Genotype-guided de-escalation and abbreviation of dual antiplatelet therapy in patients with myocardial infarction and high bleeding risk: Design and rationale of the investigator-initiated, multicenter, randomized, controlled trial, DAN-DAPT

Abstract

Rationale

Approximately one-third of patients with myocardial infarction (MI) treated with percutaneous coronary intervention (PCI) are at high risk of bleeding side-effects when on dual antiplatelet therapy (DAPT). High bleeding risk is often accompanied by high ischemic risk, thus challenging the choice of P2Y 12 inhibitor and duration of DAPT. The optimal DAPT strategy for these patients remains debated, and it is unknown whether genotype-guided DAPT de-escalation to clopidogrel and aspirin, with or without abbreviation of DAPT to 3 months, is noninferior in terms of net adverse clinical events (NACE) and superior in reducing bleeding side-effects compared with standard DAPT for 6 months.

Design

The DAN-DAPT trial is an investigator-initiated, open-label, multicenter, multiarm, randomized controlled trial conducted at all Danish hospitals performing PCI. From 2022 to 2029, we planned to randomize 2,700 patients with MI and high bleeding risk in a 1:1:1 ratio to 1 of 3 groups: CYP2C19-genotyping and 6 months DAPT (experimental group 1), CYP2C19-genotyping and 3 months DAPT (experimental group 2), and 6 months DAPT with prasugrel (or ticagrelor) and aspirin (control group). The coprimary outcomes are NACE defined as the composite of all-cause mortality, recurrent MI, definite stent thrombosis, stroke, and BARC type 3-5 bleeding (Bleeding Academic Research Consortium), and major and minor bleedings defined as the composite of BARC type 2-5 bleedings at 1 year.

Conclusion

DAN-DAPT trial is an open-label, multicenter, randomized controlled trial comparing genotype-guided DAPT de-escalation to clopidogrel - with or without DAPT abbreviation to 3 months - and standard DAPT for 6 months after PCI in high bleeding risk patients with MI. As of March 2025, 36% of the planned 2,700 patients have been enrolled in the study.

Trial Registration

ClincialTrials.gov (NCT05262803) and EU number (2022-500125-32-00).

Background

Over the past 20 years mortality from acute coronary syndromes has declined as a result of continuous improvements in the treatment and prevention of disease progression. ^{1 Dual antiplatelet therapy (DAPT) with aspirin (ASA) and a P2Y ₁₂ inhibitor has significantly reduced the risk of ischemic events - such as recurrent myocardial infarction (MI) and stent thrombosis - in patients with MI treated with percutaneous coronary intervention (PCI). 2 , 3 Even though stent thrombosis is a rare event occurring in only 1% of patients in the first 3 years after PCI, it is important to recognize that stent thrombosis is often fatal. 4 Stent thrombosis may be caused by mechanical issues from the implantation and/or insufficient platelet inhibition. The latter can be due to nonadherence to DAPT or low responsiveness to the P2Y ₁₂ inhibitor clopidogrel due to a genetic predisposition. The CYP2C19 enzymes of the liver play a key role in the activation of clopidogrel, and approximately 30% of Caucasians carry common loss-of-function alleles in the genes encoding the CYP2C19 enzymes. 5 , 6 These low-responders of clopidogrel have higher platelet reactivity on clopidogrel, putting them at higher risk of major adverse cardiovascular events (MACE) and stent thrombosis compared with normal responders on clopidogrel. 7}

Initially, low responsiveness to clopidogrel was overcome by introducing the more potent P2Y ₁₂ inhibitors, prasugrel and ticagrelor. These drugs significantly reduced the risk of MACE compared with clopidogrel but at the cost of bleedings. ^{8 , 9 Both short- and long-term major and minor bleeding complications to DAPT can lead to increased mortality and morbidity including ischemic events mainly due to decreased oxygen delivery to the myocardium, platelet activation, and DAPT cessation. 10-12 It has been shown that up to one-third of patients with ST-segment elevation MI (STEMI) treated with PCI are at high bleeding risk, yet two-thirds of these patients are treated with potent P2Y ₁₂ inhibitors and ASA for 12 months. 13}

Identifying patients at high bleeding risk can be done with risk scores such as the predicting bleeding complications in patients undergoing stent implantation and subsequent DAPT (PRECISE-DAPT) score. ^{14 It is a 5-item score including age, hemoglobin, leucocytes, creatinine clearance, and prior spontaneous bleeding. A PRECISE-DAPT score ≥25 is considered as high bleeding risk and is associated with a 1-year risk of 1.8% of TIMI major and minor bleedings and 1% for TIMI major bleeding (thrombolysis in myocardial infarction). Although guidelines recommend assessing bleeding risk with tools like the PRECISE-DAPT score, it is not used routinely in clinical practice, 15 , 16 and most patients are treated with potent P2Y ₁₂ inhibitors and ASA for 12 months, irrespective of their bleeding risk.}

Current guidelines do not provide solid recommendations on how bleeding and ischemic risk should be balanced in patients both at high ischemic and high bleeding risk. ^{15 , 16 To mitigate bleeding risks, these guidelines suggest considering de-escalation to clopidogrel or abbreviation of DAPT. Both genotype-guided de-escalation and abbreviation of DAPT have demonstrated reassuring efficacy regarding mortality and ischemic events and superiority in reducing major and minor bleeding events. 6 , 17 , 18 However, it remains unclear whether combined strategies can further reduce bleeding side-effects in high bleeding risk patients with MI after PCI without increasing the risk of ischemic events. 15 , 16 Despite growing evidence supporting genotype-guided de-escalation to clopidogrel, development of rapid point-of-care CYP2C19 genotype tests, and improved cost-effectiveness of this strategy compared with standard DAPT, its use in clinical practice remains limited. 19-22 There are challenges to implementing a genotype-guided strategy in clinical practice including lack of clinical guidelines, lack of pharmacogenetic education, limited access to genotype testing that provides rapid results, and, to a lesser extent, patient resistance to genetic testing. 23 , 24}

The purpose of the DAN-DAPT trial is to assess the safety and efficacy of combined DAPT strategies in high bleeding risk patients with STEMI or non-STEMI. By employing genotype-guided de-escalation to clopidogrel right after PCI, with or without abbreviation of DAPT to 3 months, we aim to decrease bleeding complications without increasing net adverse clinical events (NACE). We hypothesized that genotype-guided DAPT, with or without abbreviation, is noninferior in terms of NACE and superior in terms of major and minor bleeding events compared with standard DAPT for 6 months in high bleeding risk patients with STEMI or non-STEMI treated with PCI.

Methods Trial design and sites

DAN-DAPT is an investigator-initiated, open-label, multicenter, multiarm, randomized, controlled trial, which is conducted at all Danish hospitals performing PCI. Only the authors were responsible for the design of this trial, which has been registered at ClinicalTrials.gov (NCT05262803). Enrollment was initiated in June 2022, and 36% of the planned study population has been enrolled by now (March 2025).

Patient population and inclusion/exclusion criteria

Patients with STEMI or non-STEMI treated with PCI within 72 hours are considered for inclusion, if they are at high bleeding risk according to the PRECISE-DAPT score. ^{14 , 25 Inclusion and exclusion criteria are listed in Table 1 .}

Randomization and treatment

Block randomization using a module in REDCap - Capital Region with stratification on clinical presentation with STEMI or non-STEMI is used to randomly assign patients in a 1:1:1 ratio to ( ^{Figure 1} ):

• (1) Standard DAPT
• (2) Genotype-guided DAPT
• (3) Genotype-guided and abbreviated DAPT

Treatment cannot be blinded, as DAPT is guided by the genotype in two-thirds of the patients. Patients, who are randomized to standard DAPT, will be treated preferably with prasugrel for 6 months in addition to ASA. Patients in the genotype-guided groups will be treated with clopidogrel if they are noncarriers of CYP2C19×2 and CYP2C19×3 loss-of-function alleles, and prasugrel, preferably, if they are carriers of these common loss-of-function alleles. The difference between the genotype-guided groups is the duration of DAPT, which is 3 months in the genotype-guided and abbreviated DAPT group, and 6 months in the genotype-guided DAPT group.

When potent P2Y ₁₂ inhibitors are used, prasugrel is preferred over ticagrelor in patients without contraindications, as prasugrel significantly reduced MACE - mainly recurrent MIs – compared with ticagrelor in the ISAR-REACT 5 trial. ^{26 Prasugrel will not be initiated in any patient with prior stroke or transient ischemic attack. Instead, these patients will receive ticagrelor. Additionally, ticagrelor may be used at the operator's discretion in other cases where prasugrel would otherwise be initiated.}

Concomitant use of ASA is initiated in all patients for the DAPT regimen. After DAPT, patients will continue ASA monotherapy unless an indication for clopidogrel monotherapy lifelong is present (e.g., prior stroke, transient ischemic attack, peripheral artery disease, or at the discretion of the treating doctor). The following dozes will be used: prasugrel 10 mg daily (5 mg daily in patients aged ≥75 years or with a body weight <60 kg), ticagrelor 90 mg twice daily, clopidogrel 75 mg daily, and ASA 75 mg daily. In the case of a switch between P2Y ₁₂ inhibitors after randomization, in the very early phase after PCI (72 h), it is recommended to load patients with the new P2Y ₁₂ inhibitor (clopidogrel 600 mg, prasugrel 60 mg, and ticagrelor 180 mg). When switching from prasugrel or ticagrelor, it is recommended to time the switch to the new P2Y ₁₂ inhibitor 24 h after the last given dose. Peri- or postprocedural use of cangrelor, glycoprotein IIb/IIIa, or bivalirudin can be prescribed at the discretion of the PCI-operator. Postprocedural treatments are managed by the treating doctor in accordance with contemporary guidelines. In patients with multivessel disease planned for staged PCI, it is emphasized that this is scheduled within 4 weeks from the index hospitalization. Patients with an indication for oral anticoagulation are excluded from participation.

CYP2C19-genotyping

The CYP2C19 genotype is assessed immediately after randomization by use of a point-of-care test. Buccal material is used for the sample, and the result of the test is available in 1 hour by using the polymerase chain reaction technique of the Cube platform (Genomadix, formerly Spartan), which is CE IVD marked (ISO 13485). The sensitivity of this point-of-care test is 100% (95% CI, 0.93-1.00) and the specificity 100% (95% CI, 0.99-1.00) when the comparator is laboratory-based testing of only the alleles that the point-of-care test targeted. ^{27 Patients with 1 (heterozygote) or 2 (homozygote) CYP2C19×2 or CYP2C19×3 loss-of-function alleles are considered intermediate and poor metabolizers of clopidogrel, respectively. Intermediate and poor metabolizers of clopidogrel will not receive clopidogrel in accordance with the “ Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy (2022 update)”, 28 whereas patients without CYP2C19×2 and CYP2C19×3 will be treated with clopidogrel.}

Follow-up

Telephone interviews are scheduled 3, 6, and 12 months after randomization (±30 days). The occurrence of serious adverse events including the defined end points, patient-reported adherence, and quality-of-life questionnaires will be assessed at these contacts. Medical reports and the Danish administrative registries will also be used for end point assessment and to validate end points and adherence to the treatment according to redeemed prescriptions from the pharmacy.

Study end points

There are 2 coprimary end points:

• (1) Net adverse clinical events (NACE) defined as the composite of all-cause mortality, recurrent MI, definite stent thrombosis, stroke, and major bleedings defined as BARC type 3-5 nonaccess site bleeding.
• (2) Major and minor bleedings defined as the composite of BARC type 2-5 nonaccess site bleeding.

Secondary end points are listed in ^{Table 2} . The primary and secondary end points are defined in accordance with standardized end point definitions. ^{29-31 A PROBE (Prospective Randomized Open Blinded Endpoint) design will be used for the end points, which require adjudication by the blinded end point committee.}

Sample size

In line with previous reports of the frequency of CYP2C19×2 and CYP2C19×3 loss-of-function alleles, 30% of patients are expected to be carriers. ^{6 Hence, 70% of patients in the genotype-guided groups are expected to be de-escalated to clopidogrel. The estimated incidences of the primary outcomes are summarized in Table 3 based on a literature search of available data. 6 , 13 , 18 , 32-37}

A multiarm design was chosen to allow for comparisons of different DAPT strategies. The following hypotheses are tested:

• (1) In terms of NACE, genotype-guided DAPT for 6 months is noninferior to standard DAPT for 6 months.
• (2) In terms of NACE, genotype-guided and abbreviated DAPT for 3 months is noninferior to standard DAPT for 6 months.
• (3) In terms of nonaccess site BARC type 2-5 bleedings, genotype-guided and abbreviated DAPT for 3 months is superior to standard DAPT for 6 months.
• (4) In terms of nonaccess site BARC type 2-5 bleedings, genotype-guided DAPT for 6 months is superior to standard DAPT for 6 months.

The hypotheses are tested in a hierarchical order to control the type 1 error rate when performing multiple tests. If noninferiority of NACE is demonstrated, superiority will be tested exploratively. All hypotheses will be tested with a power of 80%. A 1-sided alpha level of 2.5% will be used for the noninferiority analyzes and a 2-sided alpha of 5% for the superiority analyzes. Based on this, the final sample size is estimated to be 2,700 patients (900 per arm including a 2% drop-out rate).

Planned analyzes

Considering the logistics of performing genotyping and the recommendation of timing the switch to clopidogrel 24 hours after the last dose of prasugrel (or ticagrelor), the first 24 hours after index PCI will be a blanking period for the occurrence of the defined endpoints. ^{38 The planned analyzes will be performed according to the intention-to-treat principle, but per-protocol analyzes will also be performed including patients from the intention-to-treat analyzes, in whom no important protocol violations (IPVs) are present ( Table 4 ). Several sub-analyzes are planned ( Table 5 ).}

Statistics

A P-value of < .05 is considered statistically significant. Descriptive data at baseline will be presented. Kaplan-Meier curves will be plotted for end points including death and the log-rank test performed. The Aalen-Johansen estimator and Gray's test will be performed for end points excluding death, considering unrelated death as a competing risk. Everyone will contribute with risk-time until an outcome of interest, the last date of known outcome status, or 1 year after randomization, whichever came first. As randomization is stratified on clinical presentation with STEMI or non-STEMI, adjustments for this variable will be performed in all analyzes. Cox proportional-hazards model will be constructed for the prespecified sub-groups, and model control will be performed. Please refer to the statistical analyzes plan for a detailed description (Supplementary 1).

Safety

An assigned data manager will prepare data for interim analyzes after 500 and 1,000 patients have been followed for 1 year. Three independent members of the Data and Safety Monitoring Board (DSMB) will evaluate these data and give their advice to the Study Committee on whether to stop or continue the trial for reasons of safety. The DSMB Charter has been made publicly available before the first interim analysis was conducted and evaluated (Supplementary 2).

Ethical approval and quality control and assurance

Ethical approval was obtained from the Danish Research Ethics Committees and the Danish Medicines Agency (EU number: 2022-500125-32-00). This is a phase IV randomized controlled trial to test the safety and efficacy of different DAPT strategies. All DAPT strategies evaluated in this trial are recommended as potential options by contemporary guidelines for reducing DAPT in high bleeding risk patients. ^{15 , 16 All prescribed drugs used in this trial have been used for several decades, and the side-effects are well-known. In addition, side-effects to DAPT will be closely monitored, as these are also the primary end points of this trial. Good Clinical Practice units across Denmark will also monitor the quality of the trial.}

Summary

DAN-DAPT is an investigator-initiated, randomized, controlled trial evaluating combined strategies to safely reduce DAPT in high bleeding risk MI patients treated with PCI. By using a genotype-guided de-escalation to clopidogrel and ASA - with or without abbreviation of DAPT to 3 months - this trial seeks to improve the safety of DAPT without compromising efficacy. As of March 2025, 36% of the planned 2,700 patients have been enrolled in the study.

CRediT authorship contribution statement

Mia Ravn Jacobsen: Writing – review & editing, Writing – original draft, Project administration, Methodology, Investigation, Funding acquisition, Conceptualization. Reza Jabbari: Writing – review & editing, Supervision, Project administration, Methodology, Conceptualization. Erik Lerkevang Grove: Writing – review & editing, Supervision, Project administration, Methodology, Investigation, Conceptualization. Michael Mæng: Writing – review & editing, Project administration, Methodology, Investigation, Conceptualization. Karsten Veien: Writing – review & editing, Project administration, Methodology, Investigation, Conceptualization. Mikkel Hougaard: Writing – review & editing, Methodology, Investigation. Philip Freeman: Writing – review & editing, Project administration, Methodology, Investigation, Conceptualization. Henning Kelbæk: Writing – review & editing, Project administration, Methodology, Investigation, Formal analysis, Conceptualization. Mette Gitz Charlot: Writing – review & editing, Project administration, Methodology, Investigation, Formal analysis, Conceptualization. Thomas Engstrøm: Writing – review & editing, Supervision, Project administration, Methodology, Investigation, Formal analysis, Conceptualization. Rikke Sørensen: Writing – review & editing, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Conceptualization.

Conflict of interest

None related to the DAN-DAPT trial. Outside the submitted work, the authors declare the following:

RZ has received speaker honoraria from Bristol-Myers Squibb. ELG has received speaker honoraria or consultancy fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Pfizer, Novo Nordisk, Lundbeck Pharma and Organon. He is investigator in clinical studies sponsored by AstraZeneca, Idorsia or Bayer and has received unrestricted research grants from Boehringer Ingelheim. MM is supported by a grant from the Novo Nordisk Foundation (grant number NNF22OC0074083); has received lecture and/or advisory board fees from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Novo Nordisk, has received a travel grant from Novo Nordisk, has received institutional research grants from Philips, Bayer and Novo Nordisk, has ongoing research contracts with Janssen, Novo Nordisk, and Philips, and equity in Novo Nordisk, Eli Lilly & Company, and Verve Therapeutics. MGC has received speaker honoraria from Abbott and Novo Nordisk. TE has received speaker honoraria or consultancy fees from Bayer, Novo Nordisk, and Abbott. He is investigator in clinical studies sponsored by Novo Nordisk. RS has received Institutional Research Grant from Novo Nordisk Foundation, speaker honoraria from Bayer, Bristol-Myers Squibb, and Astra Zeneca, and fees from Novo Nordisk for work in data safety and monitoring board (not related to this work).

Funding

This work was supported by an unrestricted grant for investigator-initiated trials from the Novo Nordisk Foundation [grant number 0071947, 2022]; and Gangstedfonden [grant number A41879, 2022]. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ahj.2025.02.020.

Appendix Supplementary materials

Image, application 1 Image, application 2

Table 1

Inclusion and exclusion criteria

Inclusion criteria
1.	Type 1 myocardial infarction treated with PCI with contemporary drug-eluting stents
2.	PRECISE-DAPT score ≥25
3.	Age ≥18 years

Table 2

Secondary end points

Secondary end points at 3, 6, and 12 months
1.	All bleeding events according to the BARC and TIMI definitions
2.	Major adverse cardiovascular events (all-cause mortality, recurrent MI, definite stent thrombosis, ischemic stroke) and its individual components
3.	Nonhemorrhagic cardiovascular mortality
4.	Any target vessel and nontarget vessel revascularization
5.	Any rehospitalization >24 h
6.	Discontinuation, pause, or switch in the planned DAPT (eg, in the case of new indication for oral anticoagulants)
7.	Self-reported quality of life (EQ-5D-5 L)

Table 3

Estimated incidences of the primary end points

Primary end point	Standard DAPT	Genotype-guided DAPT	Genotype-guided and abbreviated DAPT
NACE	10.0%	8.5%	8.0%
BARC 2-5 nonaccess site bleeding	12.0%	8.0%	7.5%

Table 4

Important protocol violations by which study participants are excluded from the per-protocol analyzes

1.	Inclusion criteria not met
2.	Exclusion criteria met
3.	No informed consent or withdrawal of informed consent
4.	Error in randomization
5.	CYP2C19-testing not performed in genotype-guided DAPT
6.	CYP2C19-testing performed in standard-of-care DAPT
7.	Nonadherence/discontinuation with the medicinal products
8.	Nonresponders to the quality-of-life questionnaires (only for the secondary end point evaluation)

Table 5

Prespecified subgroup analyzes

1.	Age: <70 and ≥70 y
2.	Sex: male, female
3.	Body weight at baseline: <60, ≥60 kg and body mass index at baseline
4.	Smoking status at baseline: active, previous, never
5.	Weekly alcohol consumption
6.	Comorbidities at baseline: diabetes, heart failure, chronic kidney disease, spontaneous bleeding, cancer (excluding nonmelanoma skin cancer), prior myocardial infarction, prior PCI, prior CABG, peripheral artery disease, stroke/transient ischemic attack
7.	Baseline renal function and the according creatinine clearance and estimated glomerular filtration rate: <60, ≥60 mL/min.
8.	Concomitant use of proton-pump inhibitors, nonsteroidal anti-inflammatory drugs, or corticosteroids
9.	Adherence/nonadherence
10.	Loading with >1 P2Y 12-inhibitor
11.	Patients at high bleeding risk according to other risk scores (e.g., Academic Research Consortium – High Bleeding Risk evaluator)
12.	Frailty
13.	STEMI and non-STEMI
14.	Single and multivessel disease
15.	Verification of the point-of-care test results
16.	High ischemic risk will be assessed according to a list of criteria, which has been validated and endorsed by contemporary guidelines