Cardiogenic shock (CS) is a devastating and fatal complication of acute myocardial infarction (AMI). CS can affect the pharmacokinetics and pharmacodynamics of medications. The unique properties of cangrelor make it the optimal P2Y12 inhibitor for CS-AMI, in terms of both efficacy and safety. The DAPT-SHOCK-AMI trial (ClinicalTrials.gov: NCT03551964; EudraCT: 2018-002161-19) will assess the benefits of cangrelor in patients with an initial CS-AMI undergoing primary angioplasty. This randomised, multicentre, placebo-controlled trial of approximately 550 patients (with an allowed 10% increase) in 5 countries using a double-blind design will compare initial P2Y12 inhibitor treatment strategies in patients with CS-AMI of (A) intravenous cangrelor and (B) ticagrelor administered as crushed tablets at a loading dose of 180 mg. The primary clinical endpoint is a composite of all-cause death, myocardial infarction (MI), or stroke within 30 days. The main secondary endpoints are (1) the net clinical endpoint, defined as death, MI, urgent revascularisation of the infarct-related artery, stroke, or major bleeding as defined by the Bleeding Academic Research Consortium criteria; (2) cardiovascular-related death, MI, urgent revascularisation, or heart failure; (3) heart failure; and (4) cardiovascular-related death, all (1-4) within 1 year after study enrolment. A platelet reactivity study that tests the laboratory antiplatelet benefits of cangrelor, when given in addition to standard antiplatelet therapy, will be conducted using vasodilator-stimulated phosphoprotein phosphorylation. The primary laboratory endpoints are the periprocedural rate of onset and the proportion of patients who achieve effective P2Y12 inhibition. The DAPT-SHOCK-AMI study is the first randomised trial to evaluate the benefits of cangrelor in patients with CS-AMI.

• MeSH
• adenosinmonofosfát * analogy a deriváty   terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• antagonisté purinergních receptorů P2Y aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• dvojitá slepá metoda MeSH
• fosfoprotein stimulovaný vazodilatátorem MeSH
• fosfoproteiny MeSH
• infarkt myokardu * komplikace   MeSH
• inhibitory agregace trombocytů * škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• kardiogenní šok * mortalita   MeSH
• koronární angioplastika škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• multicentrické studie jako téma MeSH
• randomizované kontrolované studie jako téma MeSH
• senioři MeSH
• ticagrelor * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• protokol klinické studie MeSH
• Názvy látek
• adenosinmonofosfát * MeSH
• antagonisté purinergních receptorů P2Y MeSH
• cangrelor MeSH Prohlížeč
• fosfoprotein stimulovaný vazodilatátorem MeSH
• fosfoproteiny MeSH
• inhibitory agregace trombocytů * MeSH
• ticagrelor * MeSH

BACKGROUND: Whether ticagrelor may reduce periprocedural myocardial necrosis after elective percutaneous coronary intervention (PCI) in patients with and without chronic clopidogrel therapy is unclear. OBJECTIVES: This study sought to compare ticagrelor vs clopidogrel in patients with and without chronic clopidogrel therapy before undergoing elective PCI. METHODS: In this prespecified analysis of the ALPHEUS (Assessment of Loading With the P2Y12 Inhibitor Ticagrelor or Clopidogrel to Halt Ischemic Events in Patients Undergoing Elective Coronary Stenting) trial, patients were defined as clopidogrel(+) and clopidogrel(-) according to the presence and absence of clopidogrel treatment for ≥7 days before PCI, respectively. The primary endpoint was the composite of PCI-related myocardial infarction and major injury as defined by the third and fourth universal definition 48 hours after PCI. RESULTS: A total of 1,882 patients were included, 805 (42.7%) of whom were clopidogrel(+). These patients were older, had more comorbidities, and had more frequent features of complex PCI. The primary endpoint was less frequently present in clopidogrel(-) compared to clopidogrel(+) patients (32.8% vs 40.0%; OR: 0.73; 95% CI: 0.60-0.88), but no significant differences were reported for the risk of death, myocardial infarction, stroke, or transient ischemic attack at 48 hours or 30 days. Ticagrelor did not reduce periprocedural myocardial necrosis or the risk of adverse outcomes, and there was no significant interaction regarding the presence of chronic clopidogrel treatment. CONCLUSIONS: Clopidogrel-naive patients presented less periprocedural complications compared to clopidogrel(+) patients, a difference related to a lower risk profile and less complex PCI. The absence of clopidogrel at baseline did not affect the absence of a difference between ticagrelor and clopidogrel in terms of PCI-related complications supporting the use of clopidogrel as the standard of care in elective PCI in patients with or without chronic clopidogrel treatment.

• Klíčová slova
• cardiovascular outcomes, chronic coronary syndrome, clopidogrel, dual antiplatelet therapy, elective percutaneous intervention, ticagrelor,
• MeSH
• antagonisté purinergních receptorů P2Y škodlivé účinky   terapeutické užití   MeSH
• časové faktory MeSH
• chronická nemoc MeSH
• hodnocení rizik MeSH
• infarkt myokardu * mortalita   MeSH
• inhibitory agregace trombocytů * škodlivé účinky   terapeutické užití   MeSH
• klopidogrel * škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• koronární angioplastika * škodlivé účinky   mortalita   MeSH
• krvácení chemicky indukované   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nekróza MeSH
• nemoci koronárních tepen terapie   mortalita   diagnostické zobrazování   farmakoterapie   MeSH
• rizikové faktory MeSH
• senioři MeSH
• stenty MeSH
• ticagrelor * škodlivé účinky   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• antagonisté purinergních receptorů P2Y MeSH
• inhibitory agregace trombocytů * MeSH
• klopidogrel * MeSH
• ticagrelor * MeSH

BACKGROUND: Whether ticagrelor in chronic coronary syndrome patients undergoing complex percutaneous coronary intervention (PCI) can prevent cardiovascular events is unknown. OBJECTIVES: The authors sought to evaluate outcomes of complex PCI and the efficacy of ticagrelor vs clopidogrel in stable patients randomized in the ALPHEUS (Assessment of Loading with the P2Y12 inhibitor ticagrelor or clopidogrel to Halt ischemic Events in patients Undergoing elective coronary Stenting) trial. METHODS: All PCI procedures were blindly reviewed and classified as complex if they had at least 1 of the following criteria: stent length >60 mm, 2-stent bifurcation, left main, bypass graft, chronic total occlusion, use of atherectomy or guiding catheter extensions, multiwire technique, multiple stents. The primary endpoint was a composite of type 4a or b myocardial infarction (MI) and major myocardial injury during the 48 hours after PCI. We compared the event rates according to the presence or not of complex PCI criteria and evaluated the interaction with ticagrelor or clopidogrel. RESULTS: Among the 1,866 patients randomized, 910 PCI (48.3%) were classified as complex PCI. The primary endpoint was more frequent in complex PCI (45.6% vs 26.6%; P < 0.001) driven by higher rates of type 4 MI and angiographic complications (12.2% vs 4.8 %; P < 0.001 and 19.3% vs 8.6%; P < 0.05, respectively). The composite of death, MI, and stroke at 48 hours (12.7% vs 5.1 %; P < 0.05) and at 30 days (13.4% vs 5.3%; P < 0.05) was more frequent in complex PCI. No interaction was found between PCI complexity and the randomized treatment for the primary endpoint (Pinteraction = 0.47) nor the secondary endpoints. CONCLUSIONS: In chronic coronary syndrome, patients undergoing a complex PCI have higher rates of periprocedural and cardiovascular events that are not reduced by ticagrelor as compared with clopidogrel.

• Klíčová slova
• chronic coronary syndrome, complex percutaneous coronary intervention, coronary artery disease, myocardial infarction, ticagrelor,
• MeSH
• akutní koronární syndrom * diagnostické zobrazování   terapie   komplikace   MeSH
• infarkt myokardu * etiologie   MeSH
• inhibitory agregace trombocytů škodlivé účinky   terapeutické užití   MeSH
• klopidogrel škodlivé účinky   terapeutické užití   MeSH
• koronární angioplastika * škodlivé účinky   MeSH
• lidé MeSH
• ticagrelor škodlivé účinky   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• inhibitory agregace trombocytů MeSH
• klopidogrel MeSH
• ticagrelor MeSH

Background Coronary stent type and risk of stent thrombosis remain important factors affecting recommended duration of dual antiplatelet therapy. We investigated the efficacy and safety of long-term ticagrelor in patients with prior coronary stenting enrolled in the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) trial. Methods and Results Patients in PEGASUS-TIMI 54 had a myocardial infarction 1 to 3 year prior and were randomized 1:1:1 to ticagrelor 60 or 90 mg BID or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular events). Stent thrombosis was prospectively adjudicated (Academic Research Consortium definition). Baseline characteristics were compared by most recent stent type (bare metal versus drug-eluting stent and first- versus later-generation drug-eluting stent). Treatment arms were compared using Cox proportional hazards models. Of 21 162 patients randomized, 80% (n=16 891) had prior coronary stenting. Following randomization, myocardial infarction was the most frequent ischemic event in patients with prior stenting in the placebo arm, occurring in 5.2% of patients (Type 1: 4.1%), followed by cardiovascular death (2.3%), stroke (1.7%), and stent thrombosis (0.9%). Ticagrelorpooled reduced major adverse cardiovascular events (7.0% versus 8.0%; hazard ratio [HR], 0.85; 95% CI, 0.75-96) regardless of stent type (bare metal stent versus drug-eluting stent: pinteraction=0.767; first versus later generation: pinteraction=0.940). The rate of any stent thrombosis was numerically lower with ticagrelorpooled (0.7% versus 0.9%; HR, 0.73; 95% CI, 0.50-1.05) and Thrombolysis in Myocardial Infarction major bleeding was increased (HR, 2.65; 95% CI, 1.90-3.68). Conclusions Long-term ticagrelor reduces major adverse cardiovascular events in patients with prior myocardial infarction and coronary stenting regardless of stent type, with the benefit driven predominantly by reduction in de novo events. Nonfatal major bleeding is increased with ticagrelor. Registration Information clinicaltrials.gov. Identifier: NCT01225562.

• Klíčová slova
• P2Y12 inhibitor, PCI, acute coronary syndrome, antiplatelet therapy,
• MeSH
• cévní mozková příhoda * farmakoterapie   etiologie   prevence a kontrola   MeSH
• infarkt myokardu * farmakoterapie   prevence a kontrola   MeSH
• inhibitory agregace trombocytů škodlivé účinky   terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• koronární angioplastika MeSH
• krvácení chemicky indukované   epidemiologie   MeSH
• lidé MeSH
• sekundární prevence MeSH
• stenty uvolňující léky * MeSH
• stenty MeSH
• ticagrelor škodlivé účinky   terapeutické užití   MeSH
• trombóza * farmakoterapie   prevence a kontrola   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• inhibitory agregace trombocytů MeSH
• ticagrelor MeSH

BACKGROUND: Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear. METHODS: In this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria. RESULTS: A total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P = 0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P = 0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P = 0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02). CONCLUSIONS: In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. (Funded by AstraZeneca; THEMIS ClinicalTrials.gov number, NCT01991795.).

• MeSH
• Aspirin škodlivé účinky   terapeutické užití   MeSH
• cévní mozková příhoda epidemiologie   prevence a kontrola   MeSH
• diabetes mellitus 2. typu komplikace   farmakoterapie   mortalita   MeSH
• dvojitá slepá metoda MeSH
• incidence MeSH
• infarkt myokardu epidemiologie   prevence a kontrola   MeSH
• inhibitory agregace trombocytů škodlivé účinky   terapeutické užití   MeSH
• Kaplanův-Meierův odhad MeSH
• kombinovaná farmakoterapie škodlivé účinky   MeSH
• krvácení chemicky indukované   epidemiologie   mortalita   MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• nemoci koronárních tepen komplikace   farmakoterapie   mortalita   MeSH
• senioři MeSH
• ticagrelor škodlivé účinky   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• Aspirin MeSH
• inhibitory agregace trombocytů MeSH
• ticagrelor MeSH

AIMS: In PEGASUS-TIMI 54, ticagrelor significantly reduced the risk of the composite of major adverse cardiovascular (CV) events by 15-16% in stable patients with a prior myocardial infarction (MI) 1-3 years earlier. We report the efficacy and safety in the subpopulation recommended for treatment in the European (EU) label, i.e. treatment with 60 mg b.i.d. initiated up to 2 years from the MI, or within 1 year after stopping previous adenosine diphosphate receptor inhibitor treatment. METHODS AND RESULTS: Of the 21 162 patients enrolled in PEGASUS-TIMI 54, 10 779 patients were included in the primary analysis for this study, randomized to ticagrelor 60 mg (n = 5388) or matching placebo (n = 5391). The cumulative proportions of patients with events at 36 months were calculated by the Kaplan-Meier (KM) method. The composite of CV death, MI, or stroke occurred less frequently in the ticagrelor group (7.9% KM rate vs. 9.6%), hazard ratio (HR) 0.80 [95% confidence interval (CI) 0.70-0.91; P = 0.001]. Ticagrelor also reduced the risk of all-cause mortality, HR 0.80 (0.67-0.96; P = 0.018). Thrombolysis in myocardial infarction major bleeding was more frequent in the ticagrelor group 2.5% vs. 1.1%; HR 2.36 (1.65-3.39; P < 0.001). The corresponding HR for fatal or intracranial bleeding was 1.17 (0.68-2.01; P = 0.58). CONCLUSION: In PEGASUS-TIMI 54, treatment with ticagrelor 60 mg as recommended in the EU label, was associated with a relative risk reduction of 20% in CV death, MI, or stroke. Thrombolysis in myocardial infarction major bleeding was increased, but fatal or intracranial bleeding was similar to placebo. There appears to be a favourable benefit-risk ratio for long-term ticagrelor 60 mg in this population. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT01225562.

• Klíčová slova
• Coronary artery disease, Dual antiplatelet treatment, Post-myocardial infarction,
• MeSH
• antagonisté purinergních receptorů P2Y aplikace a dávkování   škodlivé účinky   MeSH
• Aspirin aplikace a dávkování   MeSH
• časové faktory MeSH
• hodnocení rizik MeSH
• infarkt myokardu diagnóza   farmakoterapie   mortalita   MeSH
• inhibitory agregace trombocytů aplikace a dávkování   škodlivé účinky   MeSH
• kombinovaná farmakoterapie MeSH
• krvácení chemicky indukované   mortalita   MeSH
• lidé středního věku MeSH
• lidé MeSH
• randomizované kontrolované studie jako téma MeSH
• recidiva MeSH
• rizikové faktory MeSH
• schvalování léčiv MeSH
• senioři MeSH
• ticagrelor aplikace a dávkování   škodlivé účinky   MeSH
• výsledek terapie MeSH
• značení léčiv MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• antagonisté purinergních receptorů P2Y MeSH
• Aspirin MeSH
• inhibitory agregace trombocytů MeSH
• ticagrelor MeSH

BACKGROUND: Various antiplatelet drugs are used following Acute Coronary Syndromes (ACS). Of them, adenosine diphosphate receptor P2Y12 inhibitors clopidogrel, prasugrel and ticagrelor are currently used for post-ACS long-term treatment. Although they act on the same receptor, they differ in pharmacodynamics and pharmacokinetics. Several enzymes and transporters involved in the metabolism of P2Y12 inhibitors show genetic variability with functional impact. This includes Pglycoprotein, carboxylesterase 1 and, most notably, CYP2C19 that is important in clopidogrel activation. Common gain-of-function or loss-of-function alleles of CYP2C19 gene are associated with lower or higher platelet reactivity that may impact clinical outcomes of clopidogrel treatment. Prasugrel is considered to be less dependent on CYP2C19 variability as it is also metabolized by other CYP450 isoforms. Some studies, however, showed the relevance of CYP2C19 variants for platelet reactivity during prasugrel treatment as well. Ticagrelor is metabolized mainly by CYP3A4, which does not show functionally relevant genetic variability. Its concentrations may be modified by the variants of Pglycoprotein gene ABCB1. While no substantial difference between the clinical efficacy of prasugrel and ticagrelor has been documented, both of them have been shown to be superior to clopidogrel in post-ACS treatment. This can be partially explained by lower variability at each step of their metabolism. It is probable that factors influencing the pharmacokinetics of both drugs, including genetic factors, may predict the clinical efficacy of antiplatelet treatment in personalized medicine. CONCLUSION: We summarize the pharmacokinetics and pharmacogenetics of P2Y12 inhibitors with respect to their clinical effects in post-myocardial infarction treatment.

• Klíčová slova
• Myocardial infarction, clopidogrel, cytochrome P450, pharmacogenetic, pharmacokinetics, prasugrel, ticagrelor.,
• MeSH
• antagonisté purinergních receptorů P2Y škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• biotransformace genetika   MeSH
• cytochrom P-450 CYP3A genetika   metabolismus   MeSH
• cytochrom P450 CYP2C19 genetika   metabolismus   MeSH
• farmakogenomické varianty * MeSH
• infarkt myokardu krev   diagnóza   farmakoterapie   MeSH
• inhibitory agregace trombocytů škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• klopidogrel škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• léková rezistence genetika   MeSH
• lidé MeSH
• P-glykoproteiny genetika   metabolismus   MeSH
• prasugrel hydrochlorid škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• purinergní receptory P2Y12 krev   účinky léků   MeSH
• ticagrelor škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• trombocyty účinky léků   metabolismus   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• ABCB1 protein, human MeSH Prohlížeč
• antagonisté purinergních receptorů P2Y MeSH
• CYP2C19 protein, human MeSH Prohlížeč
• CYP3A4 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP3A MeSH
• cytochrom P450 CYP2C19 MeSH
• inhibitory agregace trombocytů MeSH
• klopidogrel MeSH
• P-glykoproteiny MeSH
• P2RY12 protein, human MeSH Prohlížeč
• prasugrel hydrochlorid MeSH
• purinergní receptory P2Y12 MeSH
• ticagrelor MeSH