The most recent American College of Cardiology/American Heart Association guidelines
on duration of dual‐antiplatelet therapy (DAPT) after percutaneous coronary intervention
(PCI) with drug‐eluting stents (DESs) give a class I recommendation to continue DAPT
for at least 12 months after an acute coronary syndrome (ACS) and at least 6 months
after revascularization in the setting of stable ischemic heart disease.1 These guidelines
also give a class IIb recommendation for continuation of DAPT beyond 6 and 12 months
in patients with stable ischemic heart disease and ACS, respectively, if these patients
have tolerated DAPT without a bleeding event and are at low risk for bleeding in the
future.1 However, they do not provide any guidance with respect to how long DAPT should
be continued and leave it to the clinician to discuss the risks versus benefits with
the patient and individualize antiplatelet therapy. Therefore, in clinical practice,
we often see patients on DAPT several years after a PCI as they are instructed by
their providers to never discontinue them. In fact, given how much the importance
of taking DAPT in the early period after PCI is emphasized, patients at times are
uncomfortable stopping the second antiplatelet agent at any time. The lack of a clear
recommendation is not surprising, despite multiple recent randomized controlled trials2,
3, 4, 5 evaluating differing durations of extended DAPT given several evolving factors
and the overall risk/benefits of DAPT.
Guidelines commenting on DAPT duration have largely included trials using clopidogrel
and early‐generation stents. The advent of more potent P2Y12 inhibitors, such as prasugrel
and ticagrelor, has reduced major adverse cardiovascular events, but at the cost of
increased bleeding.6, 7 On the other hand, the newer‐generation DESs, with their thinner
stent struts, a more biocompatible polymer, and favorable drug‐eluting characteristics,
have considerably decreased the risk of stent thrombosis, particularly late stent
thrombosis.8 Although extended DAPT duration has been associated with reduction in
recurrent myocardial infarction (MI) and cardiovascular death, there are statistically
significant increases in major bleeding events.2, 5 With the increased recognition
of bleeding events and advancements in DES technology, it has been hypothesized that
shorter durations of DAPT may be more appropriate. The European and American College
of Cardiology/American Heart Association guidelines have already reduced the minimum
absolutely required duration of DAPT by incorporating short DAPT into their recommendations.1,
9 However, the question about the value of extended DAPT duration in selected patients
still remains to be answered.
To our knowledge, there are 4 randomized controlled trials that have compared the
efficacy and bleeding outcomes of standard 12‐month therapy versus extended‐duration
DAPT (>24 months), which are listed below:
PEGASUS‐TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart
Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis
in Myocardial Infarction 54) trial.2
DAPT (Dual Antiplatelet Therapy) trial.5
DES LATE (Optimal Duration of Clopidogrel Therapy With DES to Reduce Late Coronary
Arterial Thrombotic Event) trial.4
OPTIDUAL (Optimal Dual Antiplatelet Therapy) trial.3
The summary of these trials can be seen in Table 1. Two of these trials, comparing
>24 months of DAPT with 12 months of DAPT, showed no difference in their primary efficacy
end points of cardiovascular death/MI/stroke and death/MI/stroke/major bleeding (DES‐LATE
and OPTIDUAL trials), respectively.3, 4 Unlike the other 3 trials, the OPTIDUAL trial
included major bleeding as part of the primary efficacy end points, which could be
a reason for no statistical difference.5 The other 2 trials showed an absolute risk
reduction in their primary efficacy end points by 1.6% (DAPT trial: death/MI/stroke),
1% (DAPT trial: stent thrombosis), and 1.3% (PEGASUS trial: cardiovascular death/MI/stroke)
with prolonged DAPT,2, 5 although this was accompanied by a statistically significant
increase in bleeding events (absolute increase in bleeding by 0.9% and 1.54% for DAPT
and PEGASUS trials, respectively). However, there was no statistically significant
difference in severe GUSTO or fatal bleeding.2, 5
Table 1
Randomized Controlled Trials Examining Extended Duration of Dual‐Antiplatelet Therapy
Trial and Year
Duration Comparison, mo
No. of Participants
Primary Efficacy End Point
Primary Efficacy End Point Result
Bleeding Definition
Bleeding End Point Result
P2Y12 Inhibitor
Stent Type
Patients With ACS, %
DAPT 20145
12 vs 30
9961
Composite of death, MI, and stroke
Stent thrombosis.
Decrease with extended DAPT for both the composite end point (4.3% vs 5.9%) and stent
thrombosis (0.4% vs 1.4%)
GUSTO severe or moderate bleedinga
Statistically significant increase in extended DAPT (2.5% vs 1.6%), driven by moderate
GUSTO bleeding
Clopidogrel (65%) or prasugrel (35%)
Sirolimus or paclitaxel in ≈40%, zotarolimus or everolimus in ≈60%
≈40
DES‐LATE 20144
12 vs 36
5045
Composite of cardiovascular death, MI, and stroke
No difference
TIMI majorb
No statistical difference but trend toward increase in extended DAPT
Clopidogrel
Sirolimus or paclitaxel in ≈65%, zotarolimus or everolimus in ≈30%
≈60
PEGASUS 20152
12 vs 33
21 162
Composite of cardiovascular death, MI, and stroke
Decreased with extended DAPT (7.85% vs 9.04%), primarily driven by MI and stroke.
TIMI majorb
Statistically significant increase in extended DAPT (2.6% vs 1.1%)
Ticagrelor
No stenting in 20%, BMS in 41%, DES in 39%
100% with ACS 1–3 y prior
OPTIDUAL 20153
12 vs 33
1385
Composite of death, MI, stroke, and major bleeding
No difference
International Society on Thrombosis and Hemostasisc
No difference
Clopidogrel
Sirolimus or paclitaxel in ≈35%, zotarolimus or everolimus in ≈60%
≈35
ACS indicates acute coronary syndrome; BMS, bare metal stent; DAPT, Dual Antiplatelet
Therapy; DES, drug‐eluting stent; DES‐LATE, Optimal Duration of Clopidogrel Therapy
With DES to Reduce Late Coronary Arterial Thrombotic Event; MI, myocardial infarction;
OPTIDUAL, Optimal Dual Antiplatelet Therapy; PEGASUS, Prevention of Cardiovascular
Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on
a Background of Aspirin; TIMI, Thrombolysis in Myocardial Infarction.
a
GUSTO (Global Utilization of Streptokinase and Tpa for Occluded Arteries) severe indicates
intracerebral hemorrhage or bleed, resulting in substantial hemodynamic compromise
requiring treatment. GUSTO moderate indicates requiring blood transfusion but not
resulting in hemodynamic compromise.
b
TIMI major: any intracranial bleeding (excluding microhemorrhages <10 mm evident only
on gradient‐echo magnetic resonance imaging) or clinically overt signs of hemorrhage
associated with a decrease in hemoglobin of ≥5 g/dL.
c
International Society on Thrombosis and Hemostasis: fatal bleeding and/or symptomatic
bleeding in a critical area or organ and/or bleeding causing a decrease in hemoglobin
level of ≥20 g/L or leading to transfusion of ≥2 units of whole blood or red cells.
As noted above, 2 of these 4 trials showed an improved primary efficacy end point
of >24 months DAPT compared with standard 12‐month DAPT, whereas the other 2 showed
no difference. The 2 studies showing a decrease in the primary end point were both
larger trials, and both were driven primarily by a decrease in MI.2, 5 These 2 trials
that showed a decrease in the primary efficacy end point also showed an increase in
the bleeding risk. Given these differing findings, it is important to highlight some
of the key differences between the trials. First, the PEGASUS trial, the largest of
the randomized controlled trials, was the only extended DAPT trial to use ticagrelor.2
The 2 smaller trials, DES‐LATE and OPTIDUAL trials, used solely clopidogrel as the
P2Y12 inhibitor, whereas the DAPT trial used either clopidogrel or prasugrel.3, 4,
5 In patients with ACS, both ticagrelor and prasugrel provide better cardiovascular
outcomes compared with clopidogrel6, 7; hence, it is possible that the differing results
may be, in part, because of the particular P2Y12 inhibitor used.
Certain high‐risk conditions, such as ACS presentation, complex coronary anatomical
features, diabetes mellitus, or renal failure, can influence the rate of future events.
The PEGASUS trial involved only patients who experienced a prior ACS event 1 to 3 years
before enrollment and had an additional high‐risk feature (aged >65 years, diabetes
mellitus, a second MI, multivessel disease, or chronic renal dysfunction). This key
difference, along with its larger enrollment and power, could potentially explain
the more significant decrease in primary efficacy end point compared with other trials
with patients at a lower risk for ischemic events. Hence, it is not surprising that
the event rates in the PEGASUS trial are much higher than those in other 3 trials,2,
3, 4, 5 as seen in Table 1. The other 3 trials3, 4, 5 have a few key similar limitations.
Notably, only patients who were adherent to medications and event free in the prior
12 months, without major bleeding or major adverse cardiovascular or cerebrovascular
events, were eligible to continue into the extended DAPT arm, a study design that
likely selects for those at lower risk for late adverse events and for bleeding. In
addition, as detailed in Table 1, these trials included a variable proportion of patients
receiving PCI for an ACS event to those receiving PCI without ACS.2, 3, 4, 5
Patients receiving first‐generation DESs are at higher risk for in‐stent thrombosis
because of delayed endothelialization, incomplete healing, and hypersensitivity.10
Although DAPT reduces this risk, first‐generation DESs had late and very late stent
thrombosis, leading to development of improved second‐generation DESs, which have
been safer than the first‐generation DESs.11 This is important as ≈65% of stents in
the DES‐LATE trial, ≈40% in the DAPT trial, and ≈35% in the OPTIDUAL trial were older‐generation
(sirolimus and paclitaxel) stents,3, 4, 5 which may, in part, contribute to some differences
in the results of these trials. Of note, in the PEGASUS trial, ≈20% of participants
did not receive a stent and still derived significant benefit from extended DAPT.2
So, what does the future hold for extended‐duration DAPT? It is likely that adverse
thrombotic and cardiac events will continue to decrease with the continuously improving
polymer and stent technology, including development of ultrathin struts. Indeed, current
trials, such as HOST‐IDEA (Harmonizing Optimal Strategy for Treatment of Coronary
Artery Stenosis ‐ Coronary Intervention With Next Generation Drug‐Eluting Stent Platforms
and Abbreviated Dual Antiplatelet Therapy Trial) (ClinicalTrials.gov identifier NCT02601157),
are recruiting patients to compare 2 ultrathin biodegradable and polymer‐free stents
with varying DAPT durations.12 Even in ACS, the pendulum is swinging toward shorter
DAPT durations. A recent randomized trial assessing safety of interruption of DAPT
before 12 months in patients with ST‐segment–elevation MI treated with DES reported
the noninferiority of a shorter 6‐month DAPT regimen compared with the standard treatment.13
A meta‐analysis by Udell et al showed that extended DAPT beyond 1 year among stabilized
high‐risk patients with previous MI decreased the risk of major adverse cardiovascular
events but at the cost of an increased risk of major bleeding.14 Given patients at
increased risk of cardiovascular events are often also at higher risk of fatal bleeding
events, determining which patients will benefit from extended DAPT can be challenging.
Several clinical scores have been devised to aid clinicians in decision making of
whether to continue or discontinue DAPT.15, 16 Although not perfect, the DAPT score
is a validated risk score designed to identify patients for whom anticipated reduction
in ischemia with continued DAPT outweighs the anticipated bleeding risk and vice versa.15
Factors that contribute to a high DAPT score include diabetes mellitus, current cigarette
use, prior PCI or prior MI, congestive heart failure or left ventricular ejection
fraction <30%, MI at presentation, vein graft PCI, and stent diameter <3 mm; older
age contributes to a lower DAPT score. In addition to the DAPT score, procedural complexity,
burden of coronary artery disease, and stent type should also be taken into consideration
while deciding on the optimal DAPT duration as extended DAPT reduces events progressively
in those with greater procedural complexity.17 Likewise, several subgroups from the
PEGASUS trial, including those with peripheral arterial disease, diabetes mellitus,
and renal dysfunction, had a particularly robust absolute risk reduction in major
adverse cardiovascular events with extended DAPT.18, 19, 20 Table 2 lists clinical
characteristics that may benefit from more extended durations of DAPT.
Table 2
Clinical Characteristics Benefiting From Extended‐Duration DAPT
Clinical Characteristics Benefiting From Extended‐Duration DAPT
ACS presentation/prior ACS event
Peripheral arterial disease
Diabetes mellitus
Renal dysfunction
Current cigarette use
Left ventricular ejection fraction <30%
Congestive heart failure
Increased procedure complexity
Stent diameter <3 mm
Vein graft PCI
High CAD burden
Older‐generation stents
ACS indicates acute coronary syndrome; CAD, coronary artery disease; DAPT, dual antiplatelet
therapy; PCI, percutaneous coronary intervention.
In summary, prolonged DAPT appears more beneficial in patients with ACS treated with
ticagrelor or prasugrel, with risk factors for recurrent ischemia at a cost of increased
bleeding. However, any clinician will also recognize that not all bleeding or ACS
events carry the same risk. Indeed, a clinician‐patient shared decision making seems
apt when discussing the optimal duration of DAPT. On the other hand, the clinician
must also remember that trials evaluating DAPT over 5 years are currently lacking.
Therefore, although possibly beneficial, any DAPT beyond this time period has no strong
clinical evidence. With the continuous medication and stent advances, the optimal
DAPT duration will likely be altered, but until then the current guidelines supporting
DAPT duration of 12 months in ACS with further tailoring of therapy based on an individual
risk of further ischemic or bleeding events provide an excellent framework to begin.
Evolving research will help us further understand the risks and benefits of extended‐duration
DAPT, especially with the newer‐generation stents.
Disclosures
None.