Friederike K. Keating

Pharmacodynamic effects during the transition between cangrelor and ticagrelor.

OBJECTIVES This study sought to determine pharmacodynamic effects during transition from intravenous cangrelor to oral ticagrelor and from oral ticagrelor to intravenous cangrelor. BACKGROUND Cangrelor is an intravenous antagonist of P2Y12 and its use will require transition to and from oral agents. METHODS Patients (n = 12) with stable coronary artery disease who were taking aspirin 81 mg daily were recruited. On study day 1, they received a bolus plus 2-h infusion of cangrelor plus a 180-mg dose of ticagrelor at either 0.5 h (n = 6) or 1.25 h (n = 6). Pharmacodynamic effects (light transmission platelet aggregation in response to 20 and 5 μmol/l adenosine diphosphate, VerifyNow, P2Y12 assay (Accumetrics, San Diego, California), vasodilator-stimulated phosphoprotein index, and flow cytometry) were assessed during and after the cangrelor infusion. Patients took 90 mg of ticagrelor twice daily for either 6 (n = 6) or 7 (n = 6) doses. On study day 5, pharmacodynamic effects were assessed before and during a bolus plus 2-h infusion of cangrelor. RESULTS During cangrelor infusion, extensive inhibition of platelet function reflected by limited residual platelet reactivity was apparent. After cangrelor was stopped, the antiplatelet effects of ticagrelor were preserved despite a modest increase in platelet reactivity. CONCLUSIONS Ticagrelor given before or during infusion of cangrelor did not attenuate the pharmacodynamic effects of cangrelor. The pharmacodynamic effects of ticagrelor were preserved when ticagrelor was given during infusion of cangrelor. Consistent with the reversible binding of ticagrelor, this oral P2Y12 antagonist can be administered before, during, or after treatment with cangrelor.

Pharmacodynamic effects during the transition between cangrelor and prasugrel.

ObjectiveThe aim of this study was to determine the impact of cangrelor and prasugrel on the pharmacodynamic effects of each agent. BackgroundThe development of an intravenous P2Y12 antagonist necessitates transition between intravenous and oral therapy. MethodsPatients (n=15) with stable coronary artery disease who were taking 81 mg aspirin daily were recruited. On study day 1, they received a bolus plus 2-h infusion of cangrelor plus a 60 mg dose of prasugrel at 1 h (n=3), 1.5 h (n=6), 2 h (n=3), or 2.5 h (n=3). Pharmacodynamic effects (light transmission platelet aggregation in response to 20 &mgr;mol/l ADP, VerifyNow, and flow cytometry) were assessed during and after the cangrelor infusion. Patients took 10 mg of prasugrel daily for either 5 days (n=6) or 6 days (n=6). On study day 8, pharmacodynamic effects were assessed before and during a bolus plus 2-h infusion of cangrelor. ResultsDuring cangrelor infusion (days 1 and 8), extensive inhibition of platelet function, reflected by limited residual platelet reactivity, was apparent. On day 1, transient (limited to the first hour after cangrelor was stopped) but substantial (>50%) recovery of platelet reactivity was observed. This recovery was attenuated when prasugrel was given at 1.5 h (30 min before cangrelor was stopped). ConclusionPrasugrel did not alter the antiplatelet effects of cangrelor, but transient recovery of platelet reactivity was apparent during the transition from cangrelor to prasugrel. Recovery of platelet reactivity was limited when prasugrel was administered 30 min before the end of the cangrelor infusion.

Reduction in Treatment Times Through Formalized Data Feedback : Results From a Prospective Multicenter Study of ST-Segment Elevation Myocardial Infarction

OBJECTIVES This study sought to evaluate the effect of systematic data analysis and standardized feedback on treatment times and outcome in a prospective multicenter trial. BACKGROUND Formalized data feedback may reduce treatment times in ST-segment elevation myocardial infarction (STEMI). METHODS Over a 15-month period, 1,183 patients presenting with STEMI were enrolled. Six primary percutaneous coronary intervention hospitals in Germany and 29 associated nonpercutaneous coronary intervention hospitals participated. Data from patient contact to balloon inflation were collected and analyzed. Pre-defined quality indicators, including the percentage of patients with pre-announced STEMI, direct handoff in the catheterization laboratory, contact-to-balloon time <90 min, door-to-balloon time <60 min, and door-to-balloon time <30 min were discussed with staff on a quarterly basis. RESULTS Median door-to-balloon time decreased from 71 to 58 min and contact-to-balloon time from 129 to 103 min between the first and the fifth quarter (p < 0.05 for both). Contributing were shorter stays in the emergency department, more direct handoffs from ambulances to the catheterization laboratory (from 22% to 38%, p < 0.05), and a slight increase in the number of patients transported directly to the percutaneous coronary intervention facility (primary transport). One-year mortality was reduced in the total group of patients and in the subgroup of patients with primary transport (p < 0.05). The sharpest fall in mortality was observed in patients with primary transport and TIMI (Thrombolysis In Myocardial Infarction) risk score ≥ 3 (n = 521) with a decrease in 30-day mortality from 23.1% to 13.3% (p < 0.05) and in 1-year mortality from 25.6% to 16.7% (p < 0.05). CONCLUSIONS Formalized data feedback is associated with a reduction in treatment times for STEMI and with an improved prognosis, which is most pronounced in high-risk patients. (Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction [FITT-STEMI]; NCT00794001).

Platelet-white blood cell (WBC) interaction, WBC apoptosis, and procoagulant activity in stored red blood cells

BACKGROUND: Nonleukoreduced units of red blood cells (RBCs) contain activated platelets (PLTs) that interact with white blood cells (WBCs) and may promote inflammation and thrombosis in the recipient. The aim of this study was to characterize PLT‐WBC interactions (PLT‐WBC aggregates [PLAs]), WBC apoptosis, WBC death, and the development of procoagulant activity in RBCs during storage.

Greater inhibitory effects of bivalirudin compared with unfractionated heparin plus eptifibitide on thrombin-induced platelet activation

ObjectivesThe effects of antithrombotic agents on the activation of platelets by thrombin were determined in blood from patients (n=12) with symptomatic coronary artery disease. MethodsBlood obtained immediately before cardiac catheterization was incubated in vitro with therapeutic concentrations of unfractionated heparin (1.2 and 2.0 U/ml) alone and in combination with eptifibatide (unfractionated heparin 1.2 U/ml+eptifibatide, 1.7 μg/ml) or bivalirudin (8 and 14 μg/ml). An activated clotting time was determined. Platelet activation was induced with thrombin (0, 5, 15, and 40 U/ml) and assessed with the use of flow cytometry. Fibrin polymerization was prevented by the peptide Gly-Pro-Arg-Pro. The activation of glycoprotein IIb–IIIa and surface expression of P-selectin were identified with antibodies (PAC-1 and anti-CD62). ResultsThe activated clotting time was 258±13 s with 1.2 U/ml unfractionated heparin alone, 396±8 s with unfractionated heparin+eptifibatide, and 348±9 s with 8 μg/ml bivalirudin. The binding of PAC-1 (reflecting the potential to aggregate) was decreased most effectively by bivalirudin (percentage of platelets binding PAC-1 in response to 15 U/ml thrombin − unfractionated heparin=54±7%, unfractionated heparin+eptifibatide=12±4%, bivalirudin=1±0.3% of platelets, P<0.05 for bivalirudin compared with unfractionated heparin or unfractionated heparin+eptifibatide and unfractionated heparin+eptifibatide compared with unfractionated heparin). Bivalirudin prevented thrombin-induced surface expression of P-selectin more effectively than unfractionated heparin alone or unfractionated heparin+eptifibatide (percentage of platelets expressing P-selectin in response to 15 U/ml thrombin – unfractionated heparin alone=74±5%, unfractionated heparin+eptifibatide=53±7%, bivalirudin=1±0.3%, P<0.05 for bivalirudin compared with unfractionated heparin or unfractionated heparin+eptifibatide). ConclusionComparison between pharmacologic concentrations shown to be therapeutic demonstrated that bivalirudin inhibited thrombin-induced activation of platelets to a greater extent than unfractionated heparin alone or in combination with eptifibatide.

Effect of exercise training and weight loss on platelet reactivity in overweight patients with coronary artery disease.

PURPOSE: Obesity is associated with increased platelet reactivity. Greater platelet reactivity presages adverse events in patients with coronary artery disease (CAD). We investigated whether exercise training and weight loss reduce platelet reactivity in overweight subjects with CAD. METHODS: Study subjects (N = 46) were enrolled in a prospective randomized study of exercise training and behavioral weight loss, which contrasted the amount of exercise performed (750 vs >3000 kcal/week). Platelet reactivity was assessed with the use of flow cytometry as the percentage of platelets expressing P-selectin or capable of binding fibrinogen in response to 1 &mgr;M adenosine diphosphate in blood before and after a 4-month program of exercise and behavioral weight loss. Markers of inflammation (high-sensitivity C-reactive protein), procoagulant activity (tissue plasminogen activator, plasminogen activator inhibitor 1), insulin sensitivity, body composition, physical activity, and fitness were also recorded. RESULTS: Platelet reactivity as assessed by P-selectin expression was decreased after exercise training and weight loss in study participants (from 34 ± 17% to 29 ± 17%; P = .01). The decrease was more pronounced in women (by 13% vs 2% in men; P < .01). The change in platelet reactivity was not independently associated with measures of body composition or fitness. After controlling for exercise group and gender, the change in platelet reactivity was associated with changes in high-sensitivity C-reactive protein (r = 0.46) and insulin sensitivity (r = 0.46). CONCLUSIONS: In overweight patients with CAD, exercise training and weight loss are associated with a decrease in platelet reactivity that may predict an improved prognosis.

Induction of platelet white blood cell (WBC) aggregate formation by platelets and WBCs in red blood cell units.

BACKGROUND: Transfusion of red blood cell (RBC) preparations is independently associated with adverse clinical outcomes in patients with acute cardiovascular disease. This study was designed to define mechanisms potentially contributing.

The effects of bivalirudin compared with those of unfractionated heparin plus eptifibatide on inflammation and thrombin generation and activity during coronary intervention.

ObjectiveTo characterize effects of bivalirudin compared with unfractionated heparin plus eptifibatide on inflammation, and thrombin generation and activity after percutaneous coronary intervention. MethodsWe measured the concentration in blood of fibrinopeptide A, prothrombin fragment 1+2, soluble CD40 ligand, interleukin 1 receptor antagonist, interleukin 6, and high sensitivity C-reactive protein in 63 patients treated with aspirin and clopidogrel and undergoing elective percutaneous coronary intervention, who were randomized to treatment with either bivalirudin (n=34) or unfractionated heparin plus eptifibatide (n=29). ResultsNeither generation nor activity of thrombin increased 10 min after percutaneous coronary intervention in patients randomized to bivalirudin or unfractionated heparin plus eptifibatide. However, prothrombin fragment 1+2 increased modestly and comparably in both groups after 1 day. Inflammation, reflected by concentrations of interleukin 6 and high sensitivity C-reactive protein in blood, increased similarly 1 day after percutaneous coronary intervention in patients treated with either regimen. In a subset of patients (n=12 in each group) from whom blood was obtained 30 days after percutaneous coronary intervention, the concentration of high sensitivity C-reactive protein was lower in those who had been treated with bivalirudin (by 3.5 mg/l, P=0.002). ConclusionThe early effects on inflammation and thrombin generation and activity are similar after treatment with bivalirudin alone compared with unfractionated heparin plus eptifibatide in patients treated with aspirin and clopidogrel who are undergoing percutaneous coronary intervention for symptoms of stable angina. The decreased concentration of high sensitivity C-reactive protein seen 30 days after percutaneous coronary intervention in those treated with bivalirudin is consistent with greater attenuation of inflammation that may have contributed to the trend toward reduced mortality 1 year later in those treated with bivalirudin in REPLACE-2.

Prozessentwicklung in der Herzinfarktversorgung

ZusammenfassungDie schnelle Wiedereröffnung des verschlossenen Herzkranzgefäßes ist beim akuten ST-Hebungsinfarkt (STEMI) ein wesentlicher Faktor für die Prognose des Patienten. Der Wettlauf mit der Zeit bis zur Wiedereröffnung kann aber nur gewonnen werden, wenn eine hierauf eingerichtete Basisstruktur geschaffen wird, die durch ein systematisches Qualitätsmanagement (QM) in allen Details und im Zusammenspiel begleitet und kontinuierlich optimiert wird.Zur notwendigen Basisstruktur gehört die Einrichtung eines Herzinfarktnetzes, das in einer bestimmten Region die Möglichkeit zur rund um die Uhr verfügbaren Akut-Koronarintervention schafft und auch die Krankenhäuser involviert, die selbst kein Herzkatheterlabor vor Ort zur Verfügung haben. Ein weiterer wichtiger struktureller Schritt ist die Ausrüstung des Rettungsdiensts mit Zwölf-Kanal-EKG-Systemen, die die EKG-Daten mittels Telemetrie an das Interventionszentrum übermitteln können. Dadurch können auf der Basis einer raschen und sicheren Diagnose des STEMI im Interventionszentrum und der Rückmeldung an den Rettungsdienst zwei wesentliche Ziele realisiert werden, die zu erheblichen Zeitgewinnen führen: 1. das organisierte „Bypassing der Nichtinterventionsklinik“ und 2. das systematische „Bypassing der Notaufnahme“ der Interventionsklinik.Ein effizientes Instrument zur Verbesserung des komplexen Prozessablaufs und zur Verkürzung der Zeitintervalle ist die Etablierung eines standardisierten QM-Systems. Dies beinhaltet die formalisierte Datenerfassung und -analyse sowie die systematische Ergebnisrückkopplung an alle in der Frühphase des STEMI an der Behandlung der Patienten beteiligten Personen und Systeme innerhalb des Herzinfarktnetzes. Eine wichtige Voraussetzung für den positiven Effekt einer solchen Rückkopplung auf die Ergebnisqualität ist, dass die vor Ort erfassten Daten von allen Beteiligten als nachvollziehbar und valide angesehen werden können. Daher sollten die Datendokumentation und -analyse überprüfbar gemacht werden.Bewertende Vergleiche unterschiedlicher Krankenhäuser, Rettungsdienste und Regionen zeigen sich als ausgesprochen problematisch. Hier spielen lokale Besonderheiten und auch der Einschluss oder Ausschluss von STEMI-Patienten mit hohem Mortalitätsrisiko, die unbedingt einer raschen interventionellen Behandlung zugeführt werden sollten, sowie die Gefahr eines missbräuchlichen Einsatzes aus reinen Wettbewerbsgründen eine Rolle. Vergleiche von Behandlungszeiten und Sterblichkeiten sollten daher möglichst ausschließlich innerhalb eines festen Systems vor Ort in einem „Vorher-Nachher-Ansatz“ vorgenommen werden. Des Weiteren ist eine Risikoadjustierung der Patienten unter Verwendung von einheitlichen Risikoscores zu fordern. In diesem Sinne definiert sich Qualität als dokumentiertes Bemühen um ständige Ergebnisverbesserung. Von grundsätzlicher Bedeutung ist dabei das Selbstverständnis der behandelnden Ärzte, Kliniken und Rettungsdienste als Team.Die Umsetzung der aufgezeigten Strukturen und Maßnahmen ist flächendeckend zu fordern, und die dafür nötigen Maßnahmen und Ressourcen müssen von der Politik und der Gesellschaft mitgetragen werden. Ein solcher Ansatz wird aktuell im multizentrischen FITT-STEMI-Projekt („Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction“) verfolgt.AbstractRapid revascularization of the infarct-related artery importantly affects prognosis in the treatment of acute ST elevation myocardial infarction (STEMI). Treatment results can be improved significantly when a STEMI-specific structure of care is created and when systematic quality improvement measures are implemented.The necessary structural measures include establishing or participating in myocardial infarction networks. When local hospitals collaborate in a network, it becomes feasible to offer round-the-clock primary coronary intervention to patients of those participating hospitals that do not have a catheterization laboratory on site.Another important structural step is to acquire and install prehospital twelve-lead ECG systems capable of remote telemetric transmission. This provides a solid basis for diagnosing STEMI with speed and accuracy and can prove to be highly effective in anchoring the chain of alert and treatment. As a consequence, two important goals can be realized: (1) intentionally bypassing the noninterventional hospital, and (2) systematically bypassing the emergency room of the interventional center. Both of these measures entail important time savings.An efficient instrument for improving treatment times is the implementation of a standardized quality improvement process with formalized data collection and analysis as well as with systematic data feedback to all systems and individuals involved in the early phase of treating STEMI patients within the hospital network including the emergency medical responder systems. The positive effect of such data feedback on treatment quality is contingent on the perception by all those involved that the data obtained for each patient are absolutely valid. Thus, those data need to be verifiable and an independent monitoring process should be created.Furthermore, the systematic use of standardized risk scores should be promoted in an effort to compare and adjust patient risk when analyzing network data. It is critically important that all appropriate patients – including those with a high risk of mortality – have access to rapid interventional treatment. Only when the individual risk of treated patients is taken into account will it be possible to compare quality of care and mortality rates. In general, the comparison between different hospitals, systems and regions is highly problematic and not feasible without considering local factors. It harbors the danger of inducing changes in practice in order to compete rather than in order to advance patient care, and thus it may be counterproductive when such a comparison leads to the implication that treatment may have been inferior. Therefore, the comparison of results (e.g., treatment times and mortality rates) should be undertaken as much as possible within an established system, with the use of a “before and after” design. Quality, then, will be defined as a documented consistent effort to improve results, and this approach will be distinctly productive. It is of fundamental importance that the involved hospitals, physicians and emergency staff perceive themselves as a team.The structures and processes outlined above can and should be applied broadly. The necessary resources will need to be provided through political and societal consensus. The multicenter FITT-STEMI project (“Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction”) is currently pursuing such an approach.

Increased ability of tirofiban to maintain its inhibitory effects on the binding of fibrinogen to platelets in blood from patients with and without diabetes mellitus

ObjectivesBoth tirofiban and eptifibatide release rapidly from glycoprotein IIb–IIIa but have different dissociation constants (KD of tirofiban=15 nmol/l, of eptifibatide=120 nmol/l). Binding of fibrinogen to glycoprotein IIb–IIIa is biphasic, forming an initial reversible complex (KD=155–180 nmol/l) and a second more stable complex (KD=20–70 nmol/l). Diabetes is known to alter platelet function. To determine the influence of affinity on inhibitory effects in blood from patients with (n=20) and without (n=20) diabetes mellitus, we characterized the extent of inhibition as a function of time. MethodsBlood was added to reaction tubes containing tirofiban 100 ng/ml or eptifibatide 1.7 μg/ml (concentrations previously defined to be optimal) plus a platelet agonist (1 μmol/l adenosine diphosphate or 25 μmol/l thrombin receptor agonist peptide), and fluorochrome-labeled fibrinogen before analysis by flow cytometry. ResultsThe extent of inhibition early on (30 s to 3 min) was similar (>85%) with either agent in blood from those with and without diabetes mellitus, whereas the extent of inhibition 10–15 min later was maintained more effectively with tirofiban than with eptifibatide (difference in slope P<0.01). After 15 min, the extent of inhibition in response to adenosine diphosphate in those with diabetes mellitus was 95±6% for tirofiban and 70±15% for eptifibatide (P<0.001); in those without diabetes mellitus, it was 91±9% for tirofiban and 73±19% for eptifibatide (P<0.001). ConclusionFor glycoprotein IIb–IIIa antagonists with a rapid rate of release, the biphasic binding of fibrinogen influences to a similar extent their ability to maintain inhibitory effects in blood from patients with and without diabetes mellitus.