Adam Sieg

Aldosterone and aldosterone receptor antagonists in patients with chronic heart failure

Aldosterone is a mineralocorticoid hormone synthesized by the adrenal glands that has several regulatory functions to help the body maintain normal volume status and electrolyte balance. Studies have shown significantly higher levels of aldosterone secretion in patients with congestive heart failure compared with normal patients. Elevated levels of aldosterone have been shown to elevate blood pressure, cause left ventricular hypertrophy, and promote cardiac fibrosis. An appreciation of the true role of aldosterone in patients with chronic heart failure did not become apparent until the publication of the Randomized Aldactone Evaluation Study. Until recently, the use of aldosterone receptor antagonists has been limited to patients with severe heart failure and patients with heart failure following myocardial infarction. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) study added additional evidence to support the expanded use of aldosterone receptor antagonists in heart failure patients. The results of the EMPHASIS-HF trial showed that patients with mild-to-moderate (New York Heart Association Class II) heart failure had reductions in mortality and hospitalizations from the addition of eplerenone to optimal medical therapy. Evidence remains elusive about the exact mechanism by which aldosterone receptor antagonists improve heart failure morbidity and mortality. The benefits of aldosterone receptor antagonist use in heart failure must be weighed against the potential risk of complications, ie, hyperkalemia and, in the case of spironolactone, possible endocrine abnormalities, in particular gynecomastia. With appropriate monitoring, these risks can be minimized. We now have evidence that patients with mild-to-severe symptoms associated with systolic heart failure will benefit from the addition of an aldosterone receptor antagonist to the standard therapies of angiotensin-converting enzyme inhibitors and beta-blockers. This review will address the pharmacologic basis of aldosterone receptor antagonists in patients with heart failure and the clinical impact of this therapy.

Safety and Efficacy of High-Dose Unfractionated Heparin for Prevention of Venous Thromboembolism in Overweight and Obese Patients

To determine the safety and efficacy of high‐dose subcutaneous unfractionated heparin (UFH) for prevention of venous thromboembolism (VTE) in overweight and obese patients.

Statin therapy in cardiac allograft vasculopathy progression in heart transplant patients: Does potency matter?

Cardiac allograft vasculopathy (CAV) is a unique multi-factorial pathologic process encountered following heart transplantation. Several risk factors have been identified including a combination of immunologic and non-immunologic processes. Significant research has been conducted to elucidate the driving forces of CAV as well as improved identification, prevention and treatment strategies. Statin therapy following transplant remains the standard of care to help prevent the progression of CAV. The benefits of statin therapy following transplantation correspond to cholesterol control, anti-inflammatory and immunomodulatory mechanisms as well as potentially unknown mechanisms. Despite known drug interactions with calcineurin inhibitors, the use of statins is highly recommended in the current International Society for Heart and Lung Transplantation guidelines. Limited research has been conducted on the impact of higher intensity statin therapy following heart transplant and the relative risks and benefits are unknown. This review focuses on risk factors and pathophysiology of CAV, the role of statin therapy in heart transplantation, and the potential added benefit of more intense statin therapy to limit the progression of this graft-limiting complication.

The role of pharmacotherapy in the prevention of sudden cardiac death in patients with heart failure

Sudden cardiac death remains a significant threat to the survival of patients with heart failure. Long-term cardiac remodeling predisposes these patients to develop malignant ventricular arrhythmias. Permanent implantable and temporary external defibrillators remain a mainstay for the prevention of sudden cardiac death in this population. For decades, researchers have attempted to identify reliable drug therapies to avoid such arrhythmias; however, to date, success has been inconsistent. This review aims to explore the evidence defining the role of drug therapies for direct and indirect suppression of arrhythmias that may cause sudden cardiac death in patients with heart failure.

Antiplatelet Therapy Considerations in Ischemic Cardiogenic Shock Implications of Metabolic Bioactivation

Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist remains a mainstay in the prevention of ischemic events following coronary stent placement. Significant controversy exists regarding the optimal management of high platelet reactivity despite antiplatelet therapy; however this finding has been consistently associated with poor clinical outcomes including greater risk of stent thrombosis and myocardial infarction. Variability in antiplatelet effects of clopidogrel and prasugrel has been linked to genetic polymorphisms and potential drug–drug interactions. Both of these factors have significant influence on the cytochrome P-450 enzyme system activity of the liver responsible for their biotransformation to the active form of both drugs. Very little has been publicized regarding differences in antiplatelet effects which may be associated with conditions in which the functional capacity of the liver may be temporarily compromised. Patients who present with cardiogenic shock due to acute coronary syndromes have evidence of multiorgan dysfunction including liver dysfunction that may affect the activity of these drugs. This review aims to explore existing evidence and propose additional considerations to the selection of antiplatelet therapy in patients with cardiogenic shock who receive catheter-based revascularization and stent placement.

Improved Ticagrelor Antiplatelet Effect on Discontinuation of Phenytoin

Objective: To report the influence of phenytoin on the antiplatelet effects of ticagrelor using a validated platelet aggregation study. Case Summary: A 71-year-old man with coronary artery disease underwent percutaneous coronary intervention to revascularize several major coronary arteries. The patient was previously on phenytoin and was initiated on ticagrelor for antiplatelet therapy following stent placement. While the patient was receiving both drugs, platelet aggregation studies revealed less platelet inhibition than would be expected in a patient not taking a concomitant inducer of ticagrelor metabolism. On discontinuation of phenytoin, platelet inhibition improved. Discussion: Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist following placement of coronary stents is critical to prevent stent thrombosis and subsequent myocardial infarction. Ticagrelor is a recently approved P2Y12 receptor antagonist that is subject to drug-drug interactions involving the hepatic cytochrome P450-3A4 enzyme system because of its metabolic elimination pathway. This case demonstrates ticagrelor’s drug-drug interaction with phenytoin through a platelet aggregation study and supports the manufacturer recommendation to avoid the combination of ticagrelor with any known inducers of cytochrome P450-3A4 metabolism. Conclusion: The combination of ticagrelor and phenytoin may represent a potentially clinically significant drug-drug interaction because of phenytoin induction of ticagrelor metabolism and reduced P2Y12 receptor inhibition in patients who have recently undergone percutaneous coronary intervention and cardiac stent placement.

Evaluation of Dosing Practices of Rivaroxaban and Dabigatran

Background: Anticoagulation is standard practice for the prevention and treatment of thromboembolic events. Two of the newer agents, rivaroxaban (Xarelto) and dabigatran (Pradaxa) are being utilized frequently in the inpatient and outpatient settings. Prescribers may not appreciate the need for dose reduction in the setting of renal insufficiency. Objective: The objective of this study was to evaluate whether rivaroxaban and dabigatran were dosed according to recommendations in the package insert for patients with renal insufficiency. Methods: Eligible patients were those >18 years of age who received rivaroxaban or dabigatran as an inpatient or had a prescription filled from the outpatient pharmacy. The use of the Cockcroft–Gault equation was utilized to calculate creatinine clearance to evaluate whether patients had appropriate manufacturer recommended dose reductions based on their renal function. Results: There were very few patients (8 of 355, or 2.3%) who should have received a reduced dose when creatinine clearance was calculated utilizing actual body weight. In those patients with renal insufficiency, 3 of 6 (50.0%) patients receiving rivaroxaban and 1 of 2 (50%) patients receiving dabigatran were appropriately dosed. When ideal body weight was substituted for creatinine clearance calculation, there were 15 patients receiving rivaroxaban and 10 patients receiving dabigatran who fell below the creatinine clearance threshold for dose reduction. Conclusions: Based on this evaluation, very few patients required a dose reduction due to renal insufficiency. It is important for clinicians to always monitor renal function when utilizing these medications to optimize the benefits of the new oral anticoagulants while limiting potential deleterious effects. Furthermore, it is necessary to ensure that actual body weight is being utilized for creatinine clearance calculations with the new oral anticoagulants and not to base dosing on estimated glomerular filtration rate or other calculated creatinine clearance as this could lead to inappropriate dose reductions.