Despite emphasis on the use of invasive management strategies for patients with non–ST-elevation acute coronary syndromes (NSTE ACS) in recent practice guidelines, 27% to 56% of NSTE ACS patients do ...not undergo diagnostic angiography, and a further 45% to 78% do not undergo revascularization procedures during the initial hospitalization. These medically managed patients (also termed noninvasive management) have a greater frequency of medical comorbidities and high-risk clinical characteristics and are less likely to receive guideline-recommended medications, compared with patients who undergo revascularization procedures. The rates of short and long-term adverse outcomes are also substantially higher in medically managed NSTE ACS patients, but more widespread implementation of contemporary medical therapies in this population is limited by exclusion of medically managed patients from many randomized clinical trials.
Drug-induced cardiac toxicity is a recognized challenge in development and implementation of pharmacotherapy. Appropriate biomarkers are needed to detect these abnormalities early in development and ...to manage the risk of potentially cardiotoxic drugs or biologic agents. Circulating cardiac troponin (cTn) is the most widely used biomarker for detection of myocardial injury. Although most commonly used to detect myonecrosis in the setting of ischemia, cTns are also elevated with other acute and chronic disease processes, including heart failure, renal failure, sepsis, pulmonary embolic disease, and many others. High-sensitivity assays for both cTnI and cTnT are now available that achieve acceptable imprecision (coefficient of variation <10%) at the 99th percentile of a normal reference population. Even more sensitive assays are being developed that detect cTn in ranges that are near the level of normal cellular turnover (apoptosis). These properties of cTn and the continuing evolution of highly sensitive assays position cTn as a potentially uniquely informative marker for early detection of cardiac toxicity. This article summarizes collaborative discussions among key stakeholders in the Cardiac Safety Research Consortium about the use of cTn monitoring in drug development.
In a population of patients experiencing thrombocytopenia while treated with heparin, bleeding and thromboses are well-appreciated complications, but their relative contributions to mortality have ...been less well described. In this population, the aims of this study were (1) to identify the independent predictors of bleeding and (2) to compare the incidence and the strength of association of bleeding and of new thromboses to in-hospital mortality. The independent predictors of bleeding and in-hospital mortality were identified using multivariate logistic regression models on the 1,478 patients who developed thrombocytopenia after their enrollment in the Complications After Thrombocytopenia Caused by Heparin (CATCH) study. The independent predictors of bleeding were chronic hematologic disorders, intra-aortic balloon pump, congestive heart failure, and platelet count nadir <120 × 109 /L. Although bleeding (n = 141 10%) and thromboembolic complications (n = 135 9%) were equally prevalent, the former was less strongly associated than the latter with in-hospital mortality (odds ratio 1.75, 95% confidence interval 1.01 to 3.03, and odds ratio 2.77, 95% confidence interval 1.67 to 4.61, respectively). In conclusion, medical management should be directed mainly at the prevention of thromboembolic complications, while additionally considering the risk for bleeding.
Objectives The PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy aimed to compare the antiplatelet effects of clopidogrel and ticagrelor in patients with acute coronary syndromes. ...Background The PLATO study demonstrated superiority of ticagrelor over clopidogrel in the prevention of ischemic events in patients with acute coronary syndromes. Methods Patients were randomized to receive either clopidogrel (300- to 600-mg loading dose LD, 75 mg/day) or ticagrelor (180-mg LD, 90 mg twice daily). The effects of maintenance therapy were studied in 69 patients pre- and 2 to 4 h post-dose after at least 28 days. The LD effect was studied in 24 clopidogrel-naive patients. Light transmittance aggregometry (adenosine diphosphate 5 to 20 μM), VerifyNow P2Y12, and VASP phosphorylation assays were performed. Results During maintenance therapy, ticagrelor achieved greater suppression of platelet reactivity compared with clopidogrel. The mean maximum light transmittance aggregometry responses (adenosine diphosphate 20 μM) post-maintenance dose were 44 ± 15% for clopidogrel and 28 ± 10% for ticagrelor (p < 0.001). High platelet reactivity was seen more frequently in the clopidogrel group. Proton pump inhibitor use was associated with higher platelet reactivity with clopidogrel but not ticagrelor. The ticagrelor LD also achieved greater inhibition of platelet aggregation compared with the clopidogrel LD. Conclusions Ticagrelor achieves greater antiplatelet effect than clopidogrel in patients with acute coronary syndromes, both in the first hours of treatment and during maintenance therapy.
Background Currently recommended anticoagulant agents used in the setting of percutaneous coronary intervention (PCI) inhibit, with varying degrees of intensity, 2 critical targets (factor Xa and/or ...IIa) of the coagulation cascade, yet they carry significant limitations. M118—a novel, rationally engineered heparin—provides consistent anti-Xa and anti-IIa activity with a constant anti-Xa:anti-IIa ratio over time. M118 also combines the desired anticoagulant effects of unfractionated heparin with the beneficial attributes of low-molecular-weight heparin, and may represent the next generation of heparin therapy in patients diagnosed with acute coronary syndrome. Study Design The EMINENCE trial is a prospective, randomized, open-label, multicenter phase 2 study that will evaluate the safety and feasibility of M118 as an anticoagulant versus unfractionated heparin in subjects with stable coronary artery disease undergoing PCI. The primary end point of the study will be the combined incidence of clinical events defined as the composite of 30-day death, myocardial infarction, repeat revascularization, catheter thrombus, stroke, thrombocytopenia, bailout use of glycoprotein IIb/IIIa inhibitors, and major or minor bleeding. Conclusion The EMINENCE trial will assess the safety and feasibility of M118 as an anticoagulant in the setting of PCI and will provide important information to determine the appropriate therapeutic range of activated clotting time for M118 and the appropriate dose or doses to be explored in a phase 3 clinical trial.
Objectives The purpose of our multicenter study was to examine the impact of pre-operative administration of clopidogrel on reoperation rates, incidence of life-threatening bleeding, inpatient length ...of stay, and other bleeding-related outcomes in acute coronary syndrome (ACS) patients requiring cardiopulmonary bypass (coronary artery bypass graft surgery CABG) in a broad cross section of U.S. hospitals. Background There is relative uncertainty about the relationship between clopidogrel and CABG-associated outcomes in the setting of ACS. Methods A retrospective cohort analysis was performed of randomly selected ACS patients requiring CABG in 14 hospitals across the U.S. Patients exposed to clopidogrel were compared with those not exposed to clopidogrel within 5 days prior to surgery. Results Of the 596 patients enrolled in the study, 298 had been exposed to clopidogrel within 5 days (Group A). Patients in Group A were more than 3-fold more likely to require reoperation for assessment of bleeding than patients not exposed to clopidogrel (6.4% vs. 1.7% Group B, p = 0.004). Major bleeding occurred in 35% of Group A patients versus 26% of Group B patients (p = 0.049). Length of stay was greater in Group A compared with Group B (9.7 ± 6.0 days vs. 8.6 ± 4.7 days, unadjusted p = 0.016). After logistic regression analysis, clopidogrel exposure within 5 days of CABG was the strongest predictor of reoperation (odds ratio OR: 4.60, 95% confidence interval CI: 1.45 to 14.55) and major bleeding (OR: 1.824, 95% CI: 1.106 to 3.008). Conclusions After ACS, patients who undergo CABG within 5 days of receiving clopidogrel are at increased risk for reoperation, major bleeding, and increased length of stay. These risks must be balanced by the clinical benefits of clopidogrel use demonstrated in randomized clinical trials.
Cardiology and the Critical Care Crisis Katz, Jason N., MD; Turer, Aslan T., MD; Becker, Richard C., MD
Journal of the American College of Cardiology,
03/2007, Volume:
49, Issue:
12
Journal Article
Peer reviewed
Open access
Cardiology and the Critical Care Crisis: A Perspective Jason N. Katz, Aslan T. Turer, Richard C. Becker With an aging U.S. population and a declining physician supply, the care of critically ill ...patients is quickly approaching a level of crisis. At the same time, evidence continues to mount in support of intensivist staffing to improve intensive care unit clinical outcomes and resource utilization. No longer merely an observation unit for peri-infarction complications, the traditional coronary care unit has truly evolved into an intensive care setting for patients with cardiovascular diseases. With this in mind, there becomes a significant demand for the development of cardiac intensivists and critical care training pathways within our cardiology fellowship programs.
Summary Background In the PLATO trial of ticagrelor versus clopidogrel for treatment of acute coronary syndromes, ticagrelor reduced the composite outcome of cardiovascular death, myocardial ...infarction, and stroke, but increased events of major bleeding related to non-coronary artery bypass graft (CABG). CYP2C19 and ABCB1 genotypes are known to influence the effects of clopidogrel. In this substudy, we investigated the effects of these genotypes on outcomes between and within treatment groups. Methods DNA samples obtained from patients in the PLATO trial were genotyped for CYP2C19 loss-of-function alleles (*2, *3, *4, *5, *6, *7, and *8), the CYP2C19 gain-of-function allele *17, and the ABCB1 single nucleotide polymorphism 3435C→T. For the CYP2C19 genotype, patients were stratified by the presence or absence of any loss-of-function allele, and for the ABCB1 genotype, patients were stratified by predicted gene expression (high, intermediate, or low). The primary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, or stroke after up to 12 months' treatment with ticagrelor or clopidogrel. Findings 10 285 patients provided samples for genetic analysis. The primary outcome occurred less often with ticagrelor versus clopidogrel, irrespective of CYP2C19 genotype: 8·6% versus 11·2% (hazard ratio 0·77, 95% CI 0·60–0·99, p=0·0380) in patients with any loss-of-function allele; and 8·8% versus 10·0% (0·86, 0·74–1·01, p=0·0608) in those without any loss-of-function allele (interaction p=0·46). For the ABCB1 genotype, event rates for the primary outcome were also consistently lower in the ticagrelor than in the clopidogrel group for all genotype groups (interaction p=0·39; 8·8% vs 11·9%; 0·71, 0·55–0·92 for the high-expression genotype). In the clopidogrel group, the event rate at 30 days was higher in patients with than in those without any loss-of-function CYP2C19 alleles (5·7% vs 3·8%, p=0·028), leading to earlier separation of event rates between treatment groups in patients with loss-of-function alleles. Patients on clopidogrel who had any gain-of-function CYP2C19 allele had a higher frequency of major bleeding (11·9%) than did those without any gain-of-function or loss-of-function alleles (9·5%; p=0·022), but interaction between treatment and genotype groups was not significant for any type of major bleeding. Interpretation Ticagrelor is a more efficacious treatment for acute coronary syndromes than is clopidogrel, irrespective of CYP2C19 and ABCB1 polymorphisms. Use of ticagrelor instead of clopidogrel eliminates the need for presently recommended genetic testing before dual antiplatelet treatment. Funding AstraZeneca.
Summary Background Variation in and irreversibility of platelet inhibition with clopidogrel has led to controversy about its optimum dose and timing of administration in patients with acute coronary ...syndromes. We compared ticagrelor, a more potent reversible P2Y12 inhibitor with clopidogrel in such patients. Methods At randomisation, an invasive strategy was planned for 13 408 (72·0%) of 18 624 patients hospitalised for acute coronary syndromes (with or without ST elevation). In a double-blind, double-dummy study, patients were randomly assigned in a one-to-one ratio to ticagrelor and placebo (180 mg loading dose followed by 90 mg twice a day), or to clopidogrel and placebo (300–600 mg loading dose or continuation with maintenance dose followed by 75 mg per day) for 6–12 months. All patients were given aspirin. The primary composite endpoint was cardiovascular death, myocardial infarction, or stroke. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00391872. Findings 6732 patients were assigned to ticagrelor and 6676 to clopidogrel. The primary composite endpoint occurred in fewer patients in the ticagrelor group than in the clopidogrel group (569 event rate at 360 days 9·0% vs 668 10·7%, hazard ratio 0·84, 95% CI 0·75–0·94; p=0·0025). There was no difference between clopidogrel and ticagrelor groups in the rates of total major bleeding (691 11·6% vs 689 11·5%, 0·99 0·89–1·10; p=0·8803) or severe bleeding, as defined according to the Global Use of Strategies To Open occluded coronary arteries, (198 3·2% vs 185 2·9%, 0·91 0·74–1·12; p=0·3785). Interpretation Ticagrelor seems to be a better option than clopidogrel for patients with acute coronary syndromes for whom an early invasive strategy is planned. Funding AstraZeneca.
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