More, More, More: Reducing Thrombosis in Acute Coronary Syndromes Beyond Dual Antiplatelet Therapy-Current Data and Future Directions.

© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.Common to the pathogenesis of acute coronary syndromes (ACS) is the formation of arterial thrombus, which results from platelet activation and triggering of the coagulation cascade.1 To attenuate the risk of future thrombotic events, patients with ACS are treated with dual antiplatelet therapy (DAPT), namely, the combination of aspirin with a P2Y12 inhibitor, such as clopidogrel, ticagrelor, or prasugrel. Despite DAPT, some ≈10% of ACS patients experience recurrent major adverse cardiovascular events over the subsequent 30 days,2 driving the quest for more effective inhibition of thrombotic pathways. In this review, we provide an overview of studies to date and those ongoing that aim to deliver more effective combinations of antithrombotic agents to patients with recent ACS. We have chosen to confine the review to ACS patients without atrial fibrillation because those with atrial fibrillation have a clear indication for combination therapy that includes oral anticoagulation and should, we feel, be treated as a separate cohort. In this article, we discuss the limitations of the currently available clinical trial data and future directions, with suggestions for how practice might change to reduce the risk of coronary thrombosis in those at greatest risk, with minimal impact on bleeding.Peer reviewedFinal Published versio

Cost-effectiveness Analysis of Rivaroxaban in the Secondary Prevention of Acute Coronary Syndromes in Sweden.

BACKGROUND: Worldwide, coronary heart disease accounts for 7 million deaths each year. In Sweden, acute coronary syndrome (ACS) is a leading cause of hospitalization and is responsible for 1 in 4 deaths. OBJECTIVE: The aim of this analysis was to assess the cost-effectiveness of rivaroxaban 2.5 mg twice daily (BID) in combination with standard antiplatelet therapy (ST-APT) versus ST-APT alone, for the secondary prevention of ACS in adult patients with elevated cardiac biomarkers without a prior history of stroke/transient ischemic attack (TIA), from a Swedish societal perspective, based on clinical data from the global ATLAS ACS 2-TIMI 51 trial, literature-based quality of life data and costs sourced from Swedish national databases. METHODS: A Markov model was developed to capture rates of single and multiple myocardial infarction (MI), ischemic and hemorrhagic stroke, thrombolysis in myocardial infarction (TIMI) major, minor, and "requiring medical attention" bleeds, revascularization events, and associated costs and utilities in patients who were stabilized after an initial ACS event. Efficacy and safety data for the first 2 years came from the ATLAS ACS 2-TIMI 51 trial. Long-term probabilities were extrapolated using safety and effectiveness of acetylsalicylic acid data, which was estimated from published literature, assuming constant rates in time. Future cost and effects were discounted at 3.0%. Univariate and probabilistic sensitivity analyses were conducted. RESULTS: In the base case, the use of rivaroxaban 2.5 mg BID was associated with improvements in survival and quality-adjusted life years (QALYs), yielding an incremental cost per QALY of 71,246 Swedish Krona (SEK) (€8045). The outcomes were robust to changes in inputs. The probabilistic sensitivity analysis demonstrated rivaroxaban 2.5 mg BID to be cost-effective in >99.9% of cases, assuming a willingness-to-pay threshold of SEK 500,000 (€56,458). CONCLUSION: Compared with ST-APT alone, the use of rivaroxaban 2.5 mg BID in combination with ST-APT can be considered a cost-effective treatment option for ACS patients with elevated cardiac biomarkers without a prior history of stroke/TIA in Sweden. FUNDING: Bayer Pharma AG

Neuropsychiatric symptoms in 921 elderly subjects with dementia: a comparison between vascular and neurodegenerative types.

Objective:  i) to describe the neuropsychiatric profile of elderly subjects with dementia by comparing vascular (VaD) and degenerative dementias, i.e. dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD); ii) to assess whether the severity and type of dementia are associated with clinically relevant neuropsychiatric symptoms (CR‐NPS). Method:  One hundred and thirty‐one out‐patients with VaD, 100 with DLB and 690 with AD were studied. NPS were evaluated by the neuropsychiatric inventory (NPI). Results:  Vascular dementia had lower total and domain‐specific NPI scores and a lower frequency of CR‐NPS than AD and DLB, for which frequency of CR‐NPS increased significantly with disease severity, particularly in AD. Logistic regression analysis showed that a higher CDR score and a diagnosis of degenerative dementia were independently associated with CR‐NPS. Conclusion:  Vascular dementia is associated less with CR‐NPS than AD and DLB. Frequency of CR‐NPS increases with disease severity in AD and, to a lesser extent, in DLB

Stroke genetics: prospects for personalized medicine.

Epidemiologic evidence supports a genetic predisposition to stroke. Recent advances, primarily using the genome-wide association study approach, are transforming what we know about the genetics of multifactorial stroke, and are identifying novel stroke genes. The current findings are consistent with different stroke subtypes having different genetic architecture. These discoveries may identify novel pathways involved in stroke pathogenesis, and suggest new treatment approaches. However, the already identified genetic variants explain only a small proportion of overall stroke risk, and therefore are not currently useful in predicting risk for the individual patient. Such risk prediction may become a reality as identification of a greater number of stroke risk variants that explain the majority of genetic risk proceeds, and perhaps when information on rare variants, identified by whole-genome sequencing, is also incorporated into risk algorithms. Pharmacogenomics may offer the potential for earlier implementation of 'personalized genetic' medicine. Genetic variants affecting clopidogrel and warfarin metabolism may identify non-responders and reduce side-effects, but these approaches have not yet been widely adopted in clinical practice

Edoxaban: an update on the new oral direct factor Xa inhibitor.

Edoxaban is a once-daily oral anticoagulant that rapidly and selectively inhibits factor Xa in a concentration-dependent manner. This review describes the extensive clinical development program of edoxaban, including phase III studies in patients with non-valvular atrial fibrillation (NVAF) and symptomatic venous thromboembolism (VTE). The ENGAGE AF-TIMI 48 study (N = 21,105; mean CHADS2 score 2.8) compared edoxaban 60 mg once daily (high-dose regimen) and edoxaban 30 mg once daily (low-dose regimen) with dose-adjusted warfarin [international normalized ratio (INR) 2.0-3.0] and found that both regimens were non-inferior to warfarin in the prevention of stroke and systemic embolism in patients with NVAF. Both edoxaban regimens also provided significant reductions in the risk of hemorrhagic stroke, cardiovascular mortality, major bleeding and intracranial bleeding. The Hokusai-VTE study (N = 8,292) in patients with symptomatic VTE had a flexible treatment duration of 3-12 months and found that following initial heparin, edoxaban 60 mg once daily was non-inferior to dose-adjusted warfarin (INR 2.0-3.0) for the prevention of recurrent VTE, and also had a significantly lower risk of bleeding events. Both studies randomized patients at moderate-to-high risk of thromboembolic events and were further designed to simulate routine clinical practice as much as possible, with edoxaban dose reduction (halving dose) at randomisation or during the study if required, a frequently monitored and well-controlled warfarin group, a well-monitored transition period at study end and a flexible treatment duration in Hokusai-VTE. Given the phase III results obtained, once-daily edoxaban may soon be a key addition to the range of antithrombotic treatment options

TREM-1 expression on neutrophils and monocytes of septic patients: relation to the underlying infection and the implicated pathogen

<p>Abstract</p> <p>Background</p> <p>Current knowledge on the exact ligand causing expression of TREM-1 on neutrophils and monocytes is limited. The present study aimed at the role of underlying infection and of the causative pathogen in the expression of TREM-1 in sepsis.</p> <p>Methods</p> <p>Peripheral venous blood was sampled from 125 patients with sepsis and 88 with severe sepsis/septic shock. The causative pathogen was isolated in 91 patients. Patients were suffering from acute pyelonephritis, community-acquired pneumonia (CAP), intra-abdominal infections (IAIs), primary bacteremia and ventilator-associated pneumonia or hospital-acquired pneumonia (VAP/HAP). Blood monocytes and neutrophils were isolated. Flow cytometry was used to estimate the TREM-1 expression from septic patients.</p> <p>Results</p> <p>Within patients bearing intrabdominal infections, expression of TREM-1 was significantly lower on neutrophils and on monocytes at severe sepsis/shock than at sepsis. That was also the case for severe sepsis/shock developed in the field of VAP/HAP. Among patients who suffered infections by Gram-negative community-acquired pathogens or among patients who suffered polymicrobial infections, expression of TREM-1 on monocytes was significantly lower at the stage of severe sepsis/shock than at the stage of sepsis.</p> <p>Conclusions</p> <p>Decrease of the expression of TREM-1 on the membrane of monocytes and neutrophils upon transition from sepsis to severe sepsis/septic shock depends on the underlying type of infection and the causative pathogen.</p

Drug metabolizing enzyme activities versus genetic variances for drug of clinical pharmacogenomic relevance

Enzymes are critically important in the transportation, metabolism, and clearance of most therapeutic drugs used in clinical practice today. Many of these enzymes have significant genetic polymorphisms that affect the enzyme's rate kinetics. Regarding drug metabolism, specific polymorphisms to the cytochrome (CYP) P450 enzyme family are linked to phenotypes that describe reaction rates as "ultra", "intermediate", and "poor," as referenced to "extensive" metabolizers that are assigned to wildtype individuals. Activity scores is an alternate designation that provides more genotype-to-phenotype resolution. Understanding the relative change in enzyme activities or rate of clearance of specific drugs relative to an individual's genotypes is an important component in the interpretation of pharmacogenomic data for personalized medicine. Currently, the most relevant drug metabolizing enzymes are CYP 2D6, CYP 2C9, CYP 2C19, thiopurine methyltransferase (TPMT) and UDP-glucuronosyltransferase (UGT). Each of these enzymes is reactive to a host of different drug substrates. Pharmacogenomic tests that are in routine clinical practice include CYP 2C19 for clopidogrel, TPMT for thiopurine drugs, and UDP-1A1 for irinotecan. Other tests where there is considerable data but have not been widely implemented includes CYP 2C9 for warfarin, CYP 2D6 for tamoxifen and codeine, and CYP 2C19 for the proton pump inhibitors

Clinical implementation of rapid CYP2C19 genotyping to guide antiplatelet therapy after percutaneous coronary intervention

© 2018 The Author(s). Background: The CYP2C19 nonfunctional genotype reduces clopidogrel effectiveness after percutaneous coronary intervention (PCI). Following clinical implementation of CYP2C19 genotyping at University Florida (UF) Health Shands Hospital in 2012, where genotype results are available approximately 3 days after PCI, testing was expanded to UF Health Jacksonville in 2016 utilizing a rapid genotyping approach. We describe metrics with this latter implementation. Methods: Patients at UF Health Jacksonville undergoing left heart catheterization with intent to undergo PCI were targeted for genotyping using the Spartan RX™ system. Testing metrics and provider acceptance of testing and response to genotype results were examined, as was antiplatelet therapy over the 6 months following genotyping. Results: In the first year, 931 patients, including 392/505 (78%) total patients undergoing PCI, were genotyped. The median genotype test turnaround time was 96 min. Genotype results were available for 388 (99%) PCI patients prior to discharge. Of 336 genotyped PCI patients alive at discharge and not enrolled in an antiplatelet therapy trial, 1/6 (17%) poor metabolizers (PMs, with two nonfunctional alleles), 38/93 (41%) intermediate metabolizers (IMs, with one nonfunctional allele), and 119/237 (50%) patients without a nonfunctional allele were prescribed clopidogrel (p = 0.110). Clopidogrel use was higher among non-ACS versus ACS patients (78.6% vs. 42.2%, p < 0.001). Six months later, among patients with follow-up data, clopidogrel was prescribed in 0/4 (0%) PMs, 33/65 (51%) IMs, and 115/182 (63%) patients without a nonfunctional allele (p = 0.008 across groups; p = 0.020 for PMs versus those without a nonfunctional allele). Conclusion: These data demonstrate that rapid genotyping is clinically feasible at a high volume cardiac catheterization facility and allows informed chronic antiplatelet prescribing, with lower clopidogrel use in PMs at 6 months

Feasibility of pharmacy-initiated pharmacogenetic screening for CYP2D6 and CYP2C19

PURPOSE: Our purpose was to investigate the feasibility of pharmacy-initiated pharmacogenetic (PGt) screening in primary care with respect to patient willingness to participate, quality of DNA collection with saliva kits, genotyping, and dispensing data retrieved from the pharmacy. METHODS: Polypharmacy patients aged >60 years who used at least one drug with Anatomical Therapeutic Chemical (ATC) code N06AA01-N06AX19 (antidepressants), A02BC01-A02BC05 (proton-pump inhibitors), N05AA01-N05AH04 (antipsychotics), or C07AB02 (metoprolol) in the preceding 2 years were randomly selected. DNA was collected with saliva kits and genotyped for CYP2D6 and CYP2C19 with the AmpliChip. Pharmacy dispensing records were retrieved and screened for drugs interacting with the patient's CYP2D6 and CYP2C19 genotype by using the evidence-based PGt guidelines from the Dutch Pharmacogenetics Working Group. RESULTS: Out of the 93 invited patients, 54 (58.1%) provided informed consent. Nine saliva samples (16.7%) contained too little DNA. Call rates for CYP2D6 and CYP2C19 were 93.3% and 100%, respectively. Frequencies of genotype-predicted phenotype were 2.4%, 38.1%, 54.8%, and 4.8% for CYP2D6 poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM), and ultrarapid metabolizers (UM) respectively. For CYP2C19 genotype-predicted phenotype, frequencies were 2.2%, 15.6%, and 82.2% for PM, IM, and EM, respectively. CONCLUSIONS: This study shows that pharmacy-initiated PGt screening is feasible for a primary care setting