Patrick Henry

Prasugrel compared with high-dose clopidogrel in acute coronary syndrome. The randomised, double-blind ACAPULCO study.

Compared with the approved dose regimen of clopidogrel (300-mg loading dose [LD], 75-mg maintenance dose [MD]), prasugrel has been demonstrated to reduce ischaemic events in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). In ACS, antiplatelet effects of a prasugrel MD regimen have not been previously compared with either a higher clopidogrel MD or after switching from a higher clopidogrel LD. The objective of this study was to evaluate the antiplatelet effect of a prasugrel 10-mg MD versus a clopidogrel 150-mg MD in patients with ACS who had received a clopidogrel 900-mg LD. Patients with non-ST elevation ACS, treated with aspirin and a clopidogrel 900-mg LD, were randomised within 24 hours post-LD to receive a prasugrel 10-mg or clopidogrel 150-mg MD. After 14 days of the initial MD, subjects switched to the alternative treatment for 14 days. The primary endpoint compared maximum platelet aggregation (MPA, 20 microM adenosine diphosphate [ADP]) between prasugrel and clopidogrel MDs for both periods. Responder analyses between treatments were performed using several platelet-function methods. Of 56 randomised subjects, 37 underwent PCI. MPA was 26.2% for prasugrel 10 mg and 39.1% for clopidogrel 150 mg (p<0.001). The prasugrel MD regimen reduced MPA from the post-900-mg LD level (41.2% to 29.1%, p=0.003). Poor response ranged from 0% to 6% for prasugrel 10 mg and 4% to 34% for clopidogrel 150 mg. Thus, in ACS patients a prasugrel 10-mg MD regimen resulted in significantly greater platelet inhibition than clopidogrel at twice its approved MD or a 900-mg LD.

24-hour time-dependent aspirin efficacy in patients with stable coronary artery disease

Aspirin-induced cyclooxygenase (COX)-1 acetylation is irreversible and it is assumed that the platelet thromboxane-A2 aggregation pathway is inhibited for at least 24 hours (h) after aspirin ingestion. However, time course of biological efficacy of daily low-dose aspirin has rarely been assessed in patients with coronary artery disease (CAD). We aimed to assess the 24-h biological efficacy of daily low-dose aspirin in CAD patients. The peak and trough (2 h-24 h) effect of a chronic treatment with once daily dose aspirin were studied in 150 consecutive stable CAD patients. The main outcome measure was light transmission aggregometry (LTA) triggered with 0.5 mg/ml arachidonic acid (AA). In the last 47 consecutive patients, additional tests were conducted at 6, 12, 16, 20 h after last aspirin administration. 4.7% of the patients had significant aggregation (>20% maximal intensity LTA-AA) 2 h after aspirin ingestion and 24.7% at 24 h (p<0.0001). The more precise assessments in the last 47 patients showed that significant platelet aggregation progressively reappeared with time after aspirin intake (2 h--4% of patients, 6 h-- 4%, 12 h--11%, 16 h--16%, 20 h--19% and 24 h--28%). Concordant results were observed using production of thromboxane-B2 and other techniques evaluating AA-induced platelet aggregation/activation. No significant differences were found between lower (75-100 mg/day) and higher (>100 mg/day) dose aspirin. Such aspirin «resistance» at 24 h after ingestion was related to biological inflammatory markers, current smoking and diabetes. In conclusion, once daily aspirin does not provide stable 24-h antiplatelet protection in a significant proportion of CAD patients. Any biological assessment of aspirin efficacy should take time since last aspirin intake into consideration.

High incidence of myocardial ischemia during postpartum hemorrhage

BACKGROUND: Postpartum hemorrhage remains a major cause of global maternal morbidity and mortality, even in developed countries, despite the use of intensive care units. This study sought to (1) assess whether myocardial ischemia could be associated with and even aggravate hemorrhagic shock in young parturients admitted for postpartum hemorrhage, and (2) identify the independent risk factors for myocardial ischemia. METHODS: On their referral to the intensive care unit, a multidisciplinary team managed parturients with severe postpartum hemorrhage. Ventilation, transfusion, catecholamines, surgery, or angiography with uterine embolization were provided as clinically indicated. Plasma cardiac troponin I levels were used as a surrogate marker of acute myocardial injury and electrocardiograms of myocardial ischemia. RESULTS: A total of 55 parturients were referred with severe postpartum hemorrhage, all in hemorrhagic shock. Twenty-eight parturients (51%) had elevated serum levels of cardiac troponin I (9.4 microg/l [3.7-26.6 microg/l]), which were associated with electrocardiographic signs of ischemia and deteriorated myocardial contractility and correlated with the severity of hemorrhagic shock. Indeed, multivariate analysis identified low systolic and diastolic arterial blood pressure ( 115 beats/min) as independent predictors of myocardial injury. In addition, all patients who were given catecholamines also had elevated cardiac troponin I levels. CONCLUSIONS: These results suggest that treatment of postpartum hemorrhage-induced hemorrhagic shock should be coupled with concomitant prevention of myocardial ischemia, even in young parturients.

Value of post-resuscitation electrocardiogram in the diagnosis of acute myocardial infarction in out-of-hospital cardiac arrest patients

BACKGROUNDnDiagnosis of acute myocardial infarction (AMI) in out-of-hospital cardiac arrest (OHCA) patients is important because immediate coronary angiography with coronary angioplasty could improve outcome in this setting. However, the value of acute post-resuscitation electrocardiographic (ECG) data for the detection of AMI is debatable.nnnMETHODSnWe assessed the diagnostic characteristics of post-resuscitation ECG changes in a retrospective single centre study evaluating several ECG criteria of selection of patients undergoing AMI, in order to improve sensitivity, even at the expense of specificity. Immediate post resuscitation coronary angiogram was performed in all patients. AMI was defined angiographically using coronary flow and plaque morphology criteria.nnnRESULTSnWe included 165 consecutive patients aged 56 (IQR 48-67) with sustained return of spontaneous circulation after OHCA between 2002 and 2008. 84 patients had shockable, 73 non-shockable and 8 unknown initial rhythm; 36% of the patients had an AMI. ST-segment elevation predicted AMI with 88% sensitivity and 84% specificity. The criterion including ST-segment elevation and/or depression had 95% sensitivity and 62% specificity. The combined criterion including ST-segment elevation and/or depression, and/or non-specific wide QRS complex and/or left bundle branch block provided a sensitivity and negative predictive value of 100%, a specificity of 46% and a positive predictive value of 52%.nnnCONCLUSIONnIn patients with OHCA without obvious non-cardiac causes, selection for coronary angiogram based on the combined criterion would detect all AMI and avoid the performance of the procedure in 30% of the patients, in whom coronary angiogram did not have a therapeutic role.

Biological efficacy of twice daily aspirin in type 2 diabetic patients with coronary artery disease

BACKGROUNDnDiabetes is associated with a high rate of events after acute coronary syndrome and percutaneous coronary intervention despite aspirin treatment. Once daily aspirin might not provide 24-hour stable biological efficacy in patients with diabetes. We compared the biological efficacy of the same daily dose of aspirin given either once (OPD) or divided twice per day in a population of diabetic patients with previous coronary artery disease.nnnMETHODSnNinety-two consecutive diabetic patients with at least 1 criteria of time-dependent aspirin efficacy, elevated high-sensibility C-reactive protein (hs-CRP), fibrinogen, platelet count, or active smoking were prospectively included. Consecutive patients were randomly treated with 150-mg aspirin daily given either OPD (150 mg in the morning) or twice per day (75 mg in the morning and 75 mg in the evening) in a crossover study. The main outcome was platelet reactivity to arachidonic acid (0.5 mg/mL) measured by light transmission aggregometry at trough level before morning aspirin intake.nnnRESULTSnMean maximum aggregation intensity triggered by arachidonic acid was 19.7% ± 15.4% on OPD and 11.9% ± 10.4% on twice per day (P < .0001). Biological resistance (maximum aggregation intensity ≥20%) was observed in 42% of patients on OPD and 17% on twice per day (P < .001). Of the 39 patients with biological resistance on OPD, 24 (62%) overcame resistance on twice per day. Of the 16 resistant on twice per day, only 1 patient (6%) overcame resistance on OPD. Results were concordant with global evaluation of platelet reactivity by Platelet Function Analyzer-100. A better twice per day efficacy was independent of clopidogrel cotreatment.nnnCONCLUSIONnIn a population of diabetic patients with coronary artery disease and a high risk of time-dependent aspirin resistance, aspirin divided twice per day can significantly decrease the rate of biological loss of efficacy at trough level.

Structure and pharmacology of swelling‐sensitive chloride channels, ICl,swell

Since several years, the interest for chloride channels and more particularly for the enigmatic swelling‐activated chloride channel (ICl,swell) is increasing. Despite its well‐characterized electrophysiological properties, the ICl,swell structure and pharmacology are not totally elucidated. These channels are involved in a variety of cell functions, such as cardiac rhythm, cell proliferation and differentiation, cell volume regulation and cell death through apoptosis. This review will consider different aspects regarding structure, electrophysiological properties, pharmacology, modulation and functions of these swelling‐activated chloride channels.

Increased incidence of moderate stenosis among patients with diabetes: substrate for myocardial infarction?

Persons with diabetes are at higher risk for myocardial infarction and sudden death than are persons without diabetes. It has been demonstrated that the artery that occludes during acute myocardial infarction generally had less than 75% stenosis on a previous angiogram. The extent of coronary artery stenosis was analyzed for 820 consecutively examined patients who underwent coronary angiography at our institution. The patients were categorized according to the presence or absence of diabetes mellitus. The severity of stenosis was taken into consideration. Patients with diabetes had moderate (50% to 75% narrowing) stenosis much more frequently than patients without diabetes (50.6 versus 30.3%, p < 0.001). Moreover diabetes mellitus was an independent risk factor for moderate stenosis. The lesions were more frequently located on distal arteries, more frequently had a pattern of three-vessel disease, and had a trend toward more diffuse disease than described 25 years ago. This greater amount of moderate stenosis may be considered a substrate for future acute plaque rupture. It may explain the high prevalence of acute myocardial infarction and sudden death among patients with diabetes without an increase in the incidence of angina pectoris.

The volume-sensitive chloride channel inhibitors prevent both contractile dysfunction and apoptosis induced by doxorubicin through PI3kinase, Akt and Erk 1/2.

Contractile dysfunction and cardiomyopathies secondary to apoptotic cell death are limiting factors for treating cancer with doxorubicin. Inhibition of volume‐sensitive chloride currents (ICl,vol) has been reported to blunt doxorubicin‐induced apoptosis in cardiomyocytes. To investigate cellular contractility during acute induction of apoptosis by doxorubicin and to determine whether ICl,vol inhibitors are able to prevent the subsequent contractile dysfunction, electrically paced ventricular myocytes freshly isolated from adult rabbits were acutely exposed to doxorubicin in the presence and absence of ICl,vol inhibitors IAA‐94 or DIDS. Doxorubicin induced increases in both annexin V labelling and caspase‐3 activity and decreases in cell volume. Alteration in cardiac contractility was observed after doxorubicin exposure. Both IAA‐94 and DIDS abolished the doxorubicin‐induced decreases in peak shortening and cell volume as well as the increases in caspase‐3 activity and annexin V labelling. These protective effects of ICl,vol inhibitors were abolished by previous inhibition of PI3kinase, Akt and Erk 1/2. Thus, ICl,vol inhibitors prevent doxorubicin‐induced apoptosis and subsequent contractile dysfunction through PI3kinase/Akt and Erk 1/2. Inhibition of ICl,vol may represent a new pharmacological strategy for developing cytoprotective drugs against apoptotic cell death and contractile dysfunction.

Volume-sensitive chloride channels (ICl, vol) mediate doxorubicin-induced apoptosis through apoptotic volume decrease in cardiomyocytes

Apoptosis is associated with early changes in cell volume through a mechanism called apoptotic volume decrease (AVD). As volume‐sensitive chloride channels (ICl,vol) are known to play a key role in the regulation of cell volume, this study investigated the role of ICl,vol and AVD in doxorubicin‐induced apoptotic cell death in adult rabbit ventricular cardiomyocytes. Exposure of cardiomyocytes to 1u2003μm doxorubicin induced a rapid and significant reduction in cell volume of cardiomyocytes (average of 15%), i.e. AVD as well as increases in the early markers of apoptosis, annexin V labeling and caspase‐3 activity. Doxorubicin also induced the activation of a current characterized as ICl,vol on the basis of the external chloride sensitivity and pharmacological properties with the patch clamp technique. Doxorubicin‐induced AVD and apoptosis were both abolished when cardiomyocytes were exposed to the ICl,vol inhibitors 5‐nitro‐2‐(3‐phenylpropylamino) benzoic acid (NPPB) (0.1u2003mm) or indanyloxyacetic acid 94 (IAA‐94) (10u2003μm). The crucial role of ICl,vol during AVD and apoptosis was confirmed using C2‐ceramide, another pro‐apoptotic compound. These results demonstrate that activation of ICl,vol plays a major role in the mechanism leading to cell shrinkage and apoptosis‐induced AVD by agents such as doxorubicin or C2‐ceramide in adult cardiomyocytes.

Role of cardiac troponin in the diagnosis of acute myocardial infarction in comatose patients resuscitated from out-of-hospital cardiac arrest.

BACKGROUNDnTroponin is a major diagnostic criterion of acute myocardial infarction (AMI) but in out-of-hospital cardiac arrest (OHCA) patients, its diagnostic value may be altered by cardiopulmonary resuscitation.nnnMETHODSnSingle-centre study assessing the diagnostic characteristics of troponin for AMI diagnosis in consecutive patients resuscitated from OHCA between 2002 and 2008 with coronary angiogram (CA) performed on admission. Patients with obvious non-cardiac cause of OHCA, unsustained or absent return of spontaneous circulation were excluded. AMI was defined on CA by the presence of acute occlusion or critical stenosis with intracoronary fresh thrombus easily crossed by an angioplasty wire. Troponin concentration was recorded once on admission and once 6-12h after the OHCA.nnnRESULTSnA total of 163 patients aged 56 (median) years (interquartile range (IQR) 48-65) was included, all comatose. Most prevalent initial OHCA rhythms were ventricular fibrillation (49%) and asystole (41%). AMI was diagnosed on coronary angiogram in 37% of the patients. Median troponin concentration on admission was 1.7 (0.3-10)ngml(-1) and sensitivity for AMI diagnosis was 72% and specificity 75% for a 2.5ngml(-1) cut-off. A combined criterion comprising ST elevation and troponin >2.5ngml(-1) had a sensitivity of 93% and specificity of 64%. Six to twelve hours after the OHCA, median troponin concentration was 7.6ngml(-1) (1.4-47.5), sensitivity was 84% and specificity 84% for a 14.5ngml(-1) cut-off.nnnCONCLUSIONnTroponin I has a good diagnostic value for AMI diagnosis in OHCA patients. In combination with ST elevation, troponin I on admission achieves a very high sensitivity.