Interventional Cardiology

Duration of Dual Antiplatelet Therapy After Percutaneous

Coronary Intervention: Is Less More?
Rik Rozemeijer, MD, PharmD, Wijnand P van Bezouwen, MD, Michiel Voskuil, MD, PhD, and Pieter R Stella, MD, PhD

Department of Cardiology, University Medical Centre Utrecht, Utrecht, the Netherlands

Abstract
The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) using the latest-generation drug-eluting
stents remains a matter of debate. Evidence suggests short regimens of DAPT are favorable for patients with a low ischemic risk, while those
at a high risk of ischemia may benefit from taking DAPT for a long duration. An individually assessed risk profile is pivotal in guiding DAPT
duration. Risk scores may aid individual patient DAPT decisions, but the value they add to clinical outcomes still needs to be established in
a prospective randomized trial. This review aims to provide an overview on DAPT, evaluate the available evidence on DAPT duration with
a description of common pitfalls of trial interpretation, and assess available tools for individual risk assessment in patients scheduled for
PCI with the latest-generation DES.

Keywords
Coronary artery disease, ischemic heart disease, percutaneous coronary intervention, drug-eluting stent, dual antiplatelet therapy

Disclosure: The authors have no conflicts of interest to declare.

Submitted: June 29, 2018 Accepted: October 24, 2018 Citation: US Cardiology Review 2018;12(2):91–7. DOI: https://doi.org/10.15420/usc.2018.4.2
Correspondence: Pieter R Stella, University Medical Center Utrecht, Department of Cardiology, Heidelberglaan 100, Room E.04.201, 3584 CX, Utrecht, the Netherlands.
E: [email protected]

Dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitor adhesion, activation and aggregation are considered key elements in the
is prescribed in the treatment of acute coronary syndrome (ACS) or formation of arterial thrombi, and are targets of antiplatelet therapy in the
following percutaneous coronary intervention (PCI) for drug-eluting treatment of ACS or DES implantation.7,8
stent (DES) implantation. An important misconception remains that
DAPT should be prescribed to prevent stent thrombosis. Although this At present, several distinct antiplatelet agents are used in routine practice:
may seem obvious, it should be emphasized that the incidence of stent aspirin; clopidogrel; prasugrel and ticagrelor.9–11 Aspirin irreversibly
thrombosis is below 1.0  % in second-generation DES and recurrent inhibits the cyclooxygenase (COX-1) enzyme, reducing the formation of
adverse events are equally attributable to culprit lesions or non-culprit thromboxane A2 and prostaglandins from arachidonic acid, which leads
lesions which can also be prevented by DAPT.1,2 to decreased platelet activation. Several trials have demonstrated that
aspirin reduces cardiovascular events.12 However, blocking COX-1 with
Current guidelines recommend at least 12 months of DAPT for patients aspirin also leads to a dose-dependent increased risk of bleeding, mainly
with ACS who have a low bleeding risk (class 1, level A).3,4 It is advised in the upper gastrointestinal tract.13
to treat patients with a low bleeding risk for at least 6 months for stable
coronary artery disease (class 1, level A). Optimal DAPT duration remains Clopidogrel is the only agent of the purigernic G-protein-coupled P2Y12
a matter of debate. Risk assessment is key in this decision, and the receptor inhibitors that is currently recommended for stable coronary
higher bleeding risk with longer DAPT duration must be balanced with artery disease, and is one of the most widely investigated antiplatelet
the benefits of prolonged DAPT duration for patients with increased agents. A synergistic effect of clopidogrel on top of aspirin has been
ischemic risk.3-5 established.14 As a prodrug, this thienopyridine requires a two-step
oxidation process that contributes to the non-uniform inter-individual
The authors therefore aimed to evaluate current evidence regarding clopidogrel response,which has led to high-on platelet reactivity in
antiplatelet agents, DAPT duration and risk assessment of patients 30–40 % of patients; this has prompted further research into other potent
scheduled for PCI with implantation of a latest-generation DES. P2Y12 inhibitors.15

Antiplatelet therapy In contrast to clopidogrel, prasugrel requires single-step oxidation by

Thrombocytes, or platelets, are anucleate cell fragments that are the hepatic cytochrome P450 iso-enzyme family, leading to a rapid-
essential for primary hemostasis and repair of the endothelium.6 Platelet onset, highly potent antiplatelet effect with less variability between

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Table 1: Characteristics of Major Studies Investigating Short Dual Antiplatelet Therapy

Study (year) Size S-DAPT L-DAPT Design Non-inferiority Time of ACS Primary endpoint Bleeding
(n) (months) (months) margin (%) randomization (%) criteria
RESET (2012)25 2,117 3 12 NI 4.0 At time of index 54 Cardiovascular death, MI, ST, TIMI
TVR, major or minor bleeding
OPTIMIZE (2013)27 3,119 3 12 NI 2.7 At time of index 32 All-cause death, MI, stroke, Modified
major bleeding REPLACE–2
and GUSTO
EXCELLENT (2012)24 1,443 6 12 NI 4.0 At time of index 51 Cardiac death, MI, TVR TIMI
SECURITY (2015)23 1,399 6 12 NI 2.0 At time of index 38 Cardiac death, MI, stroke, ST, BARC
major bleeding
ISAR-SAFE (2015)22 4,005 6 12 NI 2.0 6 months after PCI 40 All-cause death, MI, ST, stroke, TIMI
major bleeding
I-LOVE-IT 2 (2016)21 1,829 6 12 NI 3.7 At time of index 81 Cardiac death, TV–MI, TLR BARC
IVUS-XPL (2016) 26
1,400 6 12 S N/A At time of index 49 Cardiac death, MI, stroke, TIMI
major bleeding
SMART-DATE (2018)20 2,712 6 12 NI 2.0 At time of index 100 All-cause death, MI, stroke BARC
NIPPON (2017) 35
3,773 6 18 NI 2.0 At time of index 28 All-cause death, MI, stroke, BARC
major bleeding
PRODIGY (2012)34 2,013 6 24 S N/A 30 days after PCI 74 All-cause death, MI, stroke BARC
ITALIC (2017)36 1,850 6 24 NI 2.0 At time of index 43 All-cause death, MI, TVR, TIMI
stroke, major bleeding

Abbreviations: ACS = acute coronary syndrome; BARC = Bleeding Academic Research Consortium; GUSTO = Global Use of Strategies to Open Occluded Arteries; L-DAPT = long dual antiplatelet
therapy; NI = non-inferiority; REPLACE = Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events; S = superiority; S-DAPT = short dual antiplatelet therapy; ST = stent thrombosis;
TIMI = thrombolysis in myocardial infarction; TLR = target lesion revascularization; TVR = target vessel revascularization; TV-MI = target vessel myocardial infarction. Study acronyms:
EXCELLENT = the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting; I–LOVE–IT 2 = Evaluate Safety and Effectiveness of the Tivoli DES and the Firebird DES for Treatment
of Coronary Revascularization; ISAR–SAFE = Intracoronary Stenting and Antithrombotic Regimen: Safety And EFficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting; ITALIC
= Is There a Life for DES After Discontinuation of Clopidogrel; IVUS–XPL = Impact of Intravascular Ultra-sound Guidance on Outcomes of XIENCE PRIME Stents in Long Lesions; NIPPON = Nobori
Dual Antiplatelet Therapy as Appropriate Duration; OPTIMIZE = Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice;
PRODIGY = Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study; RESET = REal Safety and Efficacy of 3–month dual antiplatelet Therapy following Endeavor
zotarolimus-eluting stent implantation; SMART–DATE = Smart Angioplasty Research Team: Safety of 6-month Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in
Patients With Acute Coronary Syndromes; SECURITY = Second Generation Drug-Eluting Stent Implantation Followed by Six- Versus Twelve-Month Dual Antiplatelet Therapy.

individuals than clopidogrel.16,17 Prasugrel should be administered Evidence on Short Duration of Dual
only after the coronary anatomy of a patient has been established, Antiplatelet Therapy
except for those with ST-elevation myocardial infarction (STEMI), The primary motivators to study short DAPT (S-DAPT; 3–6 months) or
who will undergo primary PCI. Notably, prasugrel is associated ultra-short DAPT (US-DAPT; 3 months or less) are the increased risk of
with significantly higher rates of TIMI (thrombolysis in MI) major major bleedings caused by DAPT and the improved safety profile of the
bleeding, life-threatening bleeding and fatal bleeding, and should latest generation DES,which reduces the risks for late and very late stent
not be administered to those with a history of stroke or transient thrombosis (ST).19 To date, eight trials have investigated S-DAPT (n=6) or
ischemic attack.10 US-DAPT (n=2) and compared these to 12 months of therapy (Table 1).
All trials demonstrated S-DAPT or US-DAPT to be non-inferior to 12 months
Ticagrelor, as a first-in-class cyclopentyltriazolopyrimidine, can be of therapy in a comparison of primary composite outcomes (Table 2).20–27
administered before assessment of the coronary anatomy and acts
by reversible and direct inhibition of platelets by allostatic modulation When interpreting the evidence, several aspects should be kept in mind.
of the P2Y12 receptor, leading to a highly potent, rapid-onset and First, most trials investigating S-DAPT or US-DAPT had a non-inferiority
more predictable antiplatelet effect compared to clopidogrel.11,18 With a design. Accompanying non-inferiority margins range from 2  % in three
plasma half-life of 8–12 hours, ticagrelor requires administration twice trials to up to 4 %,which is rather wide to conclude non-inferiority.20,22–25
daily, which may be unattractive to patients with poor compliance. An Second, the trials were not powered for individual endpoints like ST, but
important adverse effect of ticagrelor is dyspnea (usually self-limiting), for composite primary endpoints, which were differently composed,
which occurred in roughly 20 % of patients in major trials and accounted complicating interpretation and compatibility. For example, three trials
for a substantial number of withdrawals.11 did not include major bleeding in the primary endpoint.20,21,24 Patient
selection is the third and probably most important consideration when
Ever since the introduction of DAPT, extensive research has tried to interpreting different trials. Most trials included a variety of patient
establish the optimal duration of DAPT. This has led the adoption of two groups or at least combined people with stable coronary artery disease
main strategies for patients scheduled for PCI: abbreviated, or short and ACS, thereby limiting translation to individual patients. Two trials
DAPT; and prolonged DAPT. investigating S-DAPT had stricter inclusion criteria, including only patients

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Table 2: Results of Major Studies Investigating Short Dual Antiplatelet Therapy

Study (year) Effect Primary All-cause death MI ST (definite or Stroke Major bleeding
estimate endpoint probable)
RESET (2012)25 RD (95 % CI) 0.0 % (−2.5–2.5) −0.5 % (−1.4–0.4) −0.2 % (−0.7–0.3) −0.1 % (−0.5–0.3) 0.1 % (−0.1–1.0) −0.4 % (−0.9–0.1)
OPTIMIZE (2013)27 HR (95 % CI) 1.03 (0.77–1.38) 0.95 (0.63–1.45) 1.17 (0.77–1.76) 1.08 (0.49–2.36) 0.99 (0.29–3.44) 0.71 (0.32–1.60)
EXCELLENT (2012) 24
HR (95 % CI) 1.14 (0.70–1.86) 0.57 (0.17–1.95) 1.86 (0.74–4.67) 6.02 (0.72–49.96) 0.60 (0.14–2.51) 0.50 (0.09–2.73)
SECURITY (2015)23 RD (95 % CI) 0.8 % (−2.4–1.7) −0.1 % (−0.7–0.5) 0.2 % (−1.2–1.7) −0.1 % (−0.7–0.4) 0.6 % (−0.2–1.3) −0.5 (−1.4–0.4)
ISAR-SAFE (2015)22 HR (95 % CI) 0.91 (0.55–1.50) 0.66 (0.27–1.63) 0.93 (0.44–1.97) 1.25 (0.33–4.65) 1.40 (0.44–4.41) 0.80 (0.21–2.98)
I-LOVE-IT 2 (2016) 21
Cumulative 7.2 % versus 1.1 % versus 1.4 % 4.4 % versus 3.9 % 0.6 % versus 0.2 % 1.2 % versus 1.4 % 1.2 % versus
incidence, 6.4 % p=0.53 p=0.57 p=0.53 p=0.25 p=0.71 0.7 % p=0.21
log-rank p-value
IVUS-XPL (2016)26 HR (95 % CI) 1.07 (0.52–2.22) 0.50 (0.17–1.45) N/A 1.00 (0.14–7.11) 2.00 (0.50–7.99) 0.71 (0.23–2.25)
SMART-DATE (2018)20 HR (95 % CI) 1.13 (0.79–1.62) 0.9 (0.57–1.42) 2.41 (1.15–5.05) 1.5 (0.68–3.35) 0.92 (0.41–20.8) 0.6 (0.22–1.65)
NIPPON (2017) 35
RD (95 % CI) −0.6 % (−1.5–0.3) −0.5 (−1.2–0.0) −0.2 (−0.6–0.1) −0.1 (−0.4–0.2) −0.1 (−0.6–0.4) 0.1 % (−0.6–0.7)
PRODIGY (2012)34 HR (95 % CI) 0.98 (0.74–1.29) 1.00 (0.72–1.40) 1.06 (0.69–1.63) 1.15 (0.55–2.41) 0.60 (0.29–1.23) 0.56 (0.32–0.98)
ITALIC (2017)36 HR (95 % CI) 0.94 (0.58–1.52) 0.55 (0.26–1.15) 1.34 (0.56–3.17) 2.00 (0.50–7.98) 0.85 (0.29–2.53) N/A

Abbreviations: N/A = not available; RD = risk difference; ST = stent thrombosis. Study acronyms: EXCELLENT = Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting;
I–LOVE–IT 2 = Evaluate Safety and Effectiveness of the Tivoli DES and the Firebird DES for Treatment of Coronary Revascularization; ISAR–SAFE = Intracoronary Stenting and Antithrombotic Regimen:
Safety And EFficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting; ITALIC = Is There a Life for DES After Discontinuation of Clopidogrel; IVUS–XPL = Impact of Intravascular Ultra-
sound Guidance on Outcomes of XIENCE PRIME Stents in Long Lesions; NIPPON = Nobori Dual Antiplatelet Therapy as Appropriate Duration; OPTIMIZE = Optimized Duration of Clopidogrel Therapy
Following Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice; PRODIGY = Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study;
RESET = REal Safety and Efficacy of 3–month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation; SMART–DATE = Smart Angioplasty Research Team: Safety of 6–
month Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With Acute Coronary Syndromes; SECURITY = Second Generation Drug-Eluting Stent Implantation
Followed by Six- Versus Twelve-Month Dual Antiplatelet Therapy.

with stable angina, silent ischemia or unstable angina or studied only results, it is important to address the definition used for bleeding-related
those with biomarker positive ACS.20,23 Overall, mostly patients with a death, where death was considered to be possibly bleeding related if
relatively low ischemic risk (stable coronary artery disease or biomarker occurring within 1 year of the bleeding episode, which is a rather liberal
negative ACS) were included in the majority of these trials. Finally, trials definition, leading to an overestimated result. On the other hand, most
used homogeneous and different bleeding endpoint criteria, which patients were treated with clopidogrel. With the availability of more
complicates the interpretation of results. potent P2Y12 inhibitors in current practice, the effects on bleeding events
or even mortality in these trials may be underestimated. Of course,
Multiple meta-analyses have attempted to compare the outcomes of causality cannot be established, but the impact of bleeding should not be
trials investigating S-DAPT.28–33 The results of these meta-analyses are underestimated. More studies have found bleedings associated with an
consistent and none of them show a difference in mortality. Importantly, increased risk of recurrent bleeding and all-cause mortality.39,40
the risks for ST, MI and stroke were not increased in the S-DAPT arm,
while an increased risk for major bleeding events was observed with Evidence on Prolonged Duration of Dual
12 months’ treatment. Antiplatelet Therapy
To date, four trials compared prolonged DAPT (>12 months of treatment)
Three trials compared S-DAPT to prolonged DAPT (>12 months to a standard regimen of DAPT (12 months of treatment).41–44 The trials’
of treatment).34–36 Two trials concluded S-DAPT to be non-inferior characteristics are shown in Table 3, and the main results are summarized
to prolonged DAPT, and one trial noted a trend of more complications in in Table 4. The Dual Antiplatelet Trial (DAPT) is the largest study and
the arm who were treated for 24 months.35,36 The only trial powered for was powered for superiority for the primary endpoints of definite
superiority did not find 24 months of therapy to be superior to S-DAPT, or probable ST and a composite endpoint of death, MI and stroke.41
but did notice a significant increase in BARC 3 or 5 bleeding events For both ST (definite and probable) and the composite primary endpoint,
(HR 0.56, 95 % CI [0.32–0.98], p=0.037).34 a significant decrease was found when prolonging DAPT (ST: HR 0.29,
95 % CI [0.17–0.48], p<0.001, composite endpoint: HR 0.71, 95 % CI [0.59–
It seems likely that S-DAPT may be beneficial to selected patients 0.85], p<0.001). Notably, all-cause deaths were higher in the prolonged
with a high risk of bleeding. Major bleeding events are an important DAPT arm (HR 1.36, 95  % CI [1.00–1.85], p=0.05), as a result of to the
complication because of the association between major bleedis and a larger occurrence of non-cardiovascular deaths in the prolonged DAPT
poor prognosis,in addition to the negative impact these events have arm (HR 2.23, 95 % CI [1.32–3.78], p=0.002). This difference in mortality
on a patient’s quality of life.37 Notably, a recent individual patient data was explained by a between-group imbalance of patients diagnosed with
meta-analysis found an association between bleeding-related deaths and cancer. Not surprisingly, prolonged DAPT caused an increase in bleeding
DAPT duration after PCI.38 More specifically, S-DAPT was associated with complications (HR 1.61, 95 % CI [1.21–2.16], p=0.001). In their individual
a reduction of bleeding-related deaths compared to long DAPT (L-DAPT; patient data analysis, Palmerini et al.38 observed numerically more
12 months of treatment) and prolonged DAPT. When interpreting these bleeding-related deaths in the DAPT trial.

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Table 3: Characteristics of Major Studies Investigating Long Dual Antiplatelet Therapy

Study (year) Size (n) Standard L–DAPT Design Time of ACS Primary endpoint Bleeding criteria
DAPT (months) (months) randomisation (%)
ARCTIC (2014)43 2440 12 18–30 Superiority 12 months after index 26 All-cause death, MI, ST, stroke, STEEPLE
revascularization
DAPT (2014)41 9961 12 30 Superiority 12 months after index 42 ST and death, MI, stroke BARC and GUSTO
DESLATE (2014) 42
5045 12 36 Superiority 12 months after index 61 Cardiac death, MI, stroke TIMI
OPTIDUAL (2016)44 1799 12 48 Superiority 12 months after index 27 All-cause death, MI, stroke ISTH
major bleeding

ACS = acute coronary syndrome; BARC = Bleeding Academic Research Consortium; GUSTO = Global Use of Strategies to Open Occluded Arteries; ISTH = International Society
on Thrombosis and Haemostasis; L–DAPT = long dual antiplatelet therapy; S–DAPT = short dual antiplatelet therapy; ST = stent thrombosis; STEEPLE = Safety and Efficacy of Enoxaparin in
Percutaneous Coronary Intervention Patients: an International Randomized Evaluation; TIMI = Thrombolysis In MI. Study acronyms: ARCTIC = Assessment by a double Randomisation of a
Conventional antiplatelet strategy versus a monitoring-guided strategy for drug-eluting stent implantation and, of Treatment Interruption versus Continuation 1 year after stenting;
DAPT = Dual Antiplatelet Therapy; DES–LATE = Optimal Duration of Clopidogrel Therapy With DES to Reduce Late Coronary Arterial Thrombotic Event; OPTIDUAL = OPTImal DUAL
Antiplatelet Therapy.

Table 4: Results of Major Studies Investigating Long Dual Antiplatelet Therapy

Study (year) Effect estimate Primary All-cause death MI ST (definite or Stroke Major bleeding
endpoint probable)
ARCTIC (2014)43 HR (95 % CI) 0.94 (0.66–1.35) 0.71 (0.45–1.10) 1.43 (0.80–2.58) 1.59 (0.61–4.09) 1.01 (0.55–1.85) 0.71 (0.42–1.20)
DAPT (2014) 41
HR (95 % CI) 0.71 (0.59–0.85) 1.36 (1.00–1.85) 0.47 (0.37–0.61) 0.29 (0.17–0.48) 0.68 (0.40–1.17) *RD 1.0 % (0.4–1.5)
DESLATE (2014)42 HR (95 % CI) 1.17 (0.68–2.03) 1.32 (0.49–3.55) 1.04 (0.41–2.62) N/A 0.69 (0.19–2.44) 0.15 (0.02–1.20)
OPTIDUAL (2016)44 HR (95 % CI) 0.75 (0.50–1.28) 0.65 (0.34–1.22) 0.67 (0.31–2.18) 2.97 (0.31–28.53) 0.69 (0.22–2.18) 0.98 (0.47–2.05)

*Major bleedings reported as risk difference. N/A = not available; RD = risk difference; ST = stent thrombosis. Study acronyms: ARCTIC = Assessment by a double Randomisation of a Conventional
antiplatelet strategy versus a monitoring-guided strategy for drug-eluting stent implantation and, of Treatment Interruption versus Continuation 1 year after stenting; DAPT = Dual Antiplatelet
Therapy; DES–LATE = Optimal Duration of Clopidogrel Therapy With DES to Reduce Late Coronary Arterial Thrombotic Event; OPTIDUAL = OPTImal DUAL Antiplatelet Therapy.

The Assessment by a double Randomization of a Conventional Patient-tailored Duration of Dual

antiplatelet strategy versus a monitoring-guided strategy for drug- Antiplatelet Therapy
eluting stent implantation and of Treatment Interruption versus The European Society of Cardiology’s focused update on DAPT3 states that
Continuation 1 year after stenting (ARCTIC)-Interruption trial did not find the use of risk scores to guide DAPT duration may be considered (class
a difference in the composite primary endpoint (death, MI, ST, stroke IIB recommendation). Multiple risk scores to assess a patient’s ischemic
or transient ischemic attack, and urgent revascularization).43 However, or bleeding risk have been proposed: the DAPT score,the PARIS registry
it should be emphasized that this study was prematurely terminated, risk scores, PRECISE-DAPT, and CREDO-Kyoto (Tables 5–7 and Figure 1).46–49
and the event rates were lower than anticipated. The prolonged DAPT
arm did, however, show a significant increase in STEEPLE (Safety The first risk assessment tool was the DAPT score,which was derived
and Efficacy of Enoxaparin in Percutaneous Coronary Intervention from the DAPT trial to aid clinical decision-making regarding DAPT
Patients: An International Randomized Evaluation) bleeding (HR 0.26, duration.46 This score aims to predict who would benefit from prolonged
95 % CI [0.07–0.91], p=0.04). Therefore, the ARCTIC-Interruption authors DAPT at 12 months after PCI after an event-free period of 12 months.
concluded that prolonging DAPT has no apparent benefit and could Including eight variables (age, smoking, diabetes, MI at presentation, prior
harm patients. Both the Optimal Duration of Clopidogrel Therapy with PCI or MI, paclitaxel-eluting stent, stent diameter, chronic heart failure
DES to Reduce Late Coronary Arterial Thrombotic Event (DES-LATE) and vein graft stent), the score ranges from −2 to 10. Any score below 2
trial and the OPTImal DUAL Antiplatelet Therapy (OPTIDUAL) trial did is associated with a bleeding risk that exceeds ischemic risk, indicating
not observe any potential harm from prolonging DAPT nor a beneficial DAPT cessation at 12 months. High scores (≥2) are associated with an
effect.42,44 This is explained by the fact that these studies were powered increased ischemic risk, leading to an increased net clinical benefit from
to detect major differences only. continuing DAPT treatment. Important limitations of the DAPT score are:
a limited external validity because it is derived from the DAPT study
Several meta-analyses have combined these trials. The results cohort, which included ischemic patients and those who were bleeding
for all-cause death and cardiac death are conflicting. 29,30,32,33,45 event free after 12 months; and the reduced effect when correcting for
One showed prolonged DAPT reduced cardiac death,while another paclitaxel-eluting stents, which are no longer used.
indicated non-cardiac death to be increased by prolonged DAPT.29,45
Evidence also showed prolonged DAPT reduced ischemic events at the The PARIS registry risk scores are two scores to predict bleeding and
cost of more major bleedings.29,30,32,33,45 Patients with a high ischemic ischemic risk after PCI.47 The ischemic score is composed solely of clinical
burden are most likely to benefit from prolonged DAPT or maybe even characteristics (diabetes, ACS type, smoking, creatinine clearance, prior
life-long DAPT. PCI, and prior coronary artery bypass graft), although procedural and

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Table 5: Duration of Dual Antiplatelet Therapy Risk Score Table 6: PARIS Risk Scores

Parameter Score PARIS ischemic risk score PARIS bleeding risk score
Age (years) Parameter Score Parameter Score
   ≥75 −2 Diabetes Age (years)
   65 to <75 −1 None 0 <50 0
   <65 0 Type 2 diabetes +1 50–59 +1
Cigarette smoking 1 Type 1 diabetes +3 60–69 +2
Diabetes 1 Acute coronary syndrome 70–79 +3
MI at presentation 1 No 0 ≥80 +4
Prior PCI or prior MI 1 Yes, troponin negative +1 BMI, kg/m2
Paclitaxel-eluting stent 1 Yes, troponin positive +2 <25 +2
Stent diameter <3 mm 1 Current smoking 25–34.9 0
CHF or LVEF <30 % 2 No 0 ≥35 +2
Vein graft stent 2 Yes +1 Current smoking
Total score range: −2–10 CrCl <60ml/min No 0

CHF = congestive heart failure; LVEF = left ventricular ejection fraction; PCI = percutaneous Absent 0 Yes +2
coronary intervention.
Present +2 Anemia
Prior PCI Absent 0
angiographic characteristics also influence patients’ ischemic risk.50
No 0 Present +3
The bleeding score includes age, BMI, smoking, anemia, creatinine
Yes +2 CrCl <60ml/min
clearance and triple therapy. Smoking and reduced creatinine increase
Prior CABG Absent 0
a patient’s ischemic risk as well as bleeding risk, according to the
No 0 Present +2
derivation cohort. Retrospective validation of the PARIS risk scores using
data from the platelet reactivity and clinical outcomes after coronary Yes +2 Triple therapy on discharge

artery implantation of DES (ADAPT-DES) registry resulted in moderate No 0

discrimination of both the thrombotic and bleeding risk scores. Yes +2
Total score range: 0–12 Total score range: 0–15
The PRECISE-DAPT score was developed as a standardized tool to weight
CrCl = creatinine clearance; CABG = coronary artery bypass grafting; PCI = percutaneous
bleeding risk before selecting DAPT treatment duration and aims to coronary intervention.
predict out-of-hospital bleeding events with a five-item score. The external
validation in two validation cohorts (PLATelet inhibition and patient Table 7: CREDO-Kyoto Risk Scores
Outcomes [PLATO] and the BernPCI registry) indicated replicable moderate
discriminative ability. Its clinical utility is, however, lower than those of other CREDO ischemic risk score CREDO bleeding risk score
risk scores since the score is primarily based on laboratory results.48
Parameter Score Parameter Score
Severe chronic kidney disease 2 Platelet count <100/ml 2
The CREDO-Kyoto risk scores aim to assess thrombotic and bleeding risks
AF 2 Severe chronic kidney disease 2
using two scores: an eight-item ischemic risk score and a seven-item
bleeding risk score.49 Four parameters are included in both scores. This Peripheral vascular disease 2 Peripheral vascular disease 2

raises questions about clinical applicability, as patients with a high ischemic Anemia 2 Heart failure 2
score are likely to have an increased bleeding score too, leaving the Age ≥75 years 1 Prior MI 1
question whether to prolong or shorten DAPT duration unanswered. Unlike Heart failure 1 Malignancy 1
other scoring systems, in CREDO-Kyoto, the procedural parameters were Diabetes 1 AF 1
tested and included chronic total occlusion in the final ischemic score.
Chronic total occlusion 1

Total score range: 0–12 Total score range: 0–11

In the first validation studies, the DAPT score was retrospectively
replicated in the PRODIGY study, but failed to discriminate the risk
on bleeding and ischemic events using data from the ISAR-SAFE CardioCHUVI (Cardiologia del Complejo Hospitalario Universitario de Vigo)
cohort.51,52 Hereafter, both the DAPT score and PARIS registry scores cohort (n=1,926),PARIS bleeding score and PRECISE-DAPT score were
were retrospectively validated and compared in a Chinese population retrospectively validated.54 For major bleedings, PARIS and PRECISE-DAPT
(n=5,709).53 Only the DAPT score showed modest accuracy for predicting showed a moderate discriminative power and, using decision curve
major bleedings. Both scores showed poor discriminative capacity analyses, it was concluded that the PARIS bleeding score had a superior
predicting ischemic events. Therefore, the DAPT score and risk scores performance. Recently, the DAPT score was successfully validated in
from PARIS may not be applicable in a Chinese population. In the Spanish a pooled Japanese cohort (n=12,223).55 One year after PCI, the DAPT

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 Interventional Cardiology

Figure 1: PRECISE–DAPT Score Clinical Perspectives and Future Research

Several randomized trials have established the pivotal role of DAPT
Bleeding score following PCI for latest-generation DES implantation. Individual
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 assessment of a patient’s risk profile will be essential to optimize DAPT
Points duration. A substantial proportion of patients have stable coronary
artery disease. Especially for stable patients with a low ischemic risk
≥12.0 11.5 11.0 10.5 ≤10.0
profile, the authors believe short durations of DAPT may be beneficial,
Hemoglobin (g/dl) given the improved safety profile of currently available DES. On the
≤5 8 10 12 14 16 18 ≥20 other hand, it seems obvious that patients with a high ischemic risk
3 profile may need prolonged or even lifelong DAPT.
White blood cell count (x10 cells/µl)

≤50 60 70 80 ≥90 Regarding the currently available risk scores, any clinical value
Age (years) they add needs to be determined in a prospective randomized trial.
Although the authors believe risk scores are likely to improve in aiding
≥100 80 60 40 20 0
individual patient-tailored DAPT, physicians should acknowledge
Creatinine clearance (ml/min)
the limitations of existing risk scores, and fully assess the patient’s
No Yes risk profile and coronary angiographic characteristics. Since optimal
Previous bleed durations of DAPT have been investigated for more than a decade,
many clinicians believe simplification may be required regarding
score successfully stratified ischemic and bleeding risks. However, the pharmacotherapy after PCI.
investigators observed low ischemic event rates in patients with a high
DAPT score. Therefore, questions remain over the clinical utility of the Future research may examine de-escalation of DAPT. For example,
score and the benefit of prolonging DAPT treatment. Last, in a nationwide the ongoing Ticagrelor With Aspirin or Alone in High-Risk Patients
Swedish registry (n=41,101) the DAPT score had poor discriminative After Coronary Intervention (TWILIGHT) study (NCT02270242)
capacity for ischemic events and did not discriminate bleeding risk.35 challenges the concept of DAPT as ticagrelor monotherapy for
long-term platelet inhibition in a broad population of patients
Results of these validation studies are conflicting, but differences undergoing PCI with DES. As the latest-generation DES with enhanced
between the validation cohorts need to be taken into account. Cohort safety profiles are likely to reduce adverse events even further, a
size and geographical background in particular may differ substantially paradigm shift to de-escalation of DAPT should be evaluated in future
between derivation cohorts. dedicated trials.

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