The trial designs and results of both the IABP-SHOCK II and the CULPRIT-SHOCK trial have been published previously [3, 10]. Briefly, both studies were prospective, randomized, open-label, multicentre, controlled trials in patients with acute ST-elevation myocardial infarction (STEMI) and non-STEMI complicated by cardiogenic shock with the intention to undergo early revascularization (PCI or alternatively bypass surgery [only in the IABP-SHOCK II trial], for complete inclusion and exclusion criteria see Thiele et al. [3, 10]). In total, 600 patients with AMI and cardiogenic shock were randomized to IABP or no IABP treatment in the IABP-SHOCK II trial. In the CULPRIT-SHOCK trial, 686 patients were randomly assigned to undergo either culprit-lesion-only PCI with possible staged revascularization or immediate multivessel PCI.

The use of ADP-receptor antagonists was left to the discretion of the treating physicians. There was neither a specific protocol nor randomization which drug to use or when and how to administer. The majority of the study patients were mechanically ventilated (53.9%) on admission and received the respective ADP-receptor antagonist via a naso-gastric tube to ensure enteral absorption.

The primary endpoint of this pooled, non-randomized observational sub-analysis was the post-procedural 1-year mortality with respect to three different ADP-receptor antagonists (clopidogrel vs. prasugrel vs. ticagrelor). The secondary safety endpoint was moderate or severe bleedings according to GUSTO criteria [11] until hospital discharge with respect to all three ADP-receptor antagonists. Further endpoints comprised 30-day mortality, stroke, myocardial infarction, all bleeding complications and severe or life-threatening bleedings as assessed according to GUSTO criteria during 1-year follow-up in surviving patients. Inclusion and exclusion criteria were adapted from the previously published [8] sub-analysis of the IABP-SHOCK II trial on ADP-receptor antagonists and were the following: Patients receiving either clopidogrel, prasugrel or ticagrelor as acute medical therapy qualified for inclusion into this subgroup-analysis. Patients who died before PCI, patients not receiving any ADP-receptor antagonist as acute antiplatelet therapy, patients with no information on ADP-receptor antagonist treatment and patients receiving any combination of clopidogrel, prasugrel or ticagrelor simultaneously as acute antiplatelet therapy were excluded from analysis.

Information on patients who were excluded from the analysis according to the exclusion criteria mentioned above are displayed in Supplemental Tables 8, 9, 10, 11, 12, 13, 14, 15 and 16. After exclusion of 430 patients according to the exclusion criteria, 856 patients were analysed. Of these, 507 patients (59.2%) received clopidogrel, 178 patients (20.8%) prasugrel and 171 patients ticagrelor (20.0) as acute antiplatelet therapy (Fig. 1). The mean age of the clopidogrel (69 ± 12 years) and ticagrelor (69 ± 12 years) group was similar, but patients receiving prasugrel were significantly younger (62 ± 11 years). The essential baseline characteristics of all three subgroups are shown in Table 1; cf. Supplemental Table 2 for the extended baseline characteristics of the cohorts. Regarding the clinical presentation prior randomization during the primary trials, patients treated with prasugrel or ticagrelor were more often resuscitated before randomization (Prasugrel: n = 87/178, 48.9%; Ticagrelor: n = 85/171, 49.7%; Clopidogrel: n = 204/506, 40.3%, p = 0.034), presented more often with STEMI (Prasugrel: n = 143/176, 81.3%; Ticagrelor: n = 118/167, 70.7%; Clopidogrel: n = 296/506, 58.5%, p < 0.001) and with lower levels of creatinine (Prasugrel: median = 102.27 [IQR 86.32, 133.30] µmol/l; Ticagrelor: median = 108.86 [IQR 91.05, 136.0] µmol/l; Clopidogrel: median = 116.50 [IQR 96.0, 151.0] µmol/l, p < 0.001) (Supplemental Table 3) compared to clopidogrel. The treatment strategy did not differ between the cohorts with respect to the application of PCI, although bare-metal stents (BMS) were more frequently implanted in patients treated with clopidogrel (Prasugrel: n = 41/171, 24.0%; Ticagrelor: n = 13/162, 8.0%; Clopidogrel: n = 234/466, 50.2%, p < 0.001). Glycoprotein (GP) IIb/IIIa inhibitors were more frequently used within the prasugrel (n = 79/178, 44.4%) and clopidogrel group (n = 189/507, 37.3%) compared to the ticagrelor group (n = 44/171, 25.7%, p = 0.001). In addition, a higher number of clopidogrel-treated patients required mechanical ventilation (n = 407/507, 80.3%, p = 0.023) in comparison to prasugrel (n = 126/177, 71.2%) or ticagrelor (n = 126/171, 73.7%)-treated patients. There was no difference in the use of targeted temperature management between groups (Supplemental Table 3).

In IABP SHOCK II 77.9% (n = 387) of patients were treated with clopidogrel, 19% (n = 93) with prasugrel and 3.4% (n = 17) with ticagrelor. In CULPRIT-SHOCK 33.4% (n = 120) of patients were treated with clopidogrel, 24% (n = 85) with prasugrel and 43% (n = 154) with ticagrelor (p < 0.0001, Supplemental Table 1).

The unadjusted rates of mortality at 1-year follow-up, as well as ischemic and bleeding events of all three subgroups at 30-days follow-up are listed in Table 2. The unadjusted all-cause 1-year mortality was lowest in prasugrel, followed by ticagrelor and highest in clopidogrel treated patients (34.9% [61/175] vs. 48.0% [82/171] vs. 55.9% [283/506] of patients, p < 0.001), Fig. 2. There was also a lower unadjusted all-cause 30-day mortality in prasugrel, followed by ticagrelor and highest in clopidogrel treated patients (29.8% [53/178] vs. 42.1% [72/171] vs. 43.9% [222/506], p < 0.01). The incidence of repeat myocardial infarction and ischemic stroke did not differ significantly between all three subgroups. Table 3 depicts a multivariate Cox regression model for 30-day and 1-year mortality. No significant differences were observed concerning the mortality risk with respect to the ADP-receptor antagonist applied. For 1-year mortality the adjusted hazard ratio was 0.81 (95% CI 0.60–1.09, p = 0.17) for patients treated with prasugrel vs. clopidogrel and 0.86 (95% CI 0.65–1.15, p = 0.31) for patients treated with ticagrelor vs. clopidogrel (see also Tables 4, 5).

Unadjusted moderate and severe bleeding events of surviving patients during 1-year follow-up were not significantly different and numerically highest in clopidogrel (16.1% [36/223]) vs. prasugrel (12.3% [14/114]) vs. ticagrelor (6.7% [6/89])-treated patients, p = 0.081). Moderate bleeding events during 1-year follow-up were significantly different and highest in clopidogrel (15.2% [34/223]) compared to prasugrel (7.9% [9/114]) and ticagrelor (6.7% [6/89], p = 0.039) treated patients. The rate of in-hospital bleeding events was significantly higher in clopidogrel vs. prasugrel and vs. ticagrelor treated patients (18.5% [94/507] vs. 14.1% [25/177] vs. 9.9% [17/171], p = 0.022), Figure 3. This effect was mainly driven by a difference in moderate in-hospital bleedings in clopidogrel vs. prasugrel and vs. ticagrelor treated patients (16.4% [83/507] vs. 9.0% [16/177] vs. 6.4% [11/171], p < 0.001). In a multivariate Cox regression analysis of in-hospital moderate or severe bleeding events in surviving patients, ticagrelor was associated with a significantly lower risk compared to clopidogrel (Odds ratio [OR]: 0.46, 95% CI 0.23–0.90, p = 0.024) (Tables 4, 5, Supplemental Table 7). There was no significant difference between ticagrelor- and prasugrel-treated patients (OR: 0.58, 95% CI 0.27–1.23, p = 0.16). Likewise, no significant difference was seen in the prasugrel vs. the clopidogrel group after adjustment (OR: 0.79, 95% CI 0.46–1.35, p = 0.39). Concerning moderate or severe bleeding events in survivors during 1-year follow-up, ticagrelor was associated with a significantly lower risk compared to both clopidogrel (HR: 0.43, 95% CI 0.25–0.72, p = 0.002) and prasugrel (HR: 0.51, 95% CI 0.28–0.95, p = 0.033). There was no significant difference in the 1-year bleeding risk between prasugrel- vs. clopidogrel-treated patients (HR 0.83 (CI 0.54–1.28, p = 0.40).

There are some known pharmacodynamic disparities with respect to the antiplatelet action of clopidogrel, prasugrel and ticagrelor in AMI patients suffering from cardiogenic shock. The available data are limited to smaller and predominantly retrospective cohorts [16]. A reduced enteral absorption is a key drawback of oral ADP-receptor antagonists in cardiogenic shock [17]. Therefore, cangrelor, an intravenous ADP-receptor antagonist requiring no bioactivation in-vivo, might pose a suitable alternative [17] and is currently under investigation in the ongoing DAPT-SHOCK-AMI (NCT03551964) trial. Cangrelor did not have FDA-approval during the IABP-SHOCK-II trial and was barely used in the CULPRIT-SHOCK trial. Thus, we excluded this drug from our current analysis. Still, clopidogrel is known to be associated with a relatively slow onset of action and to induce lower levels of platelet inhibition in patients with AMI complicated by cardiogenic shock [18]. Consequently, current guidelines recommend to use prasugrel or ticagrelor in these patients. As our data show, the choice of the ADP-receptor antagonist on the other hand does not seem to be decisive for the bleeding risk in patients with AMI complicated by cardiogenic shock. Maybe, not the choice of the ADP-receptor antagonist itself might drive bleeding events, but rather the individual effect of the drug on platelet aggregation as reflected by differences in the quantifiable platelet reactivity. Still, this would not explain the differences in bleeding complications observed in this study since it is plausible that ticagrelor would have achieved a higher level of platelet inhibition than clopidogrel. An investigation, whether switching patients with low platelet reactivity on potent ADP-receptor antagonist to the weaker clopidogrel leads to fewer bleeding events in cardiogenic shock patients, appears to be very interesting—a strategy which was already shown to be safe in AMI patients without cardiogenic shock in the Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment For Acute Coronary Syndromes (TROPICAL-ACS) trial [19].