Kyle A. Davis

Newer oral anticoagulants: A review of laboratory monitoring options and reversal agents in the hemorrhagic patient

PURPOSE Available evidence on laboratory monitoring of coagulation assays and reversal strategies for the management of hemorrhagic events associated with the newer anticoagulants is reviewed. SUMMARY While there are no published studies with dabigatran and prothrombinase-induced clotting time (PiCT) and no chromogenic assays available to measure the anticoagulant effects, thrombin time and activated partial thromboplastin time (aPTT ) may be used to detect the presence of dabigatran. Although ecarin clotting time is sensitive to elevated concentrations of dabigatran, only a small fraction of institutions have access to this assay. Rivaroxaban and apixaban prolong prothrombin time, dilute prothrombin time, aPTT, Heptest results, and PiCT to varying degrees, having the most- pronounced effects at higher concentrations. In contrast, the chromogenic antifactor Xa assay proved to be sensitive to lower amounts of rivaroxaban and apixaban with less variability. Despite the expectations with these newer anticoagulants, the associated risk of bleeding is significant, and there are insufficient data depicting treatment options in emergency situations. Until four-factor prothrombin complex concentrates (PCCs) become available in the United States, the obtainable options are activated PCC, three-factor PCCs, and recombinant factor VIIa. CONCLUSION Although there is currently no gold standard of measurement for any of the newer anticoagulants, the published literature enables practitioners to evaluate the efficacy and sensitivity of a majority of these assays. Prohemostatic agents can be used in instances of severe, life-threatening hemorrhagic complications.

Lomitapide: A novel agent for the treatment of homozygous familial hypercholesterolemia

PURPOSE The pharmacology, pharmacokinetics, and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia (HoFH) are reviewed. SUMMARY Lomitapide (Juxtapid, Aegerion Pharmaceuticals) is an oral microsomal triglyceride transfer protein (MTP) inhibitor indicated for the treatment of patients with HoFH, a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease. In clinical trials, the use of lomitapide alone or in combination with other lipid-lowering modalities reduced plasma concentrations of low-density lipoprotein cholesterol (LDL-C) by a mean of more than 50%. Lomitapide is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels. Lomitapide undergoes hepatic metabolism via cytochrome P-450 (CYP) isoenzyme 3A4 and interacts with CYP3A4 substrates including atorvastatin and simvastatin; dose adjustment is recommended when lomitapide is used concurrently with these agents. In patients receiving concomitant warfarin, the International Normalized Ratio (INR) should be closely monitored, as lomitapide use may increase INR values. The recommended initial dosage of lomitapide is 5 mg once daily, with subsequent upward dose adjustment at specified intervals according to tolerability. Lomitapide is contraindicated in patients with moderate-to-severe liver disease, patients with sustained abnormal liver function tests, patients taking strong or moderate CYP3A4 inhibitors, and pregnant patients. CONCLUSION Lomitapide is an oral MTP inhibitor approved for the treatment of HoFH. This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL-C goal or cannot tolerate statin therapy.

Direct-Acting Oral Anticoagulants as Emerging Treatment Options for Heparin-Induced Thrombocytopenia

Objective: To review the evidence for the use of the direct-acting oral anticoagulants (DOACs) in adult patients with heparin-induced thrombocytopenia (HIT). Data Source: A PubMed search (1950-February 2015) was collected using the terms heparin-induced thrombocytopenia, with dabigatran, rivaroxaban, or apixaban, or heparin-induced thrombocytopenia and target-specific anticoagulants, or heparin-induced thrombocytopenia and direct-acting oral anticoagulants, or heparin-induced thrombocytopenia and new oral anticoagulants. Study Selection and Data Extraction: All English-language articles were reviewed for inclusion. The references of included articles were reviewed for additional data. Data Synthesis: HIT is an immune-mediated, prothrombotic adverse reaction that requires not only discontinuation of heparin but also initiation of an alternative nonheparin anticoagulant to counter the effects of the autoimmune cascade. Pharmacotherapeutic management with argatroban is unpredictable and problematic. The DOACs display predictable pharmacokinetic and pharmacodynamic profiles and exhibit no interaction with platelet factor 4. Currently, the DOACs are approved by the Food and Drug Administration for venous thromboembolism, yet have limited evidence in both in vitro and clinical HIT studies. Conclusions: Though dabigatran, rivaroxaban, and apixaban have been used in case reports, currently data are not yet sufficient to recommend clinical use of these agents in the management of HIT. Future trial results may further substantiate management of HIT with use of the DOACs.

Dual antiplatelet therapy with clopidogrel and aspirin after ischemic stroke: A review of the evidence

PURPOSE The safety and efficacy of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel in the setting of secondary stroke prevention are reviewed. SUMMARY Antiplatelet therapy has been shown to reduce the risk of numerous vascular events, especially in the setting of secondary prevention. DAPT with aspirin and another antiplatelet agent such as clopidogrel, prasugrel, or ticagrelor has become the main stay of acute coronary syndrome (ACS) management. The underlying pathophysiologies of ACS, ischemic stroke, and transient ischemic attack (TIA) are similar. In the setting of ACS, DAPT has clearly been shown to improve outcomes over single antiplatelet therapy for up to 12 months after the ischemic event. However, the role for DAPT in the setting of ischemic stroke and TIA is less clear. The MATCH, CHARISMA, and SPS3 studies demonstrated that DAPT was associated with increased bleeding compared with single antiplatelet therapy without an appreciable reduction in ischemic events. Early initiation of DAPT proved beneficial in reducing future ischemic events in the FASTER and CHANCE trials; however, these trials did not provide enough evidence to recommend the routine use of DAPT in secondary stroke prevention, and current guidelines recommend against such therapy. DAPT with aspirin and clopidogrel appears to be effective only for patients with minor stroke or TIA when started within 24 hours of the ischemic event and continued for a maximum of 21 days. CONCLUSION Currently available evidence does not substantiate the widespread use of long-term aspirin with clopidogrel for the secondary prevention of ischemic stroke or TIA.

A Statin a Day to Keep the Doctor Away? Comparing Aspirin and Statins for Primary Prevention of Cardiovascular Disease

For the primary prevention of cardiovascular (CV) disease, aspirin reduces the risk for major vascular events by approximately 15% to 20% with an absolute reduction of approximately 0.1%. Major bleeding occurs at an excess of approximately 2 cases per 1000 patient-years with aspirin therapy. For primary prevention, statin therapy has been shown to reduce the risk of CV events by approximately 30% to 40% with an absolute reduction of 1% to 2%. Rhabdomyolysis is rare, with an incidence of 3.4 cases per 100 000 patient-years. Compared with aspirin, statins have a more favorable risk-to-benefit profile for primary prevention.

Patient considerations and clinical impact of cholesteryl ester transfer protein inhibitors in the management of dyslipidemia: focus on anacetrapib

Cardiovascular disease (CVD) is responsible for significant morbidity and mortality within the United States and worldwide. Although targeting low-density lipoprotein cholesterol (LDL-C) in the prevention of CVD has been shown to be effective, evidence exists to indicate that significant cardiovascular (CV) risk remains in patients receiving 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) – a risk that may be correlated with low levels of high-density lipoprotein cholesterol (HDL-C). Among the various tactics under investigation to increase HDL-C, inhibition of cholesteryl ester transfer protein (CETP) appears the most adept to raise these levels. Although torcetrapib, a CETP inhibitor, demonstrated significant beneficial changes in HDL-C and LDL-C after 12 months of therapy when coadministered with atorvastatin, patients in the torcetrapib arm experienced a rise in mortality, including increased risk of death from CV and non-CV causes as well as a significant rise in major CV events. Later studies established that the adverse effects of torcetrapib were produced from molecule-specific off-target effects and not to the mechanism of CETP inhibition. These untoward outcomes have not been detected with anacetrapib, the third of the CETP inhibitors to enter Phase III trials. Furthermore, treatment with anacetrapib revealed both a statistically significant decrease in LDL-C and increase in HDL-C over placebo. While the place in therapy of niacin and fibrates to reduce CV events is currently in question secondary to the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes and the Action to Control CV Risk in Diabetes trials, the ongoing large-scale, randomized–placebo, controlled-outcomes study with anacetrapib coadministered with statin treatment will not only test the hypothesis if CETP inhibition lowers residual CV risk but will also provide insight as to which patient subgroups might benefit the most from anacetrapib despite aggressive therapy with statins.

Extended use of clopidogrel and aspirin after ischemic stroke.

Drs. Shiue and Sands highlight the potential benefit of DAPT with aspirin and clopidogrel in the setting of symptomatic intracranial stenosis. Although stroke secondary to intracranial stenosis is relatively uncommon, the concept of utilizing DAPT in patients with stroke secondary to symptomatic

Optimizing Transition of Care Through the Facilitation of a Pharmacist-Managed Deep Vein Thrombosis Treatment Program

A pharmacist-managed deep vein thrombosis (DVT) treatment program was put into operation at Jackson Memorial Hospital in Miami, Florida to provide appropriate transition of care to the outpatient setting for patients diagnosed with DVT. A postgraduate year 1 pharmacy practice resident partnered with a clinical pharmacist to establish and implement the DVT pilot program in the emergency department (ED). Once contacted, the pharmacy resident or the clinical pharmacist communicated with the ED physician and made recommendations regarding appropriate anticoagulation. The pharmacist met with the patient to obtain informed consent and provide counseling regarding the anticoagulants. A timely outpatient appointment at the pharmacy-managed warfarin clinic was arranged for the patient and contact information was exchanged between the patient and the pharmacist. On average, patients enrolled in the DVT program from the ED were released 18.29 hours (±7.06) following the time of arrival. Following release from the hospital, 91% of patients attended their outpatient follow-up appointment at the warfarin clinic. Since the initiation of the DVT program, 1 patient experienced a recurrent DVT and major bleed during their treatment course. Due to successful implementation of this pharmacist-managed DVT program in the ED, the services were subsequently extended to inpatients with DVT.

Evaluation of Aspirin Use for Primary Prevention in Diabetic Patients

It is with much interest that we read the research report by Fosmire Rundgren et al evaluating whether patients with diabetes indicated for aspirin therapy were in fact taking it. Although the authors reference the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) and Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trials, neither trial demonstrated that low-dose aspirin therapy reduced the risk of the primary composite end points, including coronary heart disease and stroke. Whereas the lack of benefit with aspirin was reiterated in several small-scale meta-analyses, the larger-scale Antithrombotic Trialist’s (ATT) Collaboration evaluated 6 primary prevention trials, demonstrating a small but significant absolute risk reduction in serious vascular events (0.51% aspirin vs 0.57% control per year, P = 0.0001). Because not all patients with diabetes have the same cardiovascular disease (CVD) risk, recommendations for aspirin use are dependent on an accurate evaluation of CVD risk factors. Furthermore, the relatively high number needed to treat associated with aspirin therapy requires practitioners to evaluate risks versus benefits. Currently, there are 2 ongoing trials that will provide further guidance regarding the role of low-dose aspirin for primary prevention in patients with diabetes. Until then, it remains unclear whether aspirin for prevention of CVD events in adults with diabetes is warranted. Indeed, the authors are to be commended for their efforts in surveying patients receiving care in the community to determine indication for aspirin therapy. However, we feel that these efforts should be targeted at identifying risk factors for consideration of more established therapies. Cholesterol management with statin therapy, blood pressure control, and smoking cessation have all been proven to reduce CVD risk in patients with diabetes. Whether patients have sufficient CVD risk to warrant aspirin depends on whether these techniques have been fully incorporated. Considering the potential adverse effects associated with aspirin, if these treatments are implemented first, then fewer patients with diabetes will remain at sufficient risk to benefit from aspirin therapy. Whereas no patients in the study by Fosmire Rundgren et al were found to have a history of gastrointestinal bleed or hemorrhagic stroke, the major adverse events associated with aspirin involve both gastrointestinal and intracranial bleeds. Recently, the Food and Drug Administration issued a warning that the bleeding potential with aspirin may outweigh the benefits when used for primary prevention. Comparatively, the risk for major adverse events (rhabdomyolysis and hemorrhagic stroke) with statins is estimated to be a 100-fold more in patient-years compared with aspirin. Additionally, the benefit of statin therapy is approximately 22% for every 39 mg/dL reduction in low-density lipoprotein cholesterol, compared with a 15% relative reduction with aspirin. We are pleased with the research report that Fosmire Rundgren et al have provided and await large-scale trials to better define the role of aspirin for primary prevention in patients with diabetes. In the meantime, we advocate for the use of more-established treatment options such as statin therapy.

Davis and Dietrich's response to Abramson and colleagues' article on statins in low risk people.

Abramson and colleagues question the benefit of statins in low risk patients, as recommended by the new cholesterol treatment guidelines.1 2 This conclusion is based on the authors’ evaluation of a meta-analysis performed by the Cholesterol Treatment Trialists’ (CTT) Collaborators.3 Firstly, they state that, in the setting of primary prevention, statins have not been shown to affect all cause mortality.1 In the JUPITER trial, 17 802 otherwise healthy participants were randomised to treatment with rosuvastatin 20 mg daily or placebo.4 Over 97% of study participants had less than a 10% five …