Förbehandling med P2Y12-hämmare: evidens

Här kan du läsa en fördjupande genomgång av evidensen kring förbehandling med P2Y12-hämmare-originalpublikationen (en disputation från 2019) är på engelska:

Se även avsnitt om förbehandling på DAPT-sidan.

Evidence for pretreatment in STEMI

Pretreatment is defined12 as the administration of a P2Y12antagonist before coronary angiography. Despite the lack of definitive evidence regarding its benefit, pretreatment is a common practice.2

There has only been one trial designed to study the time of first administration of an ADP antagonist in STEMI patients. I will take a closer look at this study below. 

The ATLANTIC trial,3 published in 2014, randomized 1,862 patients with suspected ongoing STEMI to either ticagrelor at first medical contact or in the cath lab directly before angiography. The mean difference in the administration of ticagrelor in the two arms of the trial was 31 minutes. The co-primary endpoints were the surrogate parameters, the resolution of ST elevation (the proportion of patients having at least a 70% resolution of ST elevation before PCI), and the TIMI III flow grade (the proportion of patients having TIMI III flow in the IRA at angiography) that did not reach significance. 

Of note, but not discussed in the paper, was the fact that about 11% of the patients in both groups did not undergo any revascularization, so one might presume that the STEMI diagnosis was incorrect in a majority of these cases. Nevertheless, as all patients received the study drug before angiography, all patients were administered ticagrelor, even those patients who were misdiagnosed and thus lacked an indication for the drug. This strategy contradicts a fundamental advantage of non-pretreatment, namely to avoid treating patients without indications. Several other diseases can hide behind the misdiagnosis of STEMI and some of them will deteriorate with an unindicated antithrombotic treatment, such as aortic dissection. ((Hansson EC, Dellborg M, Lepore V and Jeppsson A. Prevalence, indications and appropriateness of antiplatelet therapy in patients operated for acute aortic dissection: associations with bleeding complications and mortality. Heart (British Cardiac Society). 2013;99:116-21))

Thus, ATLANTIC is not a study of pretreatment versus non-pretreatment but of early versus late pretreatment and should not be used as proof that pretreatment is safe, as compared to non-pretreatment. 

In the ATLANTIC trial, 30 patients died in the prehospital group and 19 died in the in-hospital group at 30 days, a difference reported as non-significant (p = 0.08). For three patients in the in-hospital group and one in the pre-hospital group, no cause of death was available. We do not know if any patient in the misdiagnosed cohort died, nor do we know how many patients developed bleeding among those who were treated inappropriately. The authors concluded that the prehospitaladministration of ticagrelor “is safe and may prevent postprocedural stent thrombosis”.3 This conclusion does not stand on solid scientific ground.((Redfors B, Angeras O, Petursson P, Ramunddal T and Omerovic E. The ATLANTIC trial does not support the safety of prehospital ticagrelor treatment for patients with ST-elevation myocardial infarction. International journal of cardiology. 2015;190:157-8))

First, the primary endpoint of the trial was neutral. Second, as stated above, the data cannot be used for reasoning about pretreatment versus non-pretreatment. Third, while ATLANTIC reported 30 versus 19 deaths with p = 0.08 as non-significant, one might see a trend of increased mortality at 30 days (odds ratio (OR) of 1.68; 95% confidence interval (CI) 0.94–3.01). Our research group had previously analyzed the data in the supplement and could show that the prehospital administration of ticagrelor is associated with a statistically significant difference in the risk of death within 24 hours (12 deaths in the prehospital group vs. 4 deaths in the in-hospital group, OR 3.18, 95% CI 1.02–9.90, p = 0.046).4 Fourth, the ATLANTIC paper reports a significant difference in definite ST both at 24 hours and 30 days (at 30 days: OR 0.19, 95% CI 0.04–0.86, p = 0.02). This report should be questioned in five ways: 

  1. It is problematic to draw a conclusion from a prima vista, statistically positive result for a secondary endpoint in a study with a negative primary endpoint, especially as ATLANTIC did not adjust for multiple comparisons of the secondary endpoints. ((Freemantle N. Interpreting the results of secondary end points and subgroup analyses in clinical trials: should we lock the crazy aunt in the attic? BMJ (Clinical research ed). 2001;322:989-91))5
  2. The low number of events for definite ST at 30 days (13 in total) entails a considerable risk for a Type I error, as the study was not powered for these low-rate events.
  3. There was no difference in definite or probable ST at 30 days (OR 1.1, 95% CI 0.60–2.05).4 Choosing not to publish this lack of a difference but to instead publish only the result for definiteST thrombosis is problematic: In a statement issued in 2007, the Academic Research Committee the “combination of adjudicated definite and probable stent thrombosis to best characterize this aspect of DES safety”.6 PLATO,7 DAPT,8 EXPLORE,9 and dozens of other trials adopted this definition. The main argument is that a ST, an entity with high mortality, is by definition only definite with angiographic or autopsy confirmation. Sudden cardiac deaths after discharge, with ST as one of the likely causes, are defined as probable. 
  4. It is biologically highly implausible that a difference of 31 minutes in the time of administration of ticagrelor (with no difference in platelet activity at any time in the ATLANTIC substudy)3 should reduce ST by fivefold. 
  5. The study was underpowered for the detection of ST.10

metalanalysis11 published in 2018 by the French ACTION group analyzed seven RCTs with “early versus delayed” P2Y12 antagonist administration in STEMI patients scheduled for PCI. The primary endpoint MACE was significantly reduced without an increase in bleeding. All-cause death and cardiovascular death did not differ. Besides ATLANTIC, the following trials were included in the analysis:

  • CHAMPION-STEMI  (2009),12 an RCT comparing two drugs for pretreatment, intra venously administered Cangrelor to clopidogrel both within 30 minutes before PCI in ACS patients, including 996 STEMI patients. The study was negative. 
  • CIPAMI (2012) randomized 337 STEMI patients to either 600 milligrams of clopidogrel in the prehospital phase or the same dose after an angiogram in patients scheduled for PCI. The primary endpoint TIMI 2–3 flow was negative. 
  • ERASE-MI (2009)13 was a pilot dose-escalating study testing the then-novel i.v. P2Y12antagonist elinogrel against a placebo in 70 STEMI patients one to 15 minutes before primary PCI. The development of elinogrel was terminated in 2012. All patients received a 600-milligram loading dose of clopidogrel a few minutes after the study drug. 
  • LOAD&GO14  tested a 600- versus a 900-milligram loading dose clopidogrel in 168 STEMI patients in the prehospital phase versus 300 milligrams after coronary angiography. Despite the bias of using a lower loading dose for patients who not pretreated, the study was negative regarding the primary endpoint TIMI 3 flow. 
  • PCI-CLARITY (2005)15 was a substudy of the CLARITY-TIMI 2816 trial, which tested clopidogrel versus placebo in thrombolysis for STEMI. The 1,863 patients in PCI-Clarity received 300 milligrams of clopidogrel with thrombolysis and were angiographied after a median delay of three days. 

TRITON-STEMI (2009)17 analysed the 3,534 patients with STEMI in the TRITON-TIMI 3818 trial, which randomized them to either clopidogrel or prasugrel given “as soon as possible” after randomization, but up until one hour after PCI. About 25% were administered the study drug before PCI and 75% received it during PCI. The timing was not randomized. Nearly half of the STEMI patients had a history of more than 12 hours and patients could be included up to 14 days after a STEMI. This practice had previously been criticized.19

In summary, it is questionable whether this data can support the use of an oral third-generation P2Y12antagonist for pretreatment in primary PCI for STEMI.

In a metaanalysis published in 2012,20 the same study group analyzed data from five RCTs (8,608 patients) evaluating pretreatment with clopidogrel versus placebo in stable and ACS patients, and from subgroup analyses of four RCTs. The study group found no effect on mortality, but a significant increase in TIMI major bleeding and a significant reduction in MACE, which was mainly due to periprocedural MI.

Evidence for pretreatment in Non-STE-ACS

There has only been one RCT designed to study the time of first administration of an ADP antagonist in non-STE-ACS patients: The ACCOAST trial, published in 2013, randomized 4,033 non-STEMI patients scheduled for coronary angiography to prasugrel either before angiography or after angiography when the angiography indicated PCI. A total of 67.8% of the randomized patients were treated by PCI, with a median delay of 4.3 hours from drug administration to PCI. Twenty-five percent were treated medically and 6.2% were treated with CABG, i.e., at least 6.2% were pretreated without an indication. The number of the 25% medically treated patients who had a diagnosis other than ACS at discharge, i.e., the number of those who did not have an indication for pretreatment, was not stated in the paper. There was no difference in the primary composite endpoint (cardiovascular death, MI, stroke, urgent revascularization, glycoprotein IIbIIIa rescue therapy), but major bleeding was highly significantly increased in the pretreatment group: Non-CABG TIMI major bleeding increased three-fold and life-threatening bleeding increased six-fold, which was the cause of the premature termination of the trial. 

A criticism of ACCOAST is that the short time from randomization to PCI might have led to an underestimation of the true treatment effect,21 but no interaction was found between the outcome and the time delay to angiography (there was no benefit for pretreatment in patients who waited 48 hours),10 and this short time interval is comparable to the delay in other randomized studies of NSTE-ACS.22 Based on this trial, the ESC guideline on NSTE-ACS does not recommend the use of prasugrel before coronary angiography, i.e., classifies pretreatment with prasugrel as contraindicated (Grade IIIB).2

In the 2007 TRITON-TIM 38 trial, ((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)) a RCT comparing clopidogrel to prasugrel in ACS patients, the patients received prasugrel after coronary angiography.

The CURE study is referenced in the ESC 2011 guideline:  ((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)) As stated above, this RCT tested DAPT with ASA plus clopidogrel 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 at the cost of an increase in bleeding complications, as compared to ASA monotherapy. In the trial, 21.2% of the patients were treated by PCI. Before the CURE study, it was standard practice to give clopidogrel or ticlopidine not to all NSTE-ACS patients but only to patients treated with stent implantation at the end of the procedure in the cath lab, with the intent to prevent ST.  ((Valgimigli M. Pretreatment with P2Y12 inhibitors in non-ST-segment-elevation acute coronary syndrome is clinically justified. Circulation. 2014;130:1891-903; discussion 1903)) In CURE, clopidogrel was administered with a loading dose of 300 milligrams immediately at admission, which led to the adoption of the study protocol as standard clinical practice, i.e., to starting DAPT at admission. So, the question the study answered is whether the DAPT treatment of NSTE-ACS patients with clopidogrel for an average of nine months (the trial was even positive in an analysis of the first 30 days, even if this was not the primary endpoint) is superior to treatment with ASA alone. 

The reason CURE is used as evidence for pretreatment is the substudy on invasively managed patients, i.e., the prospectively designed subgroup analysis of the 21.2% patients treated by PCI (published as the PCI-CURE study)23 that was “designed to test the hypothesis that, in addition to aspirin, treatment with clopidogrel before PCI is superior to placebo in prevention of major ischemic events afterwards”. The primary endpoint for PCI-CURE (cardiovascular death, MI, urgent target vessel revascularization within 30 days of PCI) occurred less often in the clopidogrel group. There was no difference between the two groups in cardiovascular mortality within 30 days of PCI.

In CURE, the “vast majority” of patients treated by PCI received open-label thienopyridine “for 2 to 4 weeks” and then went back to the study medication, i.e., clopidogrel or placebo. As the “vast majority” of patients received the same treatment (open-label ticlopidine or clopidogrel) after PCI, the difference in outcome at 30 days should be due to the medication administered before PCI, i.e., to pretreatment. 

Several issues limit the application of this study as evidence for pretreatment today. 

  1. Anticoagulation: All patients received heparin or low-molecular-weight heparin (LMWH) during their initial hospitalization. The paper does not state the fraction of patients who received heparin or LMWH up to PCI, but because it refers to the FRISC II study24 on the harm of treatment extending longer than one week, one might assume that this therapy was mostly limited to one week. As the median delay from randomization to PCI was ten days (in 928 patients PCI was done after discharge and the median delay to PCI was 49 days with an upper IQR of 106 days), a considerable fraction of patients was only treated with ASA for days to months before PCI. Today, all patients scheduled for invasive treatment receive anticoagulation (mainly LMWH or the selective factor Xa inhibitor fondaparinux) until PCI,1 i.e., the finding that pretreatment lessened the risk of myocardial infarction before PCI in PCI-CURE is not applicable today when anticoagulation treatment before PCI is standard. 
  2. PCI delay: The delay from randomization to PCI, with a substantial fraction of patients discharged before PCI, is not comparable to today’s delay time: The time from admission to angiography has internationally decreased substantially since CURE10 and in Sweden, the vast majority (with some local exceptions) are now angiographied within three days25 and discharge before PCI is a rarity. In a subgroup analysis, the primary endpoint was not positive for patients treated by PCI < 72 hours after randomization, who comprised a minority in PCI-CURE. 
  3. Loading dose: Eighty percent of the patients in PCI-CURE received an open-label thienopyridine after PCI, but the paper does not mention the loading doses. The loading dose is especially important as about 50% of events occur within the first two days after PCI. 
  4. Due to the different pharmacokinetics, data from clopidogrel should not directly be used as evidence for pretreatment with third-generation P2Y12 inhibitors (as shown in the ACCOAST trial). ((Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay JF, ten Berg JM, Miller DL, Costigan TM, Goedicke J, Silvain J, Angioli P, Legutko J, Niethammer M, Motovska Z, Jakubowski JA, Cayla G, Visconti LO, Vicaut E and Widimsky P. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. The New England journal of medicine. 2013;369:999-1010))
  5. DAPT after PCI: As 80% of the patients in PCI-CURE received an open-label thienopyridineafter PCI, 20% of the patients in the placebo group did not receive DAPT at any time. Today, we know that these patients have a very high risk of ST.26
  6. Length of DAPT after PCI: Eighty percent of patients in PCI-CURE received a thienopyridine“for two to four weeks” (median 30 days, IQR 19–33) after PCI, but the paper does not state the exact length of treatment in the two groups.23 It should thus be kept in mind that, as the open-label treatment after PCI lasted only for two to four weeks, within the primary endpoint’s follow-up time of 30 days after PCI in an unknown fraction of patients, the open-label P2Y12 therapy was terminated and the study medication (50% placebo) was continued. With today’sknowledge, the termination of DAPT two weeks after PCI in an ACS patient is contraindicated3. Events extending from PCI to 30 days after PCI can thus not be attributed to pretreatment before PCI.
  7. In PLATO, patients were randomized to treatment with ticagrelor or placebo. The study design resembled27 the design in CURE: Treatment was started directly at admission in all patients, regardless of the final treatment strategy. Sixty-one percent of the 18,624 randomized patients were treated with PCI and the median delay was 2.4 hours for all patients (including STEMI) and 3.8 hours (0.47–48 hours IQR) for the NSTE-ACS patients. In contrast to CURE, all patients received DAPT, i.e., PLATO did not test pretreatment versus no pretreatment. Nevertheless, pretreatment with ticagrelor did not lead to excess bleeding as compared to pretreatment with clopidogrel.  
  8. The CREDO trial, published one year after CURE in 2002, randomized elective PCI patients to receive a 300-milligram dose of bolus clopidogrel three to 24 hours before PCI, as compared to the placebo (all patients received DAPT in 4 weeks). Despite the bias introduced by randomization after angiography,2210 pretreatment did not reduce ischemic events (or bleeding) at 28 days.((Steinhubl SR, Berger PB, Mann JT, 3rd, Fry ET, DeLago A, Wilmer C and Topol EJ. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. Jama. 2002;288:2411-20))

Despite the lack of definite evidence of its benefit and the evidence of its harm with prasugrel,28 pretreatment is general practice.2 An important question is whether the harm observed with prasugrel in the only trial designed for assessing pretreatment was a class effect or related only to prasugrel. It might be regarded as inconsequential to judge the harm caused by prasugrel as an individual drug effect and, on the other hand, to refer to CURE, a study testing clopidogrel, as evidence for pretreatment with ticagrelor. 

Last Updated on July 4, 2021 by Daniella Isaksén

Christian Dworeck
Latest posts by Christian Dworeck (see all)
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