DAPT-History

Detta är en överblick över DAPTs historiska utveckling – originalpublikationen (en disputation från 2019) är på engelska:

When PCI was evolving in the late 1970s, Andreas Gruentzig chose Aspirin as an antithrombotic treatment for balloonangioplasty, ¹ a medication later (in combination with Dipyridamole) deemed effective in preventing post-PCI (balloon angioplasty) infarction. ² With stent implantation emerging in the 1990s, after the first human coronary stent implantation was done in France in 1986, ³ life-threatening ST became a new clinical problem of extensive concern, occurring in the early series in up to one of four cases, despite heavy anticoagulation with large doses of heparin and oral anticoagulation with vitamin K antagonists ^{4 5}. The underlying pathology is that balloon angioplasty and stent implantation cause endothelial defects and plaque ruptures in the treated coronary artery, resulting in an effect similar to that of acute coronary syndrome: the activation of the coagulation system as a consequence of endothelial disruption ⁶. The treatment with heparin and oral anticoagulation was not only ineffective in preventing ST, but also led to bleeding in large numbers of the treated patients ⁷.

A milestone development in the history of PCI was the subsequent generation of dual antiplatelet therapy (DAPT) with ASA and a P2Y₁₂ antagonist which, compared to oral anticoagulation, reduced both ST and bleeding complications ⁷ and became an essential prerequisite for the tremendously successful progress in PCI that has been evident since the 1990s. Thirty-five RCTs, including more than 200,000 patients, tested DAPT and today, about 3.6 million patients are treated with DAPT after ACS or PCI annually in Europe ⁸

In 1996, a German group published a study demonstrating the overwhelming superiority of DAPT with ASA and the thienopyridine ticlopidine over a combination of heparin, phenprocoumon, and ASA in patients treated with stent implantation for stable or unstable coronary artery disease (relative risk 0.25 for the primary endpoint cardiac death, MI, repeat revascularisation) ⁹. In 1998, a study published by an Anglo-American group concluded that DAPT with ASA and ticlopidine was distinctly better than ASA alone (the primary endpoint reflecting ST occurred in 0.5% vs. 3.0% of patients) and better than ASA and warfarin (2.7% ST) in the prevention of ST, while at the same time reducing bleeding complications with DATP compared to oral anticoagulation (5.5% vs. 6.2% bleeding complications) ¹⁰, a finding confirmed in a French trial published in the same year ¹¹. DAPT has since then been used as a standard treatment for all PCI.

In 2000, the proven effective drug ticlopidine was replaced by the new P2Y₁₂ antagonist clopidogrel for the indication of post-PCI DAPT, following positive results showing the comparable efficiency and fewer side effects of clopidogrel compared to ticlopidine. ¹²

At about the same time, the development of oral antiplatelet P2Y₁₂ receptor antagonists was fundamental not only in the advancement of PCI, but likewise in the treatment of patients with acute coronary syndrome, independent of PCI treatment:

In 2001, the CURE study ¹³ tested DAPT with ASA plus clopidogrel against treatment with ASA alone in 12,562 patients with NSTE-ACS and found a relative risk reduction of 0.8 for the primary endpoint cardiovascular death, nonfatal MI, and stroke (this effect was independent of PCI) at the cost of an increase in major bleeding complications (relative risk 1.38). A subgroup analysis of 2,658 patients treated by PCI in CURE (PCI-CURE study) ¹⁴ later confirmed this finding for invasively managed patients. 

In acute coronary syndrome, as in PCI, P2Y₁₂ receptor antagonists are the standard of care today ¹⁵,¹⁶ with the pathophysiological aim being the prevention of the augmentation of existing and the prevention of future thrombi as part of the otherwise natural course of an acute coronary syndrome as a thrombotic disease ¹⁷. 

Since CURE, the antithrombotic DAPT therapy with ASA plus a P2Y₁₂ antagonist has been likewise indicated for patients with ACS and patients after PCI, even if the P2Y₁₂ antagonist was further evolved to novel agents while ASA remained unchanged.

In 2007, the  TIMI 38 trial ¹⁸ compared the novel P2Y₁₂ antagonist prasugrel to clopidogrel (with the usual loading dose at that time, but not after CURRENT-OASIS 7, of 300 mg.) ¹⁹ in patients presenting with all subtypes of ACS scheduled for PCI. The trial concluded that treatment with prasugrel was associated with a reduction of ischemic events, including ST, at the cost of higher rates of bleeding (particularly in patients older than 75, weighing under 60 kg., or with a previous cerebral transitory ischemic event), including life-threatening bleeding, without differences in mortality. Notably, only STEMI patients were randomized and treated before angiography, whereas NSTE-ACS patients obtained the study drug after coronary angiography, i.e., when the coronary anatomy was established and the decision was made that the anatomy was suitable for PCI. 

Two years later, the PLATO trial tested another novel P2Y₁₂ antagonist, ticagrelor, against clopidogrel in patients again presenting with all subtypes of ACS, i.e., STEMI or NSTE-ACS with specific risk indicators. The primary endpoint (cardiovascular death, MI, stroke) occurred in 9.8% of patients in the ticagrelor arm of the study as compared to 11.7%, with a HR of 0.84, and all-cause mortality was reduced from 5.9% in clopidogrel patients to 4.5%, while ticagrelor was associated with more non-CABG bleeding than clopidogrel. No RCT has tested P2Y₁₂ against placebo in STEMI patients treated with primary PCI. 

Today (2020), the ESC guidelines recommend antiplatelet therapy for STEMI patients treated by primary PCI with DAPT consisting of ASA plus ticagrelor or prasugrel for up to 12 months ²⁰ and for NSTE-ACS-patients with defined risk markers but without specific contraindications, DAPT with ticagrelor (medically treated patients and patients revascularized with PCI), or prasugrel (PCI only) ¹⁶ for 12 months (with exceptions for patients treated by oral anticoagulation for other indications). For stable patients treated with PCI, the ESC guideline recommends treatment with DAPT, including clopidogrel ²¹, for less than 12 months.  

Some studies have evaluated DAPT prolonged beyond 12 months after ACS: The PEGASUS-TIMI-54 trial ²² (60 or 90 mg. of ticagrelor twice daily on top of ASA for 1–3 years, ACS patients only) and the DAPT trial ²³ (clopidogrel or prasugrel vs. placebo for an additional 18 months plus ASA after 12 months of DAPT, stable and ACS patients after DES implantation) found fewer ischemic endpoints (Pegasus: HR for cardiovascular death, stroke MI 0.84 for 60 mg. of Ticagrelor twice daily; DAPT trial: HR for ST 0.29; HR for MACE and cerebrovascular events 0.71), but more bleeding (Pegasus: HR for TIMI major bleeding 2.32 for Ticagrelor twice daily; DAPT trial: HR for moderate or severe bleeding 1.61), without significant differences in mortality in both studies. In summary, there is robust evidence for the effectiveness of the treatment of STEMI and NSTE-ACS patients with DAPT for 12 months.

Last Updated on March 30, 2021 by Christian Dworeck

1. Steinhubl SR and Berger PB. Aspirin following PCI: too much of a good thing? European heart journal. 2009;30:882-4[↩]
2. Schwartz L, Bourassa MG, Lesperance J, Aldridge HE, Kazim F, Salvatori VA, Henderson M, Bonan R and David PR. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. The New England journal of medicine. 1988;318:1714-9[↩]
3. Sigwart U, Puel J, Mirkovitch V, Joffre F and Kappenberger L. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. The New England journal of medicine. 1987;316:701-6.[↩]
4. Byrne RA, Joner M and Kastrati A. Stent thrombosis and restenosis: what have we learned and where are we going? The Andreas Gruntzig Lecture ESC 2014. European heart journal. 2015;36:3320-31[↩]
5. Schömig A, Kastrati A, Mudra H, Blasini R, Schühlen H, Klauss V, Richardt G and Neumann FJ. Four-year experience with Palmaz-Schatz stenting in coronary angioplasty complicated by dissection with threatened or present vessel closure. Circulation. 1994;90:2716-2724[↩]
6. Yano Y, Ohmori T, Hoshide S, Madoiwa S, Yamamoto K, Katsuki T, Mitsuhashi T, Mimuro J, Shimada K, Kario K and Sakata Y. Determinants of thrombin generation, fibrinolytic activity, and endothelial dysfunction in patients on dual antiplatelet therapy: involvement of factors other than platelet aggregability in Virchow’s triad. European heart journal. 2008;29:1729-38[↩]
7. Byrne RA, Joner M and Kastrati A. Stent thrombosis and restenosis: what have we learned and where are we going? The Andreas Gruntzig Lecture ESC 2014. European heart journal. 2015;36:3320-31.[↩][↩]
8. Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Juni P, Kastrati A, Kolh P, Mauri L, Montalescot G, Neumann FJ, Petricevic M, Roffi M, Steg PG, Windecker S, Zamorano JL and Levine GN. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). European heart journal. 2018;39:213-260.[↩]
9. Schomig A, Neumann FJ, Kastrati A, Schuhlen H, Blasini R, Hadamitzky M, Walter H, Zitzmann-Roth EM, Richardt G, Alt E, Schmitt C and Ulm K. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. The New England journal of medicine. 1996;334:1084-9[↩]
10. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, Giambartolomei A, Diver DJ, Lasorda DM, Williams DO, Pocock SJ and Kuntz RE. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. The New England journal of medicine. 1998;339:1665-71.[↩]
11. Bertrand ME, Legrand V, Boland J, Fleck E, Bonnier J, Emmanuelson H, Vrolix M, Missault L, Chierchia S, Casaccia M, Niccoli L, Oto A, White C, Webb-Peploe M, Van Belle E and McFadden EP. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (fantastic) study. Circulation. 1998;98:1597-603[↩]
12. Bertrand ME, Rupprecht HJ, Urban P and Gershlick AH. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation. 2000;102:624-9.[↩]
13. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G and Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. The New England journal of medicine. 2001;345:494-502[↩]
14. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I and Fox KA. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet (London, England). 2001;358:527-33.[↩]
15. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsky P and Group ESCSD. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). European heart journal. 2018;39:119-177.[↩]
16. Roffi M, Patrono C, Collet J-P, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S and Group ESD. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). European heart journal. 2016;37:267-315[↩][↩]
17. Zipes DP, Libby P, Bonow RO, Mann DL, Tomaselli GF and Braunwald E. Braunwald’s heart disease : a textbook of cardiovascular medicine; 2019[↩]
18. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM and Antman EM. Prasugrel versus clopidogrel in patients with acute coronary syndromes. The New England journal of medicine. 2007;357:2001-15.[↩]
19. Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Eikelboom JW, Fox KA, Granger CB, Jolly S, Joyner CD, Rupprecht HJ, Widimsky P, Afzal R, Pogue J and Yusuf S. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. The New England journal of medicine. 2010;363:930-42[↩]
20. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsky P and Group ESCSD. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). European heart journal. 2018;39:119-177[↩]
21. Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, Byrne RA, Collet JP, Falk V, Head SJ, Juni P, Kastrati A, Koller A, Kristensen SD, Niebauer J, Richter DJ, Seferovic PM, Sibbing D, Stefanini GG, Windecker S, Yadav R and Zembala MO. [2018 ESC/EACTS Guidelines on myocardial revascularization]. Kardiologia polska. 2018;76:1585-1664[↩]
22. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K, Bengtsson O, Ophuis TO, Budaj A, Theroux P, Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss RG, Murphy SA, Wiviott SD, Held P, Braunwald E and Sabatine MS. Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction. New England Journal of Medicine. 2015;372:1791-1800.[↩]
23. Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, Normand SL, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR, Jr., Krucoff MW, Hermiller J, Dauerman HL, Simon DI, Kandzari DE, Garratt KN, Lee DP, Pow TK, Ver Lee P, Rinaldi MJ and Massaro JM. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. The New England journal of medicine. 2014;371:2155-66.[↩]