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Dr. Magnus Ohman
Prof. Lars Wallentin,
Prof. Gilles Montalescot,
Do you use upstream double antiplatelet therapy routinely in the vast majority of your NSTEACS patients?
Gilles Montalescot (FR)
The idea behind pretreatment in NSTEMI is that oral P2Y12 antagonists need some time to get to the full activity and that you need the drugs during the period of medical treatment. This idea comes from the CURE study when indeed clopidogrel had a slow onset of action and was used in patients managed conservatively (80% of the CURE patients had no PCI performed). This is not true with the new P2Y12 antagonists which have a rapid onset of action and are used in patients managed invasively within 48 hours of admission like in ACCOAST (99% had catheterization performed). In ACCOAST prasugrel was effective within one hour of administration. In the pre-treatment group, there was an increase by a factor of three in all major bleeding not related to coronary bypass grafting (CABG) and an increase by a factor of six in life-threatening bleeding not related to CABG. The harm was associated with no benefit on the ischemic side and no subgroup appeared to have a favourable risk/benefit ratio of pre-treatment. The large cohort of patients undergoing PCI performed as well with prasugrel loading on the table as those who had been pre-treated by prasugrel. Pre-treatment did not prevent better peri-procedural myocardial infarction but was associated with a large excess of bleeding complications. Routine pre-treatment strategies in NSTE-ACS are not valuable options anymore when the new drugs are available at centers where patients do not wait for catheterization. There is no data to support pre-treatment with ticagrelor either, as in PLATO all patients were pre-treated and all patients may have been harmed similarly by pre-treament in both groups. However, pretreatment appears more likely to benefit patients with STEMI than patients with non-STEMI or stable CAD. The ATLANTIC study is investigating whether there is a difference in outcomes for pre-hospital administration of ticagrelor vs. in-hospital administration of the drug in STEMI patients planned for primary PCI.
ERRATUM: As opposed to what is said in the ACCA Newsletter (June 2014 issue) con's comment is made by L.Wallentin and Neutral's comment is made by M.Ohman
Lars Wallentin (SW)Acute coronary syndrome (ACS) without ST-elevation is caused by a ruptured or eroded atherosclerotic plaque with superimposed thrombotic material leading to downstream coronary embolization, coronary occlusion and myocardial infarction. Already in the 1990s it was clearly established the immediate antithrombotic treatment with aspirin1 and parenteral anticoagulants2 was paramount to reduce the risk of recurrent myocardial infarction (MI) and cardiovascular (CV) mortality. In the end of the 1990s the CURE trial3 provided further evidence that more intense platelet inhibition by dual antiplatelet treatment further reduced the risk of ischemic events in these patients. Therefore there is no biological rationale and no trial evidence supporting a delay of starting intense antithrombotic treatment in patients presenting with NSTE-ACS. Currently most patients with NSTE-ACS presenting with sign of myocardial damage, as evidenced by elevated troponin, are to be managed with early invasive procedures.4 The invasive approach will usually lead to early PCI with stenting, where there is an inherent risk for stent thrombosis unless the patient is protected by dual antiplatelet treatment. The formation of stent thrombosis starts immediately at implantation of the stent and therefore the platelet inhibition is needed already when the stent is implanted. Unfortunately there is a late onset of platelet inhibition when using clopidogrel, which leads to a need for upstream treatment in order to have the patient adequately protected at the stent implantation. Although the new generation P2Y12 inhibitors, prasugrel and ticagrelor, have a more rapid onset, there might still be a delay based on slow absorption in the acute setting. Therefore upstream start of dual antiplatelet treatment will provide full platelet inhibition at the time of stent implantation and thereby reduce the risk of peri-procedural complications, stent thrombosis and early re-infarction. There have been concerns that upstream dual antiplatelet treatment might be associated with a raised risk of complications in the few cases needing urgent coronary by-pass surgery. However, there is limited data supporting these concerns at least as long as the surgery can be postponed for five days.5 The results from the PLATO trial even indicate that more intense pre-treatment with ticagrelor might reduce the risk of mortality in association with coronary by-pass surgery.6Based on the CURE and CURE-PCI7 trials upstream dual anti-platelet treatment is since many years the recommended routine care in patients with NSTE-ACS in the European Guidelines regardless whether patients are managed with an early invasive or non-invasive strategy.8 This strategy was also part of the treatment strategy used in the randomized trial showing the advantage of a very early invasive as compared to a delayed invasive strategy in NSTE-ACS patients with a high risk of new events.9 The importance of intense platelet inhibition as early as possible in NSTE-ACS patients managed with early invasive procedures has recently been highlighted by the beneficial outcomes with higher versus lower clopidogrel loading doses and intravenous cangrelor versus clopidogrel in the respective OASIS-710 and CHAMPION11 trials. Concerning patients managed non-invasively, already the CURE trial convincingly showed the advantage of adding clopidogrel to aspirin as early as possible after presentation as there was a reduction in outcome events appearing already during the first days of treatment.The PLATO trial12 included patients with ST-elevation myocardial infarction aimed for primary PCI and patients with NSTE-ACS within 24 hours after the start of chest pain. All patients were randomized to either of two dual antiplatelet treatment regimens, including ticagrelor or clopidogrel, as soon as possible after presentation and always before an eventual PCI procedure. The randomized treatments started with a higher loading dose of the respective P2Y12 inhibitor in order to provide more intense dual platelet inhibition in association with early revascularization procedures. Therefore all results comparing ticagrelor with clopidogrel in the PLATO trial have been obtained using a regimen with upstream dual antiplatelet treatment as well in patients managed with an early invasive as with a non-invasive regimen. The results from the PLATO trial with ticagrelor, providing a significant reduction in the composite of cardiovascular death, myocardial infarction and stroke and also in the individual endpoints of myocardial infarction, cardiovascular death and stent thrombosis, are therefore based on the upstream start and long-term continuation with ticagrelor. Recently the results from the NSTE-ACS cohort in the PLATO trial were published.13 The results from this cohort was consistent with the outcomes of the main trial and showed similar results regardless whether the patients were managed with an early invasive or non-invasive treatment strategy.In summary NSTE-ACS are caused by and coronary stenting associated with plaque rupture, activation of platelets and the coagulation system and formation of thrombus leading to a high risk of down stream embolization, coronary occlusion and myocardial infarction. The immediate start of intense platelet inhibition with upstream dual antiplatelet treatment and parenteral anticoagulation has been very successful in reducing the risk of new myocardial infarction, stent thrombosis and cardiovascular mortality both in invasively and noninvasively managed patients. As long as no trials have shown that patients have better outcomes with another regimen these guideline based treatment recommendations should remain unchanged.
Magnus Ohman (USA)
Dual antiplatelet therapy has revolutionized the care for patients with non-ST-elevation acute coronary syndrome. It has simplified the treatment strategy to a large extent. While the majority of patients with this syndrome undergo early angiography with PCI as a revascularization strategy, the focus on management has by and large been to optimize the care path for patients in that category. However, a large proportion of patients are managed without cardiac catheterization and a proportion of patients (30-40%) are managed medically or with the need of coronary artery bypass grafting (5-10%) after the ACS event. In this category of patients, the value of dual antiplatelet therapy has been less clear. A dedicated trial (TRILOGY ACS) and subgroups of other trials have hinted towards a benefit, although not consistently across all subgroups.
In the large CURE trial carried out many years ago, there was a similar benefit in patients managed medically and those managed with revascularization when aspirin and clopidogrel were combined. However, this trial was carried out over a decade ago and much of the healthcare delivery has changed worldwide since that trial. In the TRILOGY ACS trial that studied patients who were managed medically without revascularization in non-ST-elevation acute coronary syndrome, there was no benefit of the more potent ADP antagonist prasugrel when compared to clopidogrel. There was no safety concern in this trial but there was some evidence of a reduction in death and MI and stroke among patients who underwent the invasive approach but not revascularized. In the large PLATO trial, there was an overall significant reduction in death, MI and stroke when ticagrelor was added to aspirin over clopidogrel and aspirin. Among the small subgroup that had non-ST-elevation acute coronary syndrome that was managed medically, there was a trend to a benefit and with a modest reduction in mortality later. There was no effect on the rate of myocardial infarction. The finding in this cohort was similar statistically to the overall trial. Thus while there is some benefit in this cohort, it is not overwhelming.
Among patients treated with PCI, one of the limitations with clopidogrel is that it requires at least 4-6 hours for complete absorption prior to the PCI to be most effective. Newer agents such as prasugrel and ticagrelor require less time, but the absorption is less reliable if given within 30 minutes of the PCI. For this reason it makes sense to preload patients prior to cardiac catheterization and /or PCI for those who are suspected to need a PCI, but recognizing that this is at best about 50% of all patients. Therefore when intravenous ADP antagonists become available, it may be reasonable to hold the loading of the oral ADP antagonist until the anatomy is described so that patients that either have no coronary disease or who will have extensive disease and need bypass surgery, that the therapy can be withheld until a later stage. For patients without significant coronary disease, there is no specific study to address this cohort, but in general it would appear that patients may be subjected to a higher bleeding rate without any true benefit, as was seen in the CHARISMA secondary prevention cohort.
For the above reasons, I do not think a mandate can be made to preload all patients with non-ST-elevation acute coronary syndrome prior to cardiac catheterization, particularly if this is performed quickly (less than 12 hours from symptom onset). If the likelihood of very severe disease is present, such as those that may need bypass surgery, then it might be reasonable to expedite care without preloading individuals. On the other hand, for patients with prior bypass surgery (who typically do not undergo a second bypass surgery), it makes sense to preload patients as the likelihood of an alternative treatment strategy is very low.
1. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. The RISC Group. Lancet. 1990;336:827-30.2. Wallentin L. Low-molecular-weight heparin during instability in coronary artery disease, Fragmin during Instability in Coronary Artery Disease (FRISC) study group. Lancet. 1996;347:561-8.3. 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. N Engl J Med. 2001;345:494-502.4. Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, Caso P, Dudek D, Gielen S, Huber K, Ohman M, Petrie MC, Sonntag F, Uva MS, Storey RF, Wijns W, Zahger D, Bax JJ, Auricchio A, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Knuuti J, Kolh P, McDonagh T, Moulin C, Poldermans D, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Torbicki A, Vahanian A, Windecker S, Windecker S, Achenbach S, Badimon L, Bertrand M, Botker HE, Collet JP, Crea F, Danchin N, Falk E, Goudevenos J, Gulba D, Hambrecht R, Herrmann J, Kastrati A, Kjeldsen K, Kristensen SD, Lancellotti P, Mehilli J, Merkely B, Montalescot G, Neumann FJ, Neyses L, Perk J, Roffi M, Romeo F, Ruda M, Swahn E, Valgimigli M, Vrints CJ and Widimsky P. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011;32:2999-3054.5. Mehta RH, Roe MT, Mulgund J, Ohman EM, Cannon CP, Gibler WB, Pollack CV, Jr., Smith SC, Jr., Ferguson TB and Peterson ED. Acute clopidogrel use and outcomes in patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass surgery. J Am Coll Cardiol. 2006;48:281-6.6. Held C, Asenblad N, Bassand JP, Becker RC, Cannon CP, Claeys MJ, Harrington RA, Horrow J, Husted S, James SK, Mahaffey KW, Nicolau JC, Scirica BM, Storey RF, Vintila M, Ycas J and Wallentin L. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol. 2011;57:672-84.7. Mehta S, Yusuf S, Peters R, Bertrand M, Lewis B, Natarajan M, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I and Fox K. Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators . Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention - the PCI-CURE study. Lancet. 2001;358:527-33 8. Hammerman H, Kloner RA, Schoen FJ, Brown EJ, Jr., Hale SL and Braunwald E. The effects of early indomethacin administration on late scar formation following myocardial infarction. Trans Assoc Am Physicians. 1982;95:104-9.9. Mehta SR, Granger CB, Boden WE, Steg PG, Bassand JP, Faxon DP, Afzal R, Chrolavicius S, Jolly SS, Widimsky P, Avezum A, Rupprecht HJ, Zhu J, Col J, Natarajan MK, Horsman C, Fox KA and Yusuf S. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med. 2009;360:2165-75.10. 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;363:930-42.11. Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, Price MJ, Leonardi S, Gallup D, Bramucci E, Radke PW, Widimsky P, Tousek F, Tauth J, Spriggs D, McLaurin BT, Angiolillo DJ, Genereux P, Liu T, Prats J, Todd M, Skerjanec S, White HD, Harrington RA and Investigators CP. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368:1303-13.12. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Investigators P, Freij A and Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045-57.13. Lindholm D, Varenhorst C, Cannon CP, Harrington RA, Himmelmann A, Maya J, Husted S, Steg PG, Cornel JH, Storey RF, Stevens SR, Wallentin L and James SK. Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial. Eur Heart J. 2014.
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