Brent N. Reed

Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease: A Scientific Statement From the American Heart Association

A drug-drug interaction (DDI) is a pharmacokinetic or pharmacological influence of 1 medication on another that differs from the known or anticipated effects of each agent alone.1 A DDI may result in a change in either drug efficacy or drug toxicity for 1 or both of the interacting medications.2 Pharmacokinetic DDIs result in altered absorption, distribution, metabolism, or excretion of a medication. A pharmacodynamic DDI occurs when 1 medication modifies the pharmacological effect of another in an additive, a synergistic, or an antagonistic fashion. It is estimated that ≈2.8% of hospital admissions occur as a direct result of DDIs.3 However, the actual incidence of hospitalization secondary to clinically significant DDIs is likely to be highly underestimated because medication-related issues are more commonly reported as adverse drug reactions. Complex underlying disease states also may make recognizing a DDI more challenging, further contributing to a lower reported incidence. The overall clinical impact of a DDI can range from mild to life-threatening. Therefore, not all DDIs require a modification in therapy. The variability in the clinical significance of a DDI depends on both medication-specific and patient-specific factors. Medication-specific factors include the individual pharmacokinetic characteristics of each medication implicated in the DDI (eg, binding affinity, half-life [t1/2]), dose of the medications, serum concentrations, timing and sequence of administration, and duration of therapy. Patient-specific factors include age, sex, lifestyle, genetic polymorphisms causing differences in enzyme expression or activity, and disease impairment affecting drug metabolism (eg, hepatic or renal impairment, cardiac failure) or predisposition to differences in efficacy or safety (eg, statin intolerance in patients with a history of myopathy). Clinically significant DDIs are usually preventable. To optimize patient safety, healthcare providers must have an understanding of the mechanisms, magnitude, and potential consequences of any given DDI. Interpreting this information …

Implementation and evaluation of a CYP2C19 genotype-guided antiplatelet therapy algorithm in high-risk coronary artery disease patients

AIM An algorithm that uses clinical factors and CYP2C19 genotype to guide P2Y12 inhibitor selection in high-risk patients undergoing percutaneous coronary intervention was implemented at our institution. We sought to evaluate use of this algorithm and identify which factors influenced P2Y12 inhibitor selection. PATIENTS & METHODS This retrospective cohort study included 264 patients receiving percutaneous coronary intervention from July-December 2012. RESULTS CYP2C19 genotype was obtained in 229 patients; of these, 30% were intermediate or poor metabolizers. CYP2C19 intermediate or poor metabolizer phenotype was among the strongest predictors for selecting prasugrel or ticagrelor as maintenance therapy (p < 0.001), and was the only significant predictor of a change in therapy (p < 0.001). CONCLUSION These findings suggest that using CYP2C19 genotype to guide P2Y12 inhibitor selection is feasible. Original submitted 27 October 2014; revision submitted 19 December 2014.

Fluconazole Prophylaxis in High-Risk Neonates

OBJECTIVE To evaluate the literature regarding the use of fluconazole prophylaxis in high-risk neonates. DATA SOURCES Literature was accessed through MEDLINE (February 2001-August 2009) using the search terms fluconazole and prophylaxis, with limits for age group (ie, birth-18 y). Reference citations from identified articles were also reviewed. DATA SELECTION AND DATA EXTRACTION All prospective and retrospective studies in English identified from MEDLINE were evaluated. DATA SYNTHESIS Critically ill neonates possess a number of risk factors that predispose them to fungal colonization with Candida spp. In many cases, colonization may progress to invasive systemic infections despite efforts aimed at early diagnosis and treatment. Because of its success among immunocompromised patients, fluconazole prophylaxis has been suggested as a possible approach for reducing the rates of both colonization and invasive fungal infections among at-risk neonates. To date, 4 prospective randomized controlled trials and 8 retrospective cohort studies have examined fluconazole prophylaxis in neonates. Although fluconazole prophylaxis appears to reduce the rates of colonization and invasive fungal infections, no trial in this review was able to demonstrate a significant difference in long-term morbidity or mortality. Concerns also remain regarding the adverse effects associated with prolonged exposure to fluconazole therapy. Lack of standardized study designs and treatment regimens also limit widespread recommendation for the use of fluconazole prophylaxis in clinical practice. CONCLUSIONS While it may be beneficial for critically ill neonates with certain predisposing risk factors (eg, central venous access, sustained exposure to broad-spectrum antibiotics, or units with significantly high incidence of invasive fungal infections), existing research does not support the use of fluconazole prophylaxis based on birth weight or gestational age alone. Multifactor analysis evaluating the effect of fluconazole prophylaxis is necessary to establish which neonates would benefit from this practice.

Safety of Nonsteroidal Antiinflammatory Drugs in Patients with Cardiovascular Disease

Nonsteroidal antiinflammatory drugs (NSAIDs) are used in the management of a variety of conditions, but their prevalence is likely underreported as a result of widespread availability and the perception that nonprescription therapies are unnecessary to report during medication history taking. However, NSAIDs are associated with a number of adverse effects, especially in patients with cardiovascular disease (CVD). Patients with CVD and comorbidities for which NSAIDs may provide symptomatic relief (e.g., osteoarthritis, rheumatoid arthritis) tend to be older, which places them at greater risk of harm. For these reasons, the use of NSAIDs in patients with CVD is a significant public health concern. An understanding of the risks associated with NSAIDs is critical for clinicians across practice settings. In this review, we detail the safety of NSAIDs in patients with CVD, provide recommendations on their use in specific disease states, and discuss therapeutic alternatives.

Medication Management of Cardiac Allograft Vasculopathy After Heart Transplantation

Cardiac allograft vasculopathy (CAV) is a common complication following heart transplantation (HT), resulting in diminished graft survival. The preferred strategy for preventing CAV is optimal medical management; however, for patients who develop CAV, delaying disease progression through effective medication management is equally important. A review of the literature regarding medication management of CAV was conducted via a search of the MEDLINE database. Studies were included if they were published in English, conducted in humans ≥ 18 years of age or older, and used noninvestigational medications. Immunosuppressive medications such as the antiproliferative mycophenolate, the calcineurin inhibitor tacrolimus, and the proliferation signal inhibitors sirolimus and everolimus have been shown to prevent the development of CAV. Certain cardiovascular medications, such as HMG‐CoA reductase inhibitors (statins), gemfibrozil, calcium channel blockers, and angiotensin‐converting enzyme inhibitors, have also demonstrated efficacy in preventing this disease process. Prevention of CAV has also been observed with prophylaxis against cytomegalovirus infection and antioxidant medications. Despite being commonly used in HT patients, neither antiplatelet agents nor glycemic control have proved effective at preventing CAV. Only sirolimus has been shown to arrest the progress of existing CAV.

Distinguishing anemia and iron deficiency of heart failure: signal for severity of disease or unmet therapeutic need?

Despite advances in the management of heart failure (HF), quality of life and other outcomes remain suboptimal for many patients. Anemia and iron deficiency are comorbidities associated with adverse outcomes, although their pathophysiology in the setting of HF is not entirely understood. Anemia and iron deficiency may exist independently and may be a consequence of the systemic inflammatory state characterized by chronic HF. However, it is unclear whether serum hemoglobin concentrations and other hematologic parameters serve as markers for the severity of disease or represent novel therapeutic targets. Research in this area has focused primarily on therapies known to be effective for these conditions in other chronic disease states with similar pathophysiologic features (e.g., end‐stage renal disease). Despite its many practical advantages, minimal evidence exists to support the use of oral iron supplementation in this setting. In contrast, intravenous iron has been the subject of several recent investigations, demonstrating improvements in both surrogate and clinical end points, although benefits seem to be the most substantial in patients with concomitant anemia. Erythropoietin‐stimulating agents demonstrated early promise in retrospective analyses and small prospective trials, but their benefit was outweighed by a lack of improvement in clinical outcomes and an excess number of thromboembolic events in the largest trial of patients with anemia and HF to date. For acute symptomatic anemia, blood transfusion may be considered, although few trials have included patients with HF, and caution must be exerted in those who are hemodynamically unstable. Based on the currently available evidence, treatment of iron deficiency appears to confer benefit in patients with HF, whereas strategies aimed at improving hemoglobin alone do not. Included is a review of the pathophysiology of these conditions in the setting of HF, clinical trials evaluating pharmacologic therapy, and recommendations for management.

Effects of an Accelerated Intravenous Iron Regimen in Hospitalized Patients With Advanced Heart Failure and Iron Deficiency

To assess the short‐term efficacy and safety of an accelerated intravenous iron regimen in hospitalized patients with heart failure and iron deficiency.

Clinical update on the management of atrial fibrillation

Atrial fibrillation (AF) is a cardiac arrhythmia associated with significant morbidity and mortality, affecting more than 3 million people in the United States and 1–2% of the population worldwide. Its estimated prevalence is expected to double within the next 50 years. During the past decade, there have been significant advances in the treatment of AF. Studies have demonstrated that a rate control strategy, with a target resting heart rate between 80 and 100 beats/minute, is recommended over rhythm control in the vast majority of patients. The CHA2DS2≥ (congestive heart failure, hypertension, age ≥ 65 yrs, diabetes mellitus, stroke or transient ischemic attack, vascular disease, female gender) scoring system is a potentially useful stroke risk stratification tool that incorporates additional risk factors to the commonly used CHADS2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke transient ischemic attack) scoring tool. Similarly, a convenient scheme, termed HAS‐BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly), to assess bleeding risk has emerged that may be useful in select patients. Furthermore, new antithrombotic strategies have been developed as potential alternatives to warfarin, including dual‐antiplatelet therapy with clopidogrel plus aspirin and the development of new oral anticoagulants such as dabigatran, rivaroxaban, and apixaban. Vernakalant has emerged as another potential option for pharmacologic conversion of AF, whereas recent trials have better defined the role of dronedarone in the maintenance of sinus rhythm. Finally, catheter ablation represents another alternative to manage AF, whereas upstream therapy with inhibitors of the renin‐angiotensin‐aldosterone system, statins, and polyunsaturated fatty acids could potentially prevent the occurrence of AF. Despite substantial progress in the management of AF, significant uncertainty surrounds the optimal treatment of this condition.

The impact of drug shortages on patients with cardiovascular disease: causes, consequences, and a call to action

Shortages of cardiovascular drugs have become increasingly common, representing an ongoing public health crisis. Given few therapeutic alternatives to many of the drugs in short supply, these shortages also pose a major challenge for cardiovascular care professionals. Although changes in the regulatory environment have led to some improvements in recent years, problems involving manufacturing processes remain the most common underlying cause. Because of the complex nature of drug shortages, sustainable solutions to prevent and mitigate them will require collaboration between regulatory agencies, drug manufacturers, and other key stakeholder groups. In this report, we describe the scope of the cardiovascular drug shortage crisis in the United States, including its underlying causes and the efforts currently being made to address it. Furthermore, we provide specific recommendations for how cardiovascular care professionals can be involved in efforts to limit the impact of drug shortages on patient care as well as policy changes aimed at preventing and mitigating them.

Efficacy and Safety of Intravenous Chlorothiazide versus Oral Metolazone in Patients with Acute Decompensated Heart Failure and Loop Diuretic Resistance.

To assess the efficacy and safety of intravenous (IV) chlorothiazide versus oral metolazone when added to loop diuretics in patients with acute decompensated heart failure (ADHF) and loop diuretic resistance.