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Stent Thrombosis: Implications for New Stent Designs and Dual Antiplatelet Therapy Duration Chapter | 16 233
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TABLE 16.3 Stent Thrombosis Risk Factors at Baseline in the Drug-Eluting Stent Randomized
Population by Treatment Group in the Dual Antiplatelet Therapy Trial
Measure
a
n [ 5020
Continued thienopyridine
Placebo
n [ 4941
Any clinical 32.51% 32.03%
Enzyme-positive ACS (STEMI or NSTEMI) 26.10% 25.87%
Renal insufficiency/failure 4.46% 4.00%
LVEF < 30%
b
1.72% 1.48%
Any lesion related 31.27% 31.31%
>2 Vessels stented 0.38% 0.59%
>2 Lesions per vessel 1.85% 1.90%
Lesion length > 30 mm
b
10.04% 10.15%
Bifurcation lesion with side branch 2.5 mm 6.49% 6.52%
In-stent restenosis of a DES 3.12% 3.19%
Vein bypass graft stented 2.53% 3.10%
Unprotected left main stented 0.38% 0.47%
Thrombus-containing lesion
b
11.83% 11.71%
Prior brachytherapy 0.26% 0.26%
Any risk factor 50.73% 50.99%
a
There were no significant differences between groups.
b
For most variables, 0%e3% of patients had missing values; 5%e10% of patients were missing thrombus-containing lesion
status, LVEF, and lesion length.
ACS, acute coronary syndrome; DES, drug-eluting stent; LVEF, left-ventricular ejection fraction; NSTEMI, non-ST-segment
elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction.
Reproduced with permission from the NEJM DAPT Trial. Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg
PG, Normand S, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR, Krucoff MW, Hermiller J, Dauerman HL, Simon DI,
Kandzari DE, Garratt KN, Lee DP, Pow TK, Lee P, Rinaldi MJ, Massaro JM. Twelve or 30 months of dual antiplatelet therapy
after drug-eluting stents. N Engl J Med 2014;371:2155e66.
10%
Stent Thrombosis
HR 0.29 (0.17-0.48)
8%
foecnedicnIevitalumuC
6%
0.4% vs. 1.4%,
P<0.001
10%
8%
6%
MACCE
HR 0.71 (0.59-0.85)
4.3% vs. 5.9%,
P<0.001
*
4%
Stent Thrombosis
2%
0%
12 15 18 21 24 27
30
33
Thienopyridine Placebo
FIGURE 16.7 Coprimary end-point time-to-event curves (stent thrombosis and MACCEs [cardiac death, myocardial infarction, stroke]) from the Dual
Antiplatelet Therapy trial. MACCE, major adverse cardiovascular or cerebrovascular event. Reproduced with permission from the NEJM DAPT trial.
Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, Normand S, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR, Krucoff MW,
Hermiller J, Dauerman HL, Simon DI, Kandzari DE, Garratt KN, Lee DP, Pow TK, Lee P, Rinaldi MJ, Massaro JM. Twelve or 30 months of dual
antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155e66.
4%
2%
Myocardial Infarcon or Stroke
Cumulave Incidence of Death,
0%
12 15 18 21 24 27 30 33
Months Aer EnrollmentMonths Aer Enrollment
*curves diverge at 30 months
234 Cardiovascular Thrombus
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was associated with a lower cumulative incidence of MI (2.1% vs. 4.1% placebo; HR [95% CI], 0.47 [0.37e0.61];
P < .001) including MI not related to ST (1.8% v s. 2.9% placebo; P < .001), which accounted for 55% of the MI
treatment benefit. Rates of death due to cardiac or v ascular causes as well as stroke were similar between randomized
DES patients. However, all-cause death was numerically increased in DES patients r eceiving continued thienopyridine (2.0% vs. 1.5% placebo; P ¼ .05), due to a relative increase in death from noncardiovascular causes (1 .0% vs.
0.5%; P ¼ .002) mostly related to cancer (n ¼ 31 vs. n ¼ 14; P ¼ .02) or bleeding due to fatal trauma (n ¼ 7vs.n ¼ 2;
P ¼ .07). A blinded review of cancer-related deaths identified a between-group imbalance in the number of patients
who underwent randomization and in whom cancer had been diagnosed before treatment (n ¼ 8vs.n ¼ 1 placebo).
When these patients were excluded in post hoc sensitivity analysis, differences in mortality were no longer significant.
Further, a separate meta-analysis of 14 RCCTs that randomly assigned 69,644 patients (w139,000 patient years of
follow-up) to different durations of antiplatelet therapy demonstrated no differences in mortality (all-cause, cardiovascular,
or n onc ar di ovas cu lar) b etw een aspirin alone or short-duration (6 months) DAPT compared with longer-duration
treatment [63]. Indeed, meta-regression analysis showed no effect of DAPT duration on hazard for all-cause, cardiovascular, or noncardiovascular mortality across trials. Finally, among DES randomi zed patients, continued thienopyridine was associated with increased rates of moderate/severe bleed ing (2.5%vs.1.6%placebo;HR[95%CI]1.61
[1.61e2.16]; P ¼ .001), although both severe and fatal bleeding were uncommon and not different between groups
(Fig. 16.8).
Concern has been expressed that three of the four DESs utilized in the DAPT trial are no longer commercially available
for use and no longer represent “state-of-the-art” technology. In this regard, it is noteworthy that consistency in treatment
effect benefit for 30 versus 12 months of DAPT was observed across all four stent types for the clinical end points of ST
(P interaction .76) and MI (P interaction .11). Subgroup analysis of the 4703 randomized patients treated with EES
demonstrated reductions in ST (HR [95% CI] ¼ 0.38 [0.15, 0.97]; P ¼ .04) and MI (0.63 [0.44, 0.91];
P ¼ .01) in favor of
30 versus 12 months of DAPT [64]. Nevertheless, meta-analysis of trials that included second-generation EES and the
Resolute ZES, as well as older 1GDESs, clearly suggests that the newer platforms with thinner struts and more
biocompatible/inert polymers derive less benefit with respect to ST reduction from longer (12 months) versus shorter
(3e6 months) duration DAPT, while still incurring similar bleeding risk hazard [65]. These data have prompted a shift in
clinical practice guideline recommendations for SIHD patients undergoing PCI with these devices to shorter durations
(6 months in the US ACC/AHA guidelines, 3 months in the European Society of Cardiology guidelines) of dual antiplatelet treatment [66,67].
FIGURE 16.8 Bleeding events during the randomized treatment period (12e30 months) following enrollment into the dual antiplatelet therapy trial by
randomized treatment (placebo or thienopyridine). Moderate or severe refers to GUSTO classification; BARC refers to Bleeding Academic Research
Consortium.
Stent Thrombosis: Implications for New Stent Designs and Dual Antiplatelet Therapy Duration Chapter | 16 235
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BARE METAL STENTS
Analysis of BMS-treated patients who were randomized to continued thienopyridine (vs. placebo) in the DAPT trial
demonstrated a consistent treatment effect benefit for reduction in ST (HR [95% CI] 0.49 [0.15, 1.65] vs. 0.29 [0.17, 0.48]
DES; P interaction .42) as well as an increase in moderate/severe bleeding (2.0% vs. 0.9% placebo; P ¼ .07) [68].
Importantly, no differences in the incidence of death (all-cause, cardiovascular, or noncardiovascular) were observed
between randomized groups of BMS-treated patients. In addition, the prospective comparison of propensity-matched
patients (matched perfectly for STEMI and with standardized variances of 10% for 55 total clinical and angiographic
lesion-related variables) treated with either DES or BMS demonstrated an increased risk for ST from 0 to 33 months
following PCI with BMS [69] (Fig. 16.9), with the greatest portion of risk difference evident within the first year following
stent deployment. Similarly, MACCE was numerically less following DES (vs. BMS) from 0 to 33 months (11.4% vs.
13.2%; P ¼ .053), especially during the first year (5.1% vs. 6.8%; P ¼ .01) following stent deployment. The integrity of
the propensity match is supported by the observation of similar rates of MI not related to ST (6.0% vs. 6.5%), stroke (1.8%
vs. 2.1%), and moderate/severe bleeding (4.0% vs. 3.7%) between DES- and BMS-matched patients, respectively [69].
Finally, multiple large-scale network meta-analyses of RCCT evaluating late and very late ST by stent type have
demonstrated a consistent w60% reduction in definite/probable ST through 2-year follow-up after 2GDES (EES)
compared with BMS [8,34,35,70]. This marked and consistent reduction in ST associated with EES has been ascribed to
thromboresistance of the permanent fluorocopolymer (PVDF) coating and/or mitigation of the inflammatory response to
endoluminal stent injury by the antiinflammatory/antiproliferative drug (everolimus).
FACTORS INFLUENCING OPTIMAL DUAL ANTIPLATELET THERAPY DURATION
Recent data suggest that multiple factors including PCI procedural complexity and procedure optimization (use of
intravascular imaging, routine high-pressure postdilation), as well patient/lesion characteristics, may influence the efficacy
and safety of DAPT duration. A meta-analysis of RCCTs comparing longer (12 months) with shorter (3e6 months)
duration of dual therapy evaluated the relative risk/benefit of therapy by procedural complexity as assessed by prespecified
complexity measures. Incremental benefit (vs. risk) was observed for longer-duration therapy with increasing procedural
complexity [71]. Complex coronary risk factors included three or more diseased vessels, three or more stents, three or more
lesions, bifurcation lesion requiring at least two stents, 60 mm of total stents used, and a chronic total occlusion. In
20%
15%
10%
5%
0%
Cumulative Incidence of Stent Thrombosis*
No. At Risk
DES 8308 8233 8181 8125 8066 8008 7948 7896 7843 7804 7702 5013
BMS 1718 1691 1666 1648 1631 1620 1611 1598 1589 1578 1563 922
*Weighted Kaplan-Meier and risk differences (RD) are presented
FIGURE 16.9 Stent thrombosis from 0 to 33 months after stenting by stent type from the prospective, prespecified propensity-matched dual antiplatelet
therapy trial comparison in 10,026 patients matched perfectly for ST-segment elevation myocardial infarction and with <10% variance for 55 total
variables. BMS, bare metal stent; DES, drug-eluting stent. Reproduced with permission from Kereiakes DJ, Yeh RW, Massaro JM, Driscoll-Shempp P,
Cutlip DE, Steg PG, Gershlick AH, Darius H, Meredith IT, Ormiston J, Tanguay JF, Windecker S, Garratt KN, Kandzari DE, Lee DP, Simon DI, Iancu
AC, Trebacz J, Mauri L, on behalf of the DAPT Study Investigators. Stent thrombosis in drug-eluting or bare-metal stents in patients receiving dual
antiplatelet therapy. JACC Cardiovasc Interv 2015;8:1552e62.
DES
BMS
3 6 9 12 15
0
0-12 Months:
RD -1.00%
0.70% vs. 1.68%
P=0.002 (Difference)
18 21 24 27 30 33
Months After Enrollment
0-33 Months:
RD -1.05%
1.70% vs. 2.61%
P<0.001 (Noninferiority)
P=0.01 (Difference)
236 Cardiovascular Thrombus
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addition, the IVUS-XPL RCCT evaluated treatment durations of 6 versus 12 months following long EES implantation
(median stent length 45 mm), using a 2 2 factorial study design involving randomization to IVUS-imaging-assisted PCI
(vs. angiography guidance alone) followed by randomization to 6 versus 12 months of DAPT [72,73]. The imp act of each
randomization on primary end-point events (composite occurrence of cardiac death, MI, stroke, TIMI [thrombolysis in
myocardial infarction] major bleed) was assessed. Following DAPT disconti nuation at 6 months, a non-statistically
significant increase in primary end-point events was observed (HR [95% CI] 2.00 [0.50e7.98]; log rank P ¼ .319),
suggesting a lack of difference in the underpowered comparison of treatment duration. However, in the powered randomized comparison of IVUS optimization, a significant treatment benefit(P interaction .018) was observed favoring
shorter-duration (6 months) therapy following IVUS optimization and longer therapy (12 months) without IVUS. Indeed,
meta-analyses of RCCTs and observational data suggest that imaging optimization of PCI (IVUS or OCT) can significantly
improve clinical outcomes following coronary stent implantation [74,75]. The benefit of procedural optimization for
reducing ST risk is inferred by very low (1.0%) cumulative rates of definite ST through 5-year follow-up in the
TWENTE RCCT, which compared EES with ZES and used routine high-pressure postdilation after stenting in 82% of all
PCI [47].
A history of MI predicts ischemic risk following stenting. In the DAPT trial, patients with MI history (either within 72 h
of PCI or longer) had an increased risk of death, MI, or ST following enrollment during the first 12 months on “open-label”
dual therapy, as well as durin g the subsequent 18 months following randomization to either placebo or continued
thienopyridine [76]. This subgroup demonstrated a consistent risk/benefit of longer duration therapy (30 vs. 12 months)
that was clearly magnified by application of a risk score to provide more individualized therapy prescription (see below).
Furthermore, underpowered subgroup analyses and/or observational data have suggested a differential benefit for reduction
in ischemic events following longer (vs. shorter)-duration DAPT after stenting for in-stent restenosis [77], for sapheno us
vein graft target stenosis [78], or in patients with symptomatic peripheral arterial disease (PAD) [79].
RISK-PREDICTIVE MODELS
The optimal duration of DAPT with aspirin and P2Y12 receptor inhibitor after PCI with stents is the subject of debate. The
DAPT trial demonstrated that continued therapy beyond 1 year decreases ST and MI but increases bleeding among patients
who had completed 1 year of therapy without having experienced either a major adverse cardiovascular or cerebrovascular
ischemic event or a moderate/severe bleeding event and who had demonstrated compliance with therapy. Continuing
DAPT involves careful assessment of the balance between bleeding and ischemic risk for the individual patient. To date,
most ischemia and bleeding risk algorithms have focused on in-hospital events or short-term risk, and factors influencing
late bleeding or ischemic hazard are less well defined. Further, risk factors related to ischemia or bleeding following PCI
overlap substantially and their respective weights may vary over time. Recently several risk-predictive models have been
developed and decision tools proposed to inform more risk-appropriate DAPT duration for individual patients.
Dual Antiplatelet Therapy Risk Score
A clinical prediction score based on ischemic and bleeding risk factors was developed from the DAPT trial (the randomized cohort) to identify patients with greater than expected benefit (vs. harm) from continuation of DAPT beyond 1
year [80]. Variables in the predictive score included patient and procedural characteristics associated with either ischemic
or bleeding events after PCI. For example, prior PCI, MI at presentation, current smoking, and diabetes mellitus are
associated with ST during the year after PCI, while advanced age, renal disease, and symptomatic PAD have been
associated with in-hospital or 30-day bleeding events. In the DAPT trial, PAD, renal insufficiency, and hypertension were
predictive of both ischemic and bleeding events and did not help to identify discordant bleeding and ischemic risk. A
simplified integer risk score was developed using only those variables that uniquely predicted either bleeding risk or
ischemic benefit(Fig. 16.10) among the 11,648 patients (both BMS and DES) randomized to either continued thieno-
pyridine or placebo at 12 months (derivation cohort) and was validated externally among 8136 patients enrolled in the
PROTECT trial. The score (median 2; range 2 to 10) assigned a weighted point score for each specific variable with the
sum total score of variables representing the score assigned to an individual patient. For patients randomized in the DAPT
trial with a predictive score 2 (high-score group; 50.8%), continued thienopyridine was associated with an absolute risk
reduction in MI/ST that was 8.2 times greater than the absolute risk increase in moderate/severe bleeding. Conversely,
among patients with scores <2 (low-score group; 49.2%), continued thienopyridine was associated with an absolute increase in bleeding risk of 2.4 times greater than the absolute reduction in MI/ST (Fig. 16.11 A and B). Thus, the DAPT
score was able to identify patients with greater ischemic benefit (DAPT score 2) or greater bleeding risk (DAPT
Stent Thrombosis: Implications for New Stent Designs and Dual Antiplatelet Therapy Duration Chapter | 16 237
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FIGURE 16.10 Predictive variables and score distribution for all randomized patients (bare metal and drug-eluting stents) in the Dual Antiplatelet
Therapy trial. Each predictive variable uniquely predicted either bleeding or ischemic events, but not both. CHF, congestive heart failure; LVEF, leftventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention. Adopted from Yeh RW, Secemsky EA, Kereiakes DJ,
Normand SL, Gershlick AH, Cohen DJ, Spertus JA, Steg PG, Cutlip DE, Rinaldi MJ, Camenzind E, Wijns W, Apruzzese PK, Song Y, Massaro JM, Mauri
L, for the DAPT Study Investigators. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after
percutaneous coronary intervention. J Am Med Assoc 2016;315:1735e49.
score <2). Higher DAPT scores indicated greater MI/ST reduction (P interaction <.001) and lower DAPT scores indicated
greater bleeding risk increase (P interaction .02) with continued thienopyridine therapy. Further application of the risk
score to important subgroups appears to improve risk-appropriate prescription of DAPT duration. For example, patients
with a history of MI have established ischemic risk. Nevertheless, a portion of these patients will experience moderate/
severe bleeding during prolonged DAPT. Addition of the DAPT risk score to the clinical measure of prior MI status
resulted in more appropriate risk reclassification of w1/3 of patients either with or without prior MI [76] (Fig. 16.12). The
clinical utility of the DAPT score to improve decision-making over single subgroup classification by MI status alone is
evident in terms of the number needed to treat to benefit or harm (NNTB, NNTH). The NNTB (avoid MI/ST) in the no-MI
population was reduced from 84 to 40 and the NNTH resulting in bleeding among patients with any MI was increased from
106 to 226 when patients with a high DAPT score were selected. Importantly, the DAPT score allowed more refined
decision-making and identified which patients with a history of MI have a risk of bleeding that outweighed any ischemic
benefit to be gained from longer-duration therapy. Conversely, among patients with no MI history, a high DAPT score
predicted ischemic risk reduction that outweighed bleeding risk. Thus, the DA PT score more accurately classified the
benefit/risk relationship of prolonged (>12 months) thienopyridine therapy for individual patients beyond what could be
attributed to MI history status alone.
Important potential limitations inherent to the DAPT score analyses include the fact that patients taking oral anticoagulants were excluded from trial enrollment, while those who experienced either a bleeding or an ischemic event during
the year of DAPT following enrollment, as well as those with therapy noncompliance, were not included in the analysis.
Thus, patients used to derive the clinical prediction score may not be fully representative of those seen in clinical practice.
Further, although the DAPT score was derived from the global DAPT study population, treatment effects within subgroups
are underpowered.
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FIGURE 16.11 Among DAPT trial patients, the DAPT clinical predictive score was able to discriminate between patients with greater ischemia benefit
(A; DAPT score 2) or greater bleeding risk (B; DAPT score <2). DAPT, dual antiplatelet therapy; MI, myocardial infarction. Adopted from Yeh RW,
Secemsky EA, Kereiakes DJ, Normand SL, Gershlick AH, Cohen DJ, Spertus JA, Steg PG, Cutlip DE, Rinaldi MJ, Camenzind E, Wijns W, Apruzzese PK,
Song Y, Massaro JM, Mauri L, for the DAPT Study Investigators. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. J Am Med Assoc 2016;315:1735e49.
Stent Thrombosis: Implications for New Stent Designs and Dual Antiplatelet Therapy Duration Chapter | 16 239
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FIGURE 16.12 DAPT risk score provides incremental predictive accuracy for either ischemic (score 2 or greater) or bleeding (score less than 2) events
among patients with or without a history of myocardial infarction. DAPT, dual antiplatelet therapy; GUSTO, global use of strategies to open occluded
arteries; MACCE, major adverse cardiovascular or cerebrovascular event; MI, myocardial infarction. Reproduced with permission from Kereiakes DJ, Yeh
RW, Massaro JM, Cutlip DE, Steg PG, Wiviott SD, Mauri L, on behalf of the DAPT Study Investigators. DAPT score utility for risk prediction in patients
with or without previous myocardial infarction. J Am Coll Cardiol 2016;67:2492e502.
Paris Risk Score
Using data from 4190 patients treated with DES enrolled into the Patterns of Non- adherence to Antiplatelet Regimen in
Stented Patients (Paris) Regist ry between July 2009 and December 2010, separate risk scores were developed to predict
coronary thrombotic events (ST or MI) as well as major bleeding (BARC [Bleeding Academic Research Consortium] type
3 or 5). Variables predictive of thrombotic or bleeding risk are shown in Table 4 [81]. Each variable received a weighted
point score with the sum (total) score of all variables present reflecting the ischemic or bleeding risk of the indi vidual
patient. The hypothetical net benefit/harm of prolonged DAPT in an individual patient (Fig. 16.13) is a function of the risk
difference (thrombotic vs. bleeding risk integer scores). Several potential limitations of the Paris risk score include the
observational design that precludes causal inference and the facts that:
1. Almost all patients were treated with clopidogrel (limiting generalizability to more potent P2Y12 inhibitors).
2. DAPT duration was not randomized and DAPT cessation was at the discretion of the treating physician.
3. Information on specific covariates such as left-ventricular function and platelet reactivity were not collected.
PRECISEeDAPT Score
Multivariable regression analyses of both RCCT and observational studies identified specific variables associated with
bleeding risk during prolonged DAPT (baseline hemoglobin, age, white blood cell count, creatinine clearance, history of
prior bleeding). Each variable is assigned a point score and the sum score of variables present represents the individual
patient’s bleeding risk, which can be converted to estimated 12-month risks of clinically significant or major bleeding using
a mobile app/Web calculator [82]. This approach is limited by lack of consideration for concomitant ischemic risk as well
as specific variables (creatinine clearance) predictive of both bleeding and ischemic risk.
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TABLE 16.4 Predictive Variables With Weighted Point
Scores for Major Bleeding and Coronary Thrombotic
Events From the PARIS Registry
Parameter Score
Integer Risk Score
Major Bleeding
Age, years
<50 0
50e59 +1
60e69 +2
70e79 +3
80 +4
BMI, kg/m
Current Smoking
CrCl <60 mL/min
Coronary Thrombotic Events
Diabetes Mellitus
Acute Coronary Syndrome
Current Smoking
2
<25 +2
25e34.9 0
35 +2
Yes +2
No 0
Anemia
Present +3
Absent 0
Present +2
Absent 0
Triple Therapy on Discharge
Yes +2
No 0
None 0
Noneinsulin-dependent +1
Insulin-dependent +3
No 0
Yes, Tn-negative +1
Yes, Tn-positive +2
Yes + 1
No 0
CrCl <60 mL/min
Present +2
Absent 0
Continued
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TABLE 16.4 Predictive Variables With Weighted Point
Scores for Major Bleeding and Coronary Thrombotic
Events From the PARIS Registrydcont’d
Prior PCI
Yes + 2
No 0
Prior CABG
Yes + 2
No 0
BMI, body mass index; CABG, coronary bypass grafting; CrCl, creatinine
clearance; PCI, percutaneous coronary intervention; Tn, troponin.
FIGURE 16.13 Paris risk score. The difference between separate thrombotic and bleeding integer risk scores results in a hypothetical net risk/benefit
nomogram. Reproduced with permission from Baber U, Mehran R, Giustino G, Cohen DJ, Henry TD, Sartori S, Ariti C, Litherland C, Dangas G, Gibson
CM, Krucoff MW, Moliterno DJ, Kirtane AJ, Stone GW, Colombo A, Chieffo A, Kini AS, Witzenbichler B, Weisz G, Steg PG, Pocock S. Coronary
thrombosis and major bleeding after PCI with drug-eluting stents. J Am Coll Cardiol 2016;67:2224e34.
DUAL ANTIPLATELET THERAPY INTERRUPTION/DISCONTINUATION
Observational data suggest that the greatest risk of ST is observed in patients who interrupt or discontinue DAPT within
30 days of stenting, regardless of stent type (BMS or DES) [2,83]. Further, the risk of late and very late ST appears greatest
in patients who stop both aspirin and thienopyridine, or in those who discontinue aspirin and have previously discontinued
thienopyridine therapy [84]. In addition, the time course for ST occurrence appears to be more abrupt when both aspirin
and thienopyridine are discontinued simultaneously.
Atherothrombotic risk associated with P2Y12 receptor discontinuation appears to vary as a function of both the clinical
syndrome prompting stent deployment (ACS vs. SIHD) and the time duration from stent deployment, with the majority of
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0.5%
0.4%
Continued Thienopyridine Placebo
p=0.02
0.3%
0.2%
0.1%
Monthly Cumulative Incidence of MI
0.0%
Thienopyridine Discontinuation
FIGURE 16.14 Monthly cumulative incidence of myocardial infarction by time period and randomized treatment arm in the dual antiplatelet therapy
trial. Patients treated with paclitaxel-eluting stents are excluded from this analysis. The apparent hazard of thienopyridine discontinuation wanes over time
beyond 12 months and is no longer evident by 30 months. MI, myocardial infarction; PCI, percutaneous coronary intervention. Reproduced with
permission from Stefanescu Schmidt AC, Kereiakes DJ, Cutlip DE, Yeh RW, D’Agostino RB, Massaro JM, Hsieh WH, Mauri L. Myocardial infarction risk
after discontinuation of thienopyridine therapy in the randomized DAPT study. Circulation 2017. https://doi.org/10.1161/CIRCULATIONAHA.116.
024835.
0.27%
0.13%
12 15
in Placebo Group
p=0.022
0.17%
0.12%
Randomized Treatment Period
Months After Index PCI
in Continued Thienopyridine Group
p=0.91
0.18%
0.17%
Aspirin Only Period
30 33
Thienopyridine Discontinuation
very late events being not attributable to the stented segment [85]. Patients stented for an ACS/MI indication and those with
a history of MI have an increased risk for ST regardless of stent type, as well as an increased incidence of ischemic events
(death, MI, stroke) despite DAPT during the first year after PCI [76]. Pooled patient-level observational data following
discontinuation of thienopyridine therapy at 3 months after 2GDES deployment suggest no incremental ST risk compared
with longer-duration therapy [86]. In the DAPT trial, protocol-driven discontinuation of thienopyridine therapy occurred in
w5000 patients at 12 months and in an additional w5000 patients at 30 months post-PCI, with both groups followed for
additional 3-month observation periods. Although thienopyridine discontinuation was associated with increased risk for
both MI and ST, w75% of MIs were not related to ST during both observational periods. The monthly cumulative risk of
MI following thienopyridine discontinuation at 12 months remains statistically significant even after excluding TAXUS
PES-treated patients from analysis [87] (Fig. 16.14). This incremental MI hazard associated with thienopyridine discontinuation appears to wane over time (15e33 months) after stenting and was not statistically significant by 30 months.
Finally, the risk of DAPT discontinuation was not predicted by DAPT risk score (<2 vs. 2) as the monthly cumulative
risk of MI was reduced to a similar degree by continued thienopyridine beyond 12 months (vs. placebo) regardless of
DAPT score group.
STOPPING DUAL ANTIPLATELET THERAPY FOR NONCARDIAC SURGERY
Observational data suggest that: (1) stent type (BMS or DES), (2) time from stent deployment to DAPT discontinuation for
surgery, and (3) acuity of the clinical syndrome prompting stent deployment infl uence the likelihood of death and/or
ischemic cardiac events following noncardiac surgery. Those patients who had stent deployment for an ACS and who
underwent noncardiac surgery within 42 days of stent deployment had the greatest risk of adverse events, regardless of
stent type (DES or BMS) [88]. Furthermore, approximately 80% of ST occurred within 10 days of performance of the
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