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]Steinhubl SR and Berger PB. Aspirin following PCI: too much of a good thing? European heart journal. 2009;30:882-4 a medication later (in combination with Dipyridamole) deemed effective in preventing post-PCI (balloon angioplasty) infarction. ^[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 … Continue reading With stent implantation emerging in the 1990s, after the first human coronary stent implantation was done in France in 1986, ^[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. … Continue reading 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]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 … Continue reading. 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]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 … Continue reading. 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]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..

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 ^[8]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. 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 ^[9]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 … Continue reading

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) ^[10]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 … Continue reading. 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) ^[11]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 … Continue reading, a finding confirmed in a French trial published in the same year ^[12]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 … Continue reading. 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. ^[13]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 … Continue reading

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 ^[14]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 … Continue reading 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) ^[15]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 … Continue reading later confirmed this finding for invasively managed patients. 

In acute coronary syndrome, as in PCI, P2Y₁₂ receptor antagonists are the standard of care today ^[16]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, … Continue reading,^[17]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, … Continue reading 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 ^[18]Zipes DP, Libby P, Bonow RO, Mann DL, Tomaselli GF and Braunwald E. Braunwald’s heart disease : a textbook of cardiovascular medicine; 2019. 

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 ^[19]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 … Continue reading 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.) ^[20]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 … Continue reading 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 ^[21]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, … Continue reading 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) ^[22]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, … Continue reading 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 ^[23]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, … Continue reading, for less than 12 months.  

Some studies have evaluated DAPT prolonged beyond 12 months after ACS: The PEGASUS-TIMI-54 trial ^[24]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, … Continue reading (60 or 90 mg. of ticagrelor twice daily on top of ASA for 1–3 years, ACS patients only) and the DAPT trial ^[25]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, … Continue reading (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