal trials reported significantly lower
bleeding with the dual antithrombotic regimen compared with triple
therapy.20-22
In the RE DUAL PCI AF, patients with atrial fibrillation who had
undergone PCI, the risk of bleeding was lower among those who received
dual therapy with dabigatran and a P2Y12inhibitor than
among those who received triple therapy with warfarin, a
P2Y12inhibitor, and aspirin. Dual therapy was
noninferior to triple therapy with respect to the risk of thromboembolic
events. In the trial, dabigatran compared to triple therapy with VKA in
2,725 randomized patients was associated with a significant reduction of
bleeding events at both 150 mg and 110 mg twice daily dosing with
dabigatran.20,21 Due to a concern for potential
increased risk for ischemic events with the lower dabigatran dose (110
mg twice daily),150 mg twice daily dosing with dabigatran is preferred
with single antiplatelet therapy.
In the PIONEER AF PCI ,participants with atrial fibrillation undergoing
PCI with placement of stents, the administration of either low-dose
rivaroxaban plus a P2Y12 inhibitor for 12 months or
very-low-dose rivaroxaban plus DAPT for 1, 6, or 12 months was
associated with a lower rate of clinically significant bleeding than was
standard therapy with a vitamin K antagonist plus DAPT for 1, 6, or 12
months. The three groups had similar efficacy rates, but the clinical
efficacy is uncertain as the study was not powered to evaluate
thrombotic events ( stent thrombosis, ischemic stroke).
The trial randomized 2,124 patients with nonvalvular AF treated with PCI
to receive 1 of 3 treatment strategies of antiplatelet therapy and OAC.
The investigators reported that the use of either low- dose rivaroxaban
plus a P2Y12 inhibitor for 12 months or very-low-dose rivaroxaban plus
DAPT was associated with lower clinically significant bleeding compared
with VKA plus DAPT.22
The AUGUSTUS trial reported the impact of apixaban with and without
aspirin in 4,614 patients with AF and an acute coronary syndrome or PCI.
The use of a P2Y12 inhibitor and apixaban without aspirin resulted in
less bleeding and fewer hospitalizations without significant differences
in the incidence of ischemic events compared with drug regimens that
included a vitamin K antagonist, aspirin, or
both.23Edoxaban is currently being studied as part of
a triple therapy regimen in the Edoxaban Treatment Versus Vitamin K
Antagonist in Patients With AF Undergoing PCI (ENTRUST-AF) trial.
There are a few highlights regarding NOACs which are important to be
considered. The various RCTs data has concluded :
- Apixaban 5 mg twice a day and Dabigatran 150mg twice a day are most
efficacious in prevention of stroke / systemic embolism. Among the two
dabigatran 150 mg has shown most efficacy.
- Apixaban has shown the most favourable outcomes in major bleeding and
intracranial haemorrhage in elderly population , making it the safest
drug for this group of population.
- Apixaban should be preferred for patients with renal impairment .
- Apixaban 2.5 mg are considered in patients with any of the two
present: age >80 years, weight< 60 kgs and
serum creatinine>1.5 mg
GUIDELINE RECOMMENDATIONS
The 2016 American College of Cardiology/American Heart Association
(ACC/AHA) focused update on duration of DAPT in patients with coronary
artery disease guideline recommendations for patients at high bleeding
risk treated with PCI supports clopidogrel as the P2Y12 inhibitor of
choice in patients on OAC therapy.24 The duration of
DAPT recommended by the ACC/AHA guidelines is based on the indication
for PCI. In patients with stable coronary artery disease,
discontinuation of the P2Y12 inhibitor at 3-months is recommended,
whereas for patients treated for acute coronary syndrome, P2Y12
inhibitors should be continued for at least 6
months.24
The 2018 ESC guidelines similarly recommend clopidogrel as the P2Y12
inhibitor of choice, with low dose (≤100 mg daily) aspirin, however
recommend keeping the duration of triple therapy as short as
possible.25
ESC guidelines recommend triple therapy with aspirin, clopidogrel and
OAC for 1 month, and up to 6 months in patients at higher ischemic risk
due to acute coronary syndrome or procedural characteristics that
outweigh bleeding risk (class IIa, level of evidence B).
When a NOAC is added to either aspirin or clopidogrel, the lowest
approved effective dose for stroke prevention tested in AF trials should
be considered (class IIa, level of evidence C).
The ESC cautions that the use of ticagrelor or prasugrel is not
recommended as part of triple antithrombotic therapy with aspirin and
OAC (class III, level of evidence C).
As per literature and evidence, we noted that majority of the patients
were initiated on NOACs by physician’s but the duration, dosage and
recommendations were varied.
The following are key perspectives from the state-of-the-art review on
management of antithrombotic therapy in atrial fibrillation (AF)
patients undergoing percutaneous coronary intervention (PCI) published
in 2019: 26
- Most patients with AF and stroke risk factors require oral
anticoagulation (OAC) to decrease their risk of stroke or systemic
embolism. This is now best achieved using direct oral anticoagulants
(DOACs) due to lower rates of intracranial haemorrhage as compared to
vitamin K antagonists (VKAs; e.g., warfarin).
- Approximately 5-10% of patients undergoing PCI have comorbid AF,
which complicates antithrombotic therapy decisions. While guidelines
recommend dual antiplatelet therapy (DAPT) for patients following PCI,
this in combination with OAC therapy places patients at high risk for
bleeding complications.
- Several randomized trials have demonstrated that a regimen of a DOAC
plus a single antiplatelet agent (usually clopidogrel) provides better
safety than a triple therapy regimen of VKA plus DAPT.
- For patients undergoing PCI with comorbid AF, strategies such as
radial access and a brief anticoagulation washout prior to PCI may be
considered to help reduce procedure-related bleeding risk.
New-generation drug-eluting stents are also preferable, as they
require shorter courses of antiplatelet therapy and are associated
with a lower risk of stent thrombosis.
- For patients undergoing PCI with comorbid AF, use of DOACs is
preferred over VKAs. DOACs should be prescribed at stroke prevention
doses (e.g., apixaban 5 mg BID) or doses specifically tested in AF
plus PCI randomized trials (e.g., rivaroxaban 15 mg daily) when
possible. Dose reduction with dabigatran (110 mg BID) may be
considered in patients at higher bleeding risk.
- Use of triple antithrombotic therapy (OAC plus DAPT) should be limited
in duration as much as possible. In many cases, this can be limited to
the peri-PCI period only. Patients at high thrombotic risk may be
considered for up to 1 month.
- When combining OAC and antiplatelet therapy, use of low-dose aspirin
(81-100 mg) is preferred. Use of clopidogrel is also preferred over
other P2Y12 inhibitor medications and over aspirin in most patients.
- Most patients with AF who undergo PCI can discontinue antiplatelet
therapy 12 months following stent placement. They should continue on
OAC therapy long-term.
RECOMMENDATIONS:
Our recommendation based on current evidenced-based medicine, best
practices, clinical experience and available pharmacologic therapies are
the following :
- The approach to a patient with AF and PCI is summarized in various
tables 1 , 2 and 3 .
- Prognosis is worse in those experiencing an adverse event whether it
is an ischemic or bleeding event following PCI, so efforts are needed
to balance these competing risks.58)
- DES should be used as the default choice of stent.
- Aspirin therapy should be limited to the minimal duration required
post PCI, with the dose restricted to low-dose aspirin
- NOAC’s offer significant advantages over VKA including less drug and
dietary interactions, less routine monitoring of blood work, and
greater time in therapeutic range, thus they should be the drug of
choice in patients of AF and PCI.
- Potent thienopyridine therapy should be used following stent
implantation in the absence of routine P2Y12 testing prior to
initiating antiplatelet monotherapy.
- Amongst P2Y12 inhibitors prasugrel is not the preferred drug;
clopidogrel or ticagrelor may be used with clopidogrel given
preference in view of the enormous literature.
- Patients on anticoagulation undergoing PCI should undergo routine
assessment with intravascular imaging as the role of high-risk
lesion-related features have increased importance prior to determining
optimal duration of treatment with DAPT.
- In RE-DUAL trial, it was shown, that without aspirin , the use of
110mg dabigatran was associated with a numerical increase in death,
myocardial infarction, stroke and stent thrombosis. Thus keeping the
ischemic and bleeding risks in mind- Dabigatran 110 mg can be used
when patients are in triple therapy treatment which can be switched to
Dabigatran 150mg when on dual therapy without aspirin.
- Dabigatran 150 mg and Apixaban 5 mg both are significantly efficacious
in prevention of ischaemic stroke, with the former more than the
latter.
- Apixaban 2.5 mg should be considered in patients of AF with PCI if age
> 80 years , weight <60 kgs and serum
creatinine >1.5 mg/dl.
- Though studies on rivaroxaban did provide evidence on decrease in
bleeding events but efficacy in view of stent thrombosis and ischemic
stroke was uncertain.
- Though the choice of NOACs amongst patients with AF and PCI are
subjective to the patient and treating physician, evidence does
support dabigatran 150mg and apixaban 5mg with minimal but significant
room for dabigatran 110mg and apixaban 2.5 mg