Summary
There are limited data on platelet reactivity and response to antiplatelet drugs in patients with cardiogenic shock. In some patients, inadequate response to antiplatelet therapy is observed, which is additionally associated with a 2-fold higher risk of adverse events. As the incidence of cardiogenic shock is relatively low (about 5–6%) and patients with shock are in a severe clinical condition, data on platelet reactivity and response to antiplatelet therapy in this population are limited.
Introduction
Antiplatelet therapy is one of the cornerstones of contemporary cardiology. In comparison with clopidogrel, novel potent antiplatelet drugs such as ticagrelor and prasugrel improve the prognosis of patients with acute coronary syndromes (ACSs) [1, 2]. On the other hand, ACS complicated by cardiogenic shock is still associated with a mortality rate of nearly 50% [3]. In some patients, inadequate response to antiplatelet therapy is observed, which is additionally associated with a 2-fold higher risk of adverse events [4]. As the incidence of cardiogenic shock is relatively low (about 5–6%) and patients with shock are in a severe clinical condition, data on platelet reactivity and response to antiplatelet therapy in this population are limited.
Aim
The aim of this study was to assess platelet reactivity on dual antiplatelet therapy with acetylsalicylic acid (ASA) and ticagrelor, a novel potent P2Y12 receptor inhibitor, in patients with cardiogenic shock in the course of ACS who received invasive treatment.
Material and methods
We enrolled consecutive patients with ACS complicated by cardiogenic shock. To assess the response to antiplatelet therapy during cardiogenic shock, only patients with symptoms persisting for at least 3 days were included, while only patients who completed a 5-day follow-up were included in further analysis. Cardiogenic shock was defined as hypotension (systolic blood pressure < 90 mm Hg) despite adequate left ventricular filling pressure, with concomitant signs and symptoms of end-organ hypoperfusion. All participants were treated according to the current guidelines for the management of patients with ACS [5, 6]. All patients underwent coronary angiography and angioplasty of the infarct-related artery. Before referral to a hemodynamics laboratory, they received a loading dose of ASA (300 mg) and ticagrelor (180 mg). Blood samples for platelet function tests were first obtained within 24 h after coronary angioplasty, and then on subsequent days in the morning. Three patients who initially met the inclusion criteria, but in whom blood samples were obtained only for 2 subsequent assays, were excluded from the study.
Platelet aggregation
Platelet aggregation was assessed with a Multiplate whole-blood impedance aggregometer (Roche, Basel, Switzerland). Blood was collected into test tubes containing hirudin (25 µg/ml) as an anticoagulant (Sarstedt, Germany). The aggregation agonists used were arachidonic acid (AA) at a target concentration of 0.5 mM, adenosine diphosphate (ADP) at a target concentration of 6.4 µM, and thrombin receptor-activating peptide (TRAP) at a target concentration of 32 µM. The reagents were provided by Roche. Platelet aggregation was assessed within 2 h from blood sampling and was presented as the area under the curve of aggregation measured in arbitrary units (AU). Each aggregation measurement was performed in duplicate, and the mean value was calculated. In the case of a 10% difference between measurements, the result was rejected and the measurement was repeated. Arachidonic acid-induced aggregation was used as a measure of response to ASA with a cutoff AU value below 30; ADP-induced aggregation was used as a measure of response to ticagrelor with a cutoff AU value below 48; and TRAP-induced aggregation was used as a measure of baseline platelet reactivity independent from ASA and ticagrelor.
Statistical analysis
Statistical analysis was conducted using the Statistica 9.0 software (StatSoft, Tulsa, Oklahoma, United States). For all patients, mean values and standard deviations were calculated, and the normality of the distribution of the parameters was tested with the Kolmogorov-Smirnov, Lilliefors, and Shapiro-Wilk tests. Differences in platelet reactivity between days 1 to 5 and a trend analysis was measured using the Friedman analysis of variance.
Results
The study included 12 patients with cardiogenic shock in the course of myocardial infarction. The clinical characteristics of patients are presented in Table I. On enrollment, all patients met the criteria for the diagnosis of cardiogenic shock and were treated with catecholamine infusion. In 3 patients, it was possible to discontinue the use of catecholamines on day 3 of hospitalization, while the remaining patients were maintained on catecholamine treatment throughout the study. One patient died on day 6 and another one on day 7 due to multiorgan failure. The other patients survived until discharge. During follow-up at the cardiac intensive care unit, we did not observe stent thrombosis, stroke, or recurrent myocardial infarction.
The first blood specimen for platelet aggregation was obtained after a mean time of 12 h ±65 min after a loading dose of antiplatelet agents.
Table I
Clinical characteristics of the study group (n = 12)
[i] ACS – acute coronary syndrome, BARC – Bleeding Academic Research Consortium, CABG – coronary artery bypass grafting, Cx – circumflex artery, eGFR – estimated glomerular filtration rate, IABP – intra-aortic balloon pump, LAD – left anterior descending artery, LMCA – left main coronary artery, LVEF – left ventricular ejection fraction, NSTEMI, non-ST-segment elevation myocardial infarction, PCI – percutaneous coronary intervention, STEMI – ST-segment elevation myocardial infarction, WBC – white blood cells.
Response to antiplatelet therapy assessed by aggregometry showed numerically higher on-ASA platelet reactivity on day one and statistically significant higher on-ticagrelor platelet reactivity on day one in comparison with following days. In the case of TRAP-induced aggregation, a non-significant tendency for higher on-treatment platelet reactivity was observed since day 2 of hospitalization (Table II, Figures 1–3).
Figure 1
Response to acetylsalicylic acid assessed by arachidonic acid-induced aggregation (square – mean, box – standard error, whiskers – standard deviation)
Figure 2
Response to ticagrelor assessed by adenosine diphosphate-induced aggregation (square – mean, box – standard error, whiskers – standard deviation)
Figure 3
Baseline platelet reactivity assessed by platelet aggregation induced by thrombin receptor- activating peptide (square – mean, box – standard error, whiskers – standard deviation)
Table II
Platelet aggregation results
a Reference range without antiplatelet treatment, 70.6–114.8 AU; on acetylsalicylic acid treatment < 30 AU, bReference range without antiplatelet treatment, 56.8–113.0 AU; on P2Y12 antagonist treatment < 48 AU, cReference range, 83.6–128.0 AU. AA – arachidonic acid, ADP – adenosine diphosphate, AU – arbitrary units, TRAP – thrombin receptor-activating peptide. *P < 0.05 for Day 1 in comparison to Day 2-5.
In 2 patients, an inadequate response to ASA was observed on day 1, and in 3 patients, to ticagrelor. On subsequent assays, all patients showed an adequate response to both antiplatelet drugs.
Discussion
Our results showed that some patients with ACS complicated by cardiogenic shock who receive invasive treatment had an inadequate response to dual antiplatelet therapy on day 1 of hospitalization, with an adequate response both to ASA and ticagrelor on subsequent days. Orban et al. [7] reported that patients with ACS after successful resuscitation who underwent targeted temperature management a worse response to antiplatelet therapy on day 3 of hospitalization. However, the reason for this finding is unknown [7]. In our study, none of the patients underwent resuscitation or targeted temperature management. Therefore, a comparison between the studies is difficult. On the other hand, in a study by Tilemann et al. [8], inadequate response to antiplatelet therapy in patients with cardiogenic shock was associated with early stent thrombosis, with no effect on late stent thrombosis and repeat myocardial infarction. However, the authors assessed the response to treatment only on day 1 of hospitalization. In our study, we also observed an inadequate response in 5 patients, but only on day 1. We did not observe stent thrombosis or repeat myocardial infarction.
A possible explanation of our results is the malabsorption of oral antiplatelet drugs from the stomach and duodenum in the state of shock, when there is hypoperfusion of the gastrointestinal tract aggravated by catecholamines. Notably, in our patients there was no use of morphine, which is known for its influence on the antiplatelet drug effect via gastrointestinal absorption interference [9].
Baseline platelet reactivity, assessed with TRAP-induced aggregation, showed an increasing tendency on subsequent assays. This may reflect a homeostatic mechanism whereby platelets are produced in the bone marrow in response to the inhibitory effects of antiplatelet drugs on 2 other platelet signaling pathways, which was reported in our previous study on patients with ACS [10].
The most important limitation of our study is the small and highly selected study group. This is because of a low incidence of cardiogenic shock in patients with ACS treated invasively. Moreover, in order to meet the inclusion criteria, the signs and symptoms of cardiogenic shock had to persist for at least 3 days, and blood samples had to be obtained for 5 consecutive days.
