JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 81, NO.
6, 2023
ª 2023 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
EDITORIAL COMMENT
Optimal Antiplatelet Therapy Revisited
When Is a Single Better Than a Double?*
Deepak L. Bhatt, MD, MPH
C ontroversy over the appropriate duration
and intensity of dual antiplatelet therapy
(DAPT) seems unending. In part, that is
because of a constant influx of new data, including
analysis of 5 randomized trials (n ¼ 22,941) of P2Y 12
inhibitor monotherapy or DAPT after an initial period
of 1 to 3 months of DAPT following PCI. One-fifth of
the patients underwent complex PCI, and of course,
randomized clinical trials, registries, and meta- they had higher rates of ischemic events than patients
analyses. Virtually any viewpoint about the exact undergoing noncomplex PCI. Interestingly, the in-
type and length of therapy with DAPT can be sup- vestigators found that the ischemic protection pro-
ported by some data source. Numerous trials have vided by de-escalation to a single P2Y12 inhibitor was
shown that DAPT is superior to aspirin monotherapy similar to that from DAPT, both in patients undergo-
in patients with acute coronary syndrome and in pa- ing noncomplex PCI, but also in those undergoing
tients undergoing percutaneous coronary interven- complex PCI. Major bleeding was essentially halved
tion (PCI), especially in the setting of complex in both subgroups. These data provide a compelling
coronary artery disease.1,2 As a general principle, argument in patients who have not had ischemic
more intense DAPT regimens (that is, with prasugrel events during the first 1 to 3 months of DAPT to
or ticagrelor) and longer durations of DAPT reduce consider dropping the aspirin and continuing the
important ischemic complications, including sponta- P2Y 12 inhibitor.
neous myocardial infarction unrelated to the stented
SEE PAGE 537
segment. However, these strategies always raise ma-
jor bleeding risk. A key question exists within this In trying to reconcile the enormous body of data
larger debate: if the decision is made to de-escalate pertaining to DAPT, it is important to go back in time
DAPT, and P2Y12 inhibitor monotherapy is chosen, a bit to the CAPRIE (Clopidogrel vs Aspirin in Patients
might that change the calculus of whether a single an- at Risk of Ischemic Events) trial. 5 This landmark study
tiplatelet agent is a better balance of ischemic protec- put clopidogrel on the map. In 19,185 patients who
tion than continued DAPT, but with an expected were high-risk secondary prevention (recent
reduction in bleeding complications? 3 myocardial infarction, recent ischemic stroke, or
In this issue of the Journal of the American College symptomatic peripheral artery disease), there was a
of Cardiology, Gragnano et al4 address this burning significant 8.7% relative risk reduction in myocardial
question. They perform an individual-patient meta- infarction, ischemic stroke, or vascular death.
Although at the time, some physicians felt the rela-
tive risk reduction was modest, as always, the abso-
lute risk reduction would depend on the baseline risk
*Editorials published in the Journal of the American College of Cardiology
of the population.
reflect the views of the authors and do not necessarily represent the
views of the Journal of the American College of Cardiology or the American
Subsequent analyses of CAPRIE showed that in
College of Cardiology. addition to the reduction in ischemic events, there
From the Mount Sinai Heart, Icahn School of Medicine at Mount Sinai
was a significant reduction in hospitalization for
Health System, New York, New York, USA. gastrointestinal bleeding with clopidogrel vs 325 mg
Athena Poppas, MD, served as Guest Editor-in-Chief for this paper. of aspirin. 6 Although it is possible that the gastroin-
The author attests they are in compliance with human studies commit-
testinal bleeding risk would have been less with
tees and animal welfare regulations of the author’s institution and Food
and Drug Administration guidelines, including patient consent where 81 mg of aspirin, the protection against ischemic
appropriate. For more information, visit the Author Center. events would not have been any better with low-dose
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2022.11.040
554 Bhatt JACC VOL. 81, NO. 6, 2023
Optimal Antiplatelet Therapy Revisited FEBRUARY 14, 2023:553–556
F I G U R E 1 DAPT Duration After PCI
De-escalate to Continue
1 month DAPT if
clopidogrel clopidogrel
high bleeding risk
monotherapy monotherapy
3 months DAPT if De-escalate to
De-escalate to
average ischemic ticagrelor 60 mg
Complex PCI ticagrelor 90 mg
risk and not high twice daily after
twice daily
bleeding risk first year?
12 months DAPT Continue DAPT if
Reassess bleeding
if high ischemic no bleeding
risk at least
risk and low during prior 12
annually
bleeding risk months
Potential strategies for dual antiplatelet therapy (DAPT) after complex percutaneous coronary intervention (PCI).
aspirin. Analyses of high-risk subgroups from CAPRIE and pharmacodynamic data suggest that there is
(eg, those with prior cardiac surgery, diabetes, or impaired absorption of enteric coated aspirin vs plain
polyvascular disease) found much more robust abso- aspirin. 12 The clinical significance of this remains to
7-9
lute risk reductions. be established, but for those who fret about the po-
For doctors who feel validation in a second trial is tential implications of CYP2C19 reduced-function
always necessary, HOST-EXAM (Harmonizing polymorphisms on clopidogrel monotherapy in
Optimal Strategy for Treatment of Coronary Artery high-risk PCI patients or platelet function tests that
Stenosis-Extended Antiplatelet Monotherapy) did suggest impaired antiplatelet response—the clinical
accomplish that, albeit over 2 decades after CAPRIE.10 significance of which is also unclear—then they
This trial of patients who had received an initial should also worry about the effects of aspirin’s
course of DAPT for 6 to 18 months followed by enteric coating (which has not been clearly shown to
randomization to clopidogrel or aspirin monotherapy reduce gastrointestinal bleeding anyway). Ticagrelor
extended the findings of CAPRIE and the cardiac monotherapy gets around all these issues, and
bypass subgroup by demonstrating significant benefit although currently more expensive than aspirin or
in patients with previous stents. 7 It is notable that clopidogrel, it should be available in generic form
HOST-EXAM enrolled East Asian patients, who have a worldwide in the next few years. If a reversal agent
higher rate of CYP2C19 reduced-function alleles. For becomes available, that could further improve the
anyone worried about clopidogrel monotherapy in safety profile of ticagrelor. 13
stented patients due to the potential for the patient to Thus, the work by Gragnano et al4 strongly sug-
be a “clopidogrel nonresponder,” it seems even less gests that a strategy of initial DAPT followed by P2Y12
likely to be an issue in Western populations who have inhibitor monotherapy provides adequate protection
a lower incidence of these polymorphisms than pa- against ischemic events with a substantially lower
tients in HOST-EXAM. It is not that the poly- risk of bleeding. These findings are consistent with
morphisms do not influence levels of clopidogrel the prior body of published data that shows P2Y12
active metabolite—they do. Rather, there are many inhibitor monotherapy is more potent than aspirin
other factors that influence clopidogrel activity, and monotherapy. A caveat is that the median duration of
genotype is only 1 contributor.11 follow-up for these pooled trials was 334 days, with a
Enteric-coated aspirin is the predominant formu- range of 275 to 365 days. This is important to note, as
lation used in nonacute settings. Pharmacokinetic the benefit of DAPT with ticagrelor plus aspirin over
JACC VOL. 81, NO. 6, 2023 Bhatt 555
FEBRUARY 14, 2023:553–556 Optimal Antiplatelet Therapy Revisited
aspirin monotherapy in THEMIS (A Study Comparing (chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial,
funded by Edwards Lifesciences), Contego Medical (chair, PERFOR-
Cardiovascular Effects of Ticagrelor Versus Placebo in
MANCE 2 trial), Duke Clinical Research Institute, Mayo Clinic, Mount
Patients With Type 2 Diabetes Mellitus), for example, Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-
did not even emerge until after 1 year of follow-up. 14 Sankyo; and for the ABILITY-DM trial, funded by Concept Medical),
Additionally, THEMIS-PCI found a benefit of DAPT vs Novartis, Population Health Research Institute, and Rutgers Univer-
sity (for the NIH-funded MINT trial); has received honoraria from the
aspirin that was statistically significant out to at least
American College of Cardiology (senior associate editor, Clinical Tri-
15
6 to 7 years from the time of the prior PCI. als and News, ACC.org, and chair of the ACC Accreditation Oversight
COMPASS-PCI (Rivaroxaban for the Prevention of Committee), Arnold and Porter law firm (work related to Sanofi/
Major Cardiovascular Events in Coronary or Periph- Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical
Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI
eral Artery Disease) also found a significant reduction
clinical trial steering committee funded by Boehringer Ingelheim;
in ischemic events from 2 antithrombotic agents vs AEGIS-II executive committee funded by CSL Boehringer), Belvoir
aspirin alone out to 10 years from the initial PCI, Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Med-
including a lower rate of all-cause mortality. 16 ical and Surgical Knowledge Translation Research Group (clinical trial
steering committees), Cowen and Company, Duke Clinical Research
Therefore, several lines of randomized evidence
Institute (clinical trial steering committees, including for the PRO-
do show benefit of 2 antithrombotic agents instead NOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global
of aspirin alone, but it does seem very plausible (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the
American College of Cardiology (guest editor; associate editor), K2P
that using a P2Y 12 inhibitor instead of aspirin may
(cochair, interdisciplinary curriculum), Level Ex, Medtelligence/
strike the best balance for many patients (Figure 1). ReachMD (CME steering committees), MJH Life Sciences, Oakstone
Certainly, when the bleeding risk is high, that CME (course director, Comprehensive Review of Interventional Cardi-
trumps high ischemic risk, and de-escalation is ology), Piper Sandler, Population Health Research Institute (for the
COMPASS operations committee, publications committee, steering
clearly warranted. The present data raise the pos-
committee, and USA national coleader, funded by Bayer), Slack
sibility that such a de-escalation strategy to P2Y 12 Publications (chief medical editor, Cardiology Today’s Intervention),
inhibitor monotherapy should perhaps be the Society of Cardiovascular Patient Care (secretary/treasurer), WebMD
default strategy, including for complex PCI, and not (CME steering committees), and Wiley (steering committee); has
other relationships with Clinical Cardiology (deputy editor), NCDR-
reserved for use only in those at perceived high
ACTION Registry Steering Committee (chair), and VA CART
bleeding risk. Potentially, adjunctive image-guided Research and Publications Committee (chair); has been named on a
optimization of stent implantation or use of drug- patent for sotagliflozin assigned to Brigham and Women’s Hospital
coated balloons could further impact consider- who assigned to Lexicon (neither Dr Bhatt nor Brigham and Women’s
Hospital receives any income from this patent); has received research
ations around duration of DAPT, and ongoing
funding from 89Bio, Abbott, Acesion Pharma, Afimmune, Aker Bio-
randomized trials should provide more clarity. marine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer
Ideally, large, adequately powered pragmatic trials Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellPro-
would be conducted to resolve all these issues thera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Faraday
Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories,
definitively. Though perhaps even then, antiplatelet
Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix,
therapy will be unlike largely algorithmic lipid- Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, Myo-
lowering therapy, and very individualized Kardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio,
PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche,
decision-making will remain necessary.
Sanofi, Stasys, Synaptic, The Medicines Company, and Youngene; has
FUNDING SUPPORT AND AUTHOR DISCLOSURES received royalties from Elsevier (editor, Cardiovascular Intervention:
A Companion to Braunwald’s Heart Disease); has been a site coinves-
tigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St.
Dr Bhatt has served on advisory boards for AngioWave, Bayer,
Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and
Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific,
Vascular Solutions; has been a trustee for the American College of
Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex,
Cardiology; and has performed unfunded research for FlowCo and
McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo
Takeda.
Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; has
served on boards of directors for AngioWave, the Boston VA Research
Institute, Bristol Myers Squibb, DRS.LINQ, High Enroll, the Society of
Cardiovascular Patient Care, and TobeSoft; has stock or stock options
with AngioWave, Bristol Myers Squibb, and DRS.LINQ; has served as
ADDRESS FOR CORRESPONDENCE: Dr Deepak L.
inaugural chair of the American Heart Association Quality Oversight Bhatt, Mount Sinai Heart, Icahn School of Medicine
Committee; has been a consultant for Broadview Ventures; has at Mount Sinai Health System, 1 Gustave Levy
served on data monitoring committees for Acesion Pharma, Assis-
Place, Box 1030, New York, New York 10029, USA.
tance Publique-Hôpitaux de Paris, the Baim Institute for Clinical
Research (formerly Harvard Clinical Research Institute, for the POR- E-mail: [email protected]. Twitter:
TICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific @DLBhattMD.
556 Bhatt JACC VOL. 81, NO. 6, 2023
Optimal Antiplatelet Therapy Revisited FEBRUARY 14, 2023:553–556
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