Konstantinos Theodoropoulos

Randomized Assessment of Ticagrelor Versus Prasugrel Antiplatelet Effects in Patients with ST-Segment–Elevation Myocardial Infarction

Background—Ticagrelor and prasugrel provide stronger platelet inhibition compared with clopidogrel. Direct pharmacodynamic comparison between them has not yet been reported in ST-segment–elevation myocardial infarction patients. Methods and Results—In a prospective, single-center, single-blind study, 55 out of 117 (47%) screened consecutive ST-segment–elevation myocardial infarction patients undergoing primary percutaneous coronary intervention were randomized to either ticagrelor 180 mg loading followed by 90 mg bid, or prasugrel 60 mg loading followed by 10 mg od for 5 days. Platelet reactivity (PR) was assessed with the VerifyNow P2Y12 function assay and the Multiplate Analyzer at 0, 1, 2, 6, 24 hours, and 5 days postrandomization. The primary end point, PR with VerifyNow at hour 1, did not differ significantly between patients randomized to ticagrelor versus prasugrel (257.3 P2Y12 reaction unit [PRU], 95% CI 230.8–283.8 versus 231.3 PRU, 95% CI 205.3–257.4; P=0.2). PR did not differ at 2, 6, and 24 hours, although at day 5 it was lower with ticagrelor than prasugrel (25.6 PRU, 95% CI 12.3–38.9 versus 50.3 PRU, 95% CI 36.4–64.1; P=0.01). At hour 2, high on-treatment PR rates (cutoff 208 PRU) were 46.2% and 34.6% for ticagrelor and prasugrel, respectively, decreased significantly thereafter, whereas did not differ significantly between the 2 agents at all the time points of the study. Conclusions—In patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, both ticagrelor and prasugrel exhibit an initial delay in the onset of their antiplatelet action. Ticagrelor did not appear superior to prasugrel in reducing PR during the first 24 hours of ST-segment–elevation myocardial infarction. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01463163.

Ticagrelor Versus Prasugrel in Acute Coronary Syndrome Patients With High On-Clopidogrel Platelet Reactivity Following Percutaneous Coronary Intervention: A Pharmacodynamic Study

OBJECTIVES The study aimed to compare the antiplatelet action of ticagrelor with prasugrel in acute coronary syndrome (ACS) patients with high on-treatment platelet reactivity (HTPR) while on clopidogrel after percutaneous coronary intervention (PCI). BACKGROUND Newer P2Y12 inhibitors like prasugrel and ticagrelor provide stronger platelet inhibition compared with clopidogrel. Both agents are efficacious in patients with HTPR while on clopidogrel, but direct comparison between them has not yet been reported. METHODS In a prospective, single-center, single-blind study, 44 (of 139 screened, 31.7%) ACS patients with HTPR while on clopidogrel 24 h post-PCI were randomized to either ticagrelor 90 mg twice daily or prasugrel 10 mg once daily for 15 days with a crossover directly to the alternate treatment for another 15 days. HTPR was defined as platelet reactivity units (PRU) ≥ 235 as assessed by the VerifyNow P2Y12 function assay. RESULTS The primary endpoint of platelet reactivity at the end of the 2 treatment periods was lower for ticagrelor (32.9 PRU, 95% confidence interval [CI]: 18.7 to 47.2) compared with prasugrel (101.3 PRU, 95% CI: 86.8 to 115.7) with a least squares mean difference of -68.3 PRU (95% CI: -88.6 to -48.1; p < 0.001). The secondary endpoint of HTPR rate was 0% for ticagrelor and 2.4% for prasugrel (1 of 42, p = 0.5). No patient exhibited a major bleeding event at either treatment group. CONCLUSIONS In patients with ACS exhibiting HTPR while on clopidogrel 24 h post-PCI, ticagrelor produces a significantly higher platelet inhibition compared with prasugrel. (Ticagrelor Versus Prasugrel in Acute Coronary Syndromes After Percutaneous Coronary Intervention; NCT01360437).

Evaluation of Radiation-Based Reference Evapotranspiration Models Under Different Mediterranean Climates in Central Greece

Eighteen radiation-based equations used to estimate reference evapotranspiration (ETref) were generalized into seven linear models. The general models were calibrated using the standard FAO-56 Penman-Monteith method. Model performance was evaluated under humid, sub-humid and semi-arid mediterranean climatic conditions in central Greece. Evaluation and comparison of the models was based on quantitative assessment of their ability to accurately estimate ETref values, generated by the FAO-56 Penman-Monteith equation. All models provided relatively accurate estimates of ETref. The Abtew model showed the best overall performance with respect to the data from all available climate stations of central Greece. The average error of the Abtew model in the monthly average daily ETref estimates was 0.24 mm, which corresponds to a relative error of 7.7 %. The Abtew method has not yet been tested under mediterranean climatic conditions. Based on our results, it seems to be a good choice for the estimation of monthly average daily ETref under different conditions in the mediterranean climate. An exception appears to be the mediterranean climate with relatively high humidity and low wind speed. Under these conditions the models of the Priestley-Taylor group, the Makkink group and the Jensen-Haise group performed better than the Abtew equation.

A successfully thrombolysed acute inferior myocardial infarction due to type A aortic dissection with lethal consequences: the importance of early cardiac echocardiography

Thrombolysis, a standard therapy for ST elevation myocardial infarction (STEMI) in non-PCI-capable hospitals, may be catastrophic for patients with aortic dissection leading to further expansion, rupture and uncontrolled bleeding. Stanford type A aortic dissection, rarely may mimic myocardial infarction. We report a case of a patient with an inferior STEMI thrombolysed with tenecteplase and followed by clinical and electrocardiographic evidence of successful reperfusion, which was found later to be a lethal acute aortic dissection. Prognostic implications of early diagnosis applying transthoracic echocardiography (TTE) are described.

Diagnostic accuracy of electrocardiographic ST-segment depression in patients with rapid atrial fibrillation for the prediction of coronary artery disease.

BACKGROUND We aimed to examine the diagnostic value of ST-segment depression in patients with rapid atrial fibrillation (AF) for the prediction of coronary artery disease (CAD). METHODS Hemodynamically stable patients with AF, and a heart rate > 80% of their maximum predicted according to their age, were allocated to 2 groups according to their electrocardiographic findings on admission: group A included patients without any ST-segment abnormalities and group B, patients with downward or horizontal ST-segment depression ≥ 1 mm in 2 or more contiguous leads. Group A patients were subjected to a dobutamine stress echo or Tl-201 myocardial single-photon emission computed tomography, followed by coronary angiography in case of abnormal results and Group B patients to coronary angiography. CAD was defined angiographically as stenosis of ≥ 50% in any major epicardial coronary vessel. RESULTS Out of 115 consecutive patients, with a mean age of 65.9 ± 10.2 years, 42.6% were male, 18.3% smokers, 68.7% hypertensive, 21.7% had diabetes, and 40% had hyperlipidemia. We enrolled 71 and 44 patients in group A and B, respectively. Prevalence of significant CAD among studied patients was 21.7%, 3/71 (4.2%) and 22/44 (50.0%) in group A and B, respectively. Overall ST-segment depression during rapid AF had 88.0% sensitivity (95% confidence interval [CI], 67.7%-96.8%) and 75.6% specificity (95% CI, 65.2%-83.7%) in predicting presence of CAD, and positive and negative predictive value was 50.0% (95% CI, 34.8%-65.2%) and 95.8% (95% CI, 87.3%-98.7%), respectively. CONCLUSIONS In consecutive patients with rapid AF, the absence of ST-segment depression might indicate absence of CAD.

Pharmacodynamic effect of prasugrel 5 mg vs clopidogrel 150 mg in elderly patients with high on-clopidogrel platelet reactivity.

BACKGROUND Elderly patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) frequently exhibit high platelet reactivity (HPR) while on clopidogrel. In the elderly cohort, either prasugrel is not recommended or, if used, halving of the dose has been suggested. We aimed to test the hypothesis that in elderly patients exhibiting HPR after standard treatment with clopidogrel, prasugrel-reduced dose (5 mg) could be more effective than high-dose (150 mg) clopidogrel. METHODS Consecutive elderly (≥75 years old) patients with ACS undergoing PCI and loaded with clopidogrel were considered for platelet reactivity (PR) assessment at 24 hours after PCI with the VerifyNow assay (Accumetrics Inc, San Diego, CA), measured in P2Y12 reaction units (PRU). Of 63 screened patients, 30 (47.6%) were found with HPR (defined as PRU ≥230) and 27 of them participated in a prospective, randomized, single-center, single-blind, investigator-initiated, crossover study of platelet inhibition by prasugrel 5 mg/d vs clopidogrel 150 mg/d, with a 15-day treatment period. RESULTS The primary end point of PR at the end of the 2 study periods was lower in patients receiving low-dose prasugrel than those receiving high-dose clopidogrel (least squares estimates 190.8 [95% CI 161.5-220.1] and 240.8 [95% CI 211.0-270.6], respectively; P = .008). The secondary end point of HPR rate at the end of treatment periods was lower for prasugrel (8/24; 33.3%) compared with clopidogrel (16/24; 66.7%), P = .02. CONCLUSIONS In elderly patients with ACS undergoing PCI and exhibiting HPR after standard clopidogrel treatment, prasugrel 5 mg/d is significantly more efficacious than clopidogrel 150 mg/d in reducing PR and HPR rate.

Estimation of Reference Potential Evapotranspiration with Focus on Vegetation Science—the EmPEst Software

Owing to the difficulties in measuring daily reference potential evapotranspiration, its estimation by means of the ASCE Penman-Monteith approach and various other empirical equations that are less demanding in terms of input data is favoured for various applications in vegetation science and climatology. This study presents the development of a Visual Basic software that can be used for the estimation of the daily PETref by means of the standardized ASCE Penman-Monteith equation for both short (clipped grass) and tall (full-cover alfalfa) crops and thirteen additional empirical equations. Statistical measures of goodness of fit are also calculated to make it easier for users to compare and detect the empirical equations that have the minimum bias of estimation against the ASCE Penman-Monteith equation.

Intrinsic platelet reactivity and thrombus burden in patients with ST-elevation myocardial infarction

INTRODUCTION In patients with ST elevation myocardial infarction (STEMI) increased platelet reactivity has been described to affect the primary percutanuous coronary intervention (PPCI) outcome. We aimed to evaluate the predictive accuracy of intrinsic platelet reactivity for intracoronary thrombus burden in P2Y12 inhibitor- naïve STEMI patients. PATIENTS AND METHODS In a prospective, observational, cohort study we enrolled 94 consecutive STEMI patients undergoing PPCI, subjected to platelet reactivity assessment prior to any P2Y12 blockade, with visible angiographic thrombus in the infarct related artery (stratified as Grade A, B and C). Platelet-function testing was performed with the VerifyNow point-of-care P2Y12 assay immediately prior to intervention. RESULTS Intrinsic platelet reactivity was higher with greater thrombus burden: Grade A 158.8±51.1 PRU, Grade B 217.4±62.1 PRU and Grade C 243.4±58.6 PRU, p=0.009 and Spearman r=0.32 (0.12-0.49 95% CI), p=0.002. ROC analysis revealed an AUC=0.7 (Standard error 0.07, p=0.03). An intrinsic platelet reactivity value of >220 PRU had 65% sensitivity (53-76 95%CI), 76% specificity (55-91 95%CI), 88% positive predictive value (76-96 95%CI) and 44% negative predictive value (29-60 95%CI) for detection of high thrombus burden. In multivariate analysis intrinsic platelet reactivity >220 PRU emerged as an independent predictor of high thrombus burden (RR=1.5, 1.15-2.07 95% CI, p=0.004). CONCLUSIONS In patients admitted with STEMI the intrinsic platelet reactivity -as assessed by a point-of-care assay- is positively associated with the degree of intracoronary thrombus, while having a moderate accuracy in predicting high thrombus burden.

Evolving pattern of on-prasugrel and on-ticagrelor platelet reactivity over time in ST elevation myocardial infarction patients

On-clopidogrel treatment platelet reactivity (PR) presents considerable variability over time. In stable coronary artery disease (CAD) and in acute coronary syndrome (ACS) patients the baseline just before PCI or the next day PR decreases when reassessed at 1–3 months later [1–3]. This has been at least partially attributed to the acuity of the disease and platelet activation inducedby PCI itself [1,4]. In the settingof STelevation myocardial infarction (STEMI) and post 600 mg of clopidogrel loading, PR is higher at 2–4 h compared to 24 h – probably as a reflection of a delayed onset of action – and stabilizing thereafter at Day 3–5 [5,6]. The newer,more potent P2Y12 inhibitors, prasugrel and ticagrelor, provide a faster, stronger andmore consistent platelet inhibition than clopidogrel. However, the PR evolution over time in patients while on-prasugrel or on-ticagrelor is not clear. PR stability was reported in prasugrel treated stable CAD patients between 3 and 6 months post PCI [3], while a high on-prasugrel PR persisted in only a minority of patients at a second assessment [7]. Following ticagrelor loading PR levels achieved at 24 h were similar to those at 6 weeks [8]. In STEMI patients following either ticagrelor or prasugrel loading we described a strong platelet inhibition as early as within 6 h, with PR remaining very low till Day 5 [9]. In the present study we aimed to identify the variability between PR assessed in the acute phase of STEMI and while on chronic (N3 months) treatment with prasugrel or ticagrelor. All patients participating in a randomized, pharmacodynamic comparison of ticagrelor vs prasugrel in the acute phase of STEMI were invited to have PR assessment while under chronic treatment with either agent. Details of the randomized study have beenpreviously reported [9]. Briefly, consecutive STEMI patients undergoing primary PCI with stent implantation were randomized to either ticagrelor 180 mg loading/90 mg twicedailymaintenancedoseorprasugrel 60 mg loading/ 10 mg once daily maintenance dose. Patients with contraindications to either agent were excluded. PR assessment was performed at randomization (Hour 0) and at Hours 1, 2, 6, 24, and on Day 5. Patients were invited for follow up PR assessment while receiving either ticagrelor 90 mg twice daily or prasugrel 10 mg once daily for N3 months, which was performed2–4 hpost last drug dose. Blood samplingwas performed as previously described [10]. Platelet-function testing was assessed with the VerifyNow (Accumetrics Inc., San Diego, CA, USA) point-of-care P2Y12 function assay with the results reported in P2Y12 reaction unit (PRU). PR values at Hour 24 PR (acute phase) and at follow-up (chronic phase) were compared with the Wilcoxon signed ranks test. Data are expressed as medians (interquartile range). Informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institutions human research committee. At follow-up, out of 51 patients discharged from the hospital, 1 died, 1 developed intracranial tumor and had prasugrel stopped and 3 had switched to clopidogrel for cost purposes. The remaining 46 patients had PR assessment at a median time of 7.5 (6–9)months post STEMI, while on chronic ticagrelor (n=25) or prasugrel (n=21) treatment. In prasugrel treated patients, PR was 23 (6.5–51) PRU in the acute phase increasing to 85 (34–119) PRU in the chronic phase, p=0.001. In ticagrelor treated patients, PRwas 31 (15–65.5) PRU and 25 (17.5–45.5) PRU in the acute and the chronic phase respectively, p=0.4. Individual PR values are shown in Fig. 1. In STEMI patients treatedwith either prasugrel or ticagrelor we have described a PR pattern evolving over time, different thanwhat has been described for clopidogrel treated patients [1,2]. Despite the acuity of the disease, high thrombotic milieu, and inflammation and PCI itself, prasugrel and ticagrelor treated patients exhibited very low PR values from the early phase of STEMI with ‘no space’ for further reduction during chronic treatment. For prasugrel, the very low PR levels of the acute phase increased during chronic treatment probably reflecting the high loading dose relative to maintenance dose effect. Of note, in stable CAD patients receiving prasugrel, the 3-month PR was 80 (42 to 124) PRU, very similar to our STEMI population [3]. For ticagrelor, the very low PR levels of the acute phase presented remarkable consistency over time. Similar consistency was observed in stable CAD patients with up to 6 weeks ticagrelor treatment [8]. In contrast to what is commonly observed in clopidogrel treated patients, none of our patients changed his ‘response status’ [1,2]. The strong and consistent platelet inhibition achieved with ticagrelor and – to a lesser degree – with prasugrel appears to mask the dynamic nature of PR. Therefore, the latter and the effect of the timing of measurement on PR level and its associationwith adverse outcomes, may not apply for prasugrel and ticagrelor. Finally, the strong platelet inhibition achieved by both agents may question the predictive value of PR thresholds for ischemia/bleeding extracted from clopidogrel treated patients. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.

Allergic reaction reveals a non-lethal late stent thrombosis. A new subtype of Kounis syndrome?

Kounis syndrome is defined as the coexistence of acute coronary syndromes (ACS) with situations associated with allergic or hypersensitivity as well as anaphylactic or anaphylactoid insults to a variety of medical conditions, environmental andmedication exposures. Activation of mast cells releasing a variety of cytokines and chemokines and inflammatory mediators such as histamine, neutral proteases, arachidonic acid products and platelet activating factor has been implicated [1,2]. Initially two subtypes had been described: concerning normal or nearly normal vessels (Type I) and severe diseased atheromatic vessels (Type II). Recently a third typeof this syndromehasbeen suggested and is associated with drug-eluded stent (DES) thrombosis [3]. In this case presentation,wedescribe a new “subtype” of this relatively novel, but not infrequent in clinical practice, syndromewhichcombines allergy reaction, ACS and late thrombosis of a DES. A 51-year old male with a history of ischemic heart disease was admitted on December 2010 to our emergency room (ER) with nausea, vertigo and generalized pruritus. His complaints had started after ingesting an oral dose of 500 mg Cefaclor for pharyngitis. On physical examination he had dyspnea with tremor and erythematous rash covering his entire body. He was treated in the ambulance with i.v. 125 mgMethylprednisolone and subsequently in the ERwith i.v. 250 mg Hydrocortisone, 50 mg Ranitidine and i.m. 0.5 ml Adrenaline (1:1000 dilution). His ECG had Q waves at the inferior leads (Fig. 1A) and the troponin-I test was normal (b0.05 ng/ml with reference values: 0.4 ng/