James C. Coons

Pharmacotherapy for acute heart failure syndromes

PURPOSE Drug therapies for patients with acute heart failure syndromes (AHFS) are reviewed, including clinical practice guideline recommendations for the treatment of hospitalized patients with heart failure (HF). SUMMARY AHFS may be defined as new-onset, gradual, or rapidly worsening HF signs and symptoms that require urgent therapy. Clinical practice guidelines from the American College of Cardiology Foundation-American Heart Association, Heart Failure Society of America, and European Society of Cardiology offer recommendations for the management of AHFS, addressing the role of diuretics, vasodilators, and inotropes. The guidelines emphasize the utility of vasodilators for patients with signs and symptoms of pulmonary congestion, including pulmonary edema or severe hypertension or both, who have not responded to diuretics. The early initiation of vasoactive medications, including diuretics and vasodilators, has been linked to improved outcomes in some reports. Conversely, the use of inotropes is de-emphasized, particularly as part of the routine management of these patients. Newer agents, including vasopressin antagonists, have also been approved recently but are not addressed by the clinical practice guidelines. The guidelines address the importance of initiating and optimizing evidence-based oral medications for long-term use, including angiotensin-converting-enzyme (ACE) inhibitors, angiotensin-receptor blockers, β-blockers, and aldosterone antagonists, during the patients hospital stay in an effort to address long-term outcomes. CONCLUSION Drug therapy of AHFS may include diuretics, vasodilators, morphine, ACE inhibitors, digoxin, inotropes, and vasopressin antagonists. Clinical practice guidelines for patients with AHFS provide a useful mechanism to incorporate available evidence and standards of practice into patient care.

An evidence based systematic review of remifentanil associated opioid-induced hyperalgesia.

Introduction: Therapeutic opioid use continues to grow, with greater than a fivefold increase in usage of fentanyl-based products over a 10-year period. Opioids are known for their side-effect profile, including bradycardia and respiratory depression; questions remain, however, regarding lesser known side effects such as opioid-induced hyperalgesia (OIH). Areas covered: A systematic review of published literature addressing remifentanil OIH in the surgical setting was completed. A search was conducted of PubMed, Embase and Ovid from 1946 until June 2013. Inclusion criteria consisted of age ≥ 18 years, humans, full-text articles and English language. A total of 35 unique articles were included. Sixteen articles reported outcomes that supported remifentanil OIH and 6 that refuted and 22 were focused on prevention. Expert opinion: There is conflicting evidence regarding the existence of remifentanil OIH. Outcomes evaluating measures of hyperalgesia frequently conclude that remifentanil OIH exists, while those evaluating opioid consumption do not. Therefore, remifentanil does induce a degree of hyperalgesia, but we do not believe that it reaches a level of clinical significance that requires prevention. If a significant concern for the development of remifentanil OIH is suspected, we suggest using the least possible effective dose of remifentanil as the primary prevention strategy.

Eptifibatide-Associated Acute, Profound Thrombocytopenia

OBJECTIVE: To describe 3 cases of eptifibatide-associated acute, profound thrombocytopenia. CASE SUMMARIES: A 40-year-old black female received eptifibatide 180-μg/kg double bolus followed by a continuous infusion of 2 μg/kg/min for percutaneous coronary intervention (PCI). The platelet count decreased from 308 times 103/mm3 to 2 times 103/mm3 4 hours after initiation of eptifibatide. Eptifibatide was discontinued and platelets were transfused. The patient developed a hematoma and petechiae. A 67-year-old white female received the same dosage regimen of eptifibatide for PCI with no serious adverse effects, with the treatment repeated one month later. At that time, she developed chest and back pain, dyspnea, wheezing, and hypotension after the first bolus. Her platelet count decreased from 334 times 103/mm3 to 6 times 103/mm3 24 hours after initiation. Eptifibatide was discontinued and platelets were transfused. The patient died due to shock. A 72-year-old white male received eptifibatide 180-μg/kg double bolus followed by a continuous infusion of 2 μg/kg/min for acute coronary syndrome. His platelet count decreased from 189 times 103/mm3 to 17 times 103/mm3, and eptifibatide was discontinued. Eptifibatide was readministered with bivalirudin for PCI once the platelet count increased to 94 times 103/mm3. Sixteen hours later, the platelet count decreased to 1 times 103/mm3. Eptifibatide was discontinued and platelets were transfused. The patient developed a hematoma. DISCUSSION: Acute, profound thrombocytopenia is a rare complication of glycoprotein IIb/IIIa inhibitor therapy characterized by a precipitous decline in platelet count to <20 times 103/mm3 within 24 hours of therapy. An objective causality assessment revealed that the adverse drug event was probable in 2 cases and possible in the other. CONCLUSIONS: Increasing use of the glycoprotein IIb/IIIa inhibitors and enhanced recognition of the potential for acute, profound thrombocytopenia reinforce the need for more vigilant monitoring and alternative management strategies.

Pharmacotherapy Update on the Use of Vasopressors and Inotropes in the Intensive Care Unit

This paper summarizes the pharmacologic properties of vasoactive medications used in the treatment of shock, including the inotropes and vasopressors. The clinical application of these therapies is discussed and recent studies describing their use and associated outcomes are also reported. Comprehension of hemodynamic principles and adrenergic and non-adrenergic receptor mechanisms are salient to the appropriate therapeutic utility of vasoactive medications for shock. Vasoactive medications can be classified based on their direct effects on vascular tone (vasoconstriction or vasodilation) and on the heart (presence or absence of positive inotropic effects). This classification highlights key similarities and differences with respect to pharmacology and hemodynamic effects. Vasopressors include pure vasoconstrictors (phenylephrine and vasopressin) and inoconstrictors (dopamine, norepinephrine, and epinephrine). Each of these medications acts as vasopressors to increase mean arterial pressure by augmenting vascular tone. Inotropes include inodilators (dobutamine and milrinone) and the aforementioned inoconstrictors. These medications act as inotropes by enhancing cardiac output through enhanced contractility. The inodilators also reduce afterload from systemic vasodilation. The relative hemodynamic effect of each agent varies depending on the dose administered, but is particularly apparent with dopamine. Recent large-scale clinical trials have evaluated vasopressors and determined that norepinephrine may be preferred as a first-line therapy for a broad range of shock states, most notably septic shock. Consequently, careful selection of vasoactive medications based on desired pharmacologic effects that are matched to the patients underlying pathophysiology of shock may optimize hemodynamics while reducing the potential for adverse effects.

Advancing Pharmacogenomics Education in the Core PharmD Curriculum through Student Personal Genomic Testing

Objective. To develop, implement, and evaluate “Test2Learn” a program to enhance pharmacogenomics education through the use of personal genomic testing (PGT) and real genetic data. Design. One hundred twenty-two second-year doctor of pharmacy (PharmD) students in a required course were offered PGT as part of a larger program approach to teach pharmacogenomics within a robust ethical framework. The program added novel learning objectives, lecture materials, analysis tools, and exercises using individual-level and population-level genetic data. Outcomes were assessed with objective measures and pre/post survey instruments. Assessment. One hundred students (82%) underwent PGT. Knowledge significantly improved on multiple assessments. Genotyped students reported a greater increase in confidence in understanding test results by the end of the course. Similarly, undergoing PGT improved student’s self-perceived ability to empathize with patients compared to those not genotyped. Most students (71%) reported feeling PGT was an important part of the course, and 60% reported they had a better understanding of pharmacogenomics specifically because of the opportunity. Conclusion. Implementation of PGT in the core pharmacy curriculum was feasible, well-received, and enhanced student learning of pharmacogenomics.

Treatment of heparin-induced thrombocytopenia : Is there a role for bivalirudin?

The recognition and management of heparin‐induced thrombocytopenia (HIT) and heparin‐induced thrombocytopenia with thrombosis syndrome (HITTS) has been evolving over the past several years. Although HIT is a relatively uncommon adverse event in patients receiving heparin therapy, it bears a significant risk of thrombotic events. If patients are left untreated, 50% can develop thrombosis. Several direct thrombin inhibitors have been studied as alternative anticoagulants in patients with HIT. Lepirudin and argatroban are both approved by the United States Food and Drug Administration (FDA) for the management of HIT. Lepirudin requires dosage adjustments in patients with renal insufficiency and has potential for antibody formation. Argatroban requires dosage adjustments in patients with hepatic insufficiency. Argatroban increases the international normalized ratio when coadministered with warfarin, leading to dosage difficulties when transitioning to warfarin therapy. Bivalirudin is the most recent direct thrombin inhibitor to be introduced to the market, but it is not currently FDA approved for HIT. Controversy stills exists over which direct thrombin inhibitor to use, especially in acutely ill patients and in those requiring invasive or surgical procedures. Bivalirudin has a relatively short half‐life and a predictable response, which makes it attractive as an anticoagulant in patients requiring invasive or surgical procedures, those who are acutely ill, or patients with both renal and hepatic insufficiency. It offers promise as an additional direct thrombin inhibitor for use in patients with HIT, but additional studies need to be performed to further define its use.

Role of Phosphodiesterase-5 Inhibitors in Heart Failure: Emerging Data and Concepts

Novel treatment of congestive heart failure (HF) involves utilizing unique pathways to improve upon contemporary therapies. Increasing the availability of cyclic guanosine monophosphate (cGMP) by inhibition of phosphodiesterase-5 (PDE5) is a relatively new, but promising therapeutic strategy. Preclinical studies suggest a favorable myocardial effect of PDE5 inhibitors by blocking adrenergic, hypertrophic and pro-apoptotic signaling, thereby supporting their use in HF. The clinical benefits of acute and chronic PDE5 inhibition on lung diffusion capacity, exercise performance and ejection fraction in humans are emerging and appear promising. Larger, controlled trials are now on-going to assess the safety, efficacy and tolerability of PDE5 inhibitors on morbidity and mortality in patients with both systolic and diastolic heart failure. If the results of these trials are positive, a new avenue for the treatment of HF will open, which will help curtail the societal effects of this costly and morbid disease.

2007 Guideline Update for Unstable Angina/Non–ST-Segment Elevation Myocardial Infarction: Focus on Antiplatelet and Anticoagulant Therapies

Objective: To summarize key changes in the 2007 American College of Cardiology/American Heart Association (ACC/AHA) guideline recommendations for pharmacologic therapy as they relate to antiplatelets and anticoagulants, and to evaluate the evidence from several landmark trials that was used to support the guideline updates for these agents. Data Sources: Literature was accessed through MEDLINE (1950–January 2008) using the search terms acute coronary syndromes, unstable angina (UA), non–ST-segment elevation myocardial infarction (NSTEMI), antiplatelet, and anticoagulant. All papers were cross-referenced to identify additional studies, Study Selection and Data Extraction: ACC/AHA guidelines, relevant original research articles, and review articles were evaluated. Studies with more than 1000 patients were the focus of the review. Data Synthesis: UA and NSTEMI are the most common presentations of acute coronary syndrome. The recently updated ACC/AHA guidelines for management of this condition were based on significant advances in pharmacotherapy including expanded use of drug-eluting stents, pretreatment with Clopidogrel, and newer anticoagulants such as bivalirudin and fondaparinux. Landmark trials have been published that describe advances in the use of antiplatelets and anticoagulants. According to the guidelines, unfractionated heparin (UFH) and enoxaparin are preferred options for both invasive and conservative management. Enoxaparin was noninferior to UFH for invasive management in the SYNERGY trial, although it was associated with a higher incidence of bleeding. Other alternatives for an invasive strategy per the guidelines include bivalirudin and fondaparinux. Bivalirudin (alone or with glycoprotein [GPJ llb/llla inhibitor) was compared with heparin plus GP llb/llla inhibitor in the ACUfTY trial of patients undergoing early invasive management. The bivalirudin groups were noninferior to standard of care, although bivalirudin alone was associated with less bleeding. Fondaparinux was found to be noninferior to enoxaparin and was associated with fewer bleeding events in the OASIS-5 study of patients who were not treated with an early invasive approach. Accordingly, the guidelines list fondaparinux as an alternative for a conservative strategy or in patients at increased risk of bleeding. Conclusions: Clinicians should be familiar with the updated 2007 ACC/AHA guidelines and the clinical trial evidence that serves as the basis for these recommendations. It is paramount for institutions to outline a preferred and consistent treatment approach. These decisions should Involve a review of established efficacy, bleeding risk, need for anticoagulant reversal, costs, and clinician familiarity with different treatment regimens.

Oral treprostinil for the treatment of pulmonary arterial hypertension in patients transitioned from parenteral or inhaled prostacyclins: case series and treatment protocol.

Oral treprostinil (TRE) is a prostacylin approved for the management of pulmonary arterial hypertension (PAH). Few data exist to guide the use of oral TRE as a replacement for parenteral or inhaled prostacyclins. Therefore, the purpose of this report was to describe our experience with oral TRE to transition patients from parenteral or inhaled TRE. We describe a case series of patients admitted for a 4-day hospital stay to transition from parenteral or inhaled TRE. Appropriate criteria for transition included stable patients with improved symptoms/functional capacity, patients who could not tolerate intravenous prostacyclin due to infection or subcutaneous prostacyclin due to pain, and patient preference for transition. The dosing protocol for transition is described. A total of 9 patients generally representative of a typical PAH demographic and background medical therapy were included. Patients were initiated at either 0.5 or 1 mg 3 times daily and discharged on a median dose of 8 mg 3 times daily. Our protocol resulted in 6 of 9 patients who successfully transitioned at a median follow-up of 47 weeks. Two patients had to return to their previous prostacyclin therapy based on the presence of clinical worsening and adverse events (n = 1) and adverse events alone (n = 1). Another patient discontinued therapy due to plans for hospice care. Oral TRE may serve an important role in prostacyclin transitions in carefully selected, stable patients who receive background oral therapy for PAH.

Worsening Heart Failure in the Setting of Dronedarone Initiation

Objective: To describe a challenging patient case in which dronedarone was selected for a patient with atrial fibrillation and heart failure; the drug may have been associated with worsening heart failure, leading to acute renal and hepatic failure. Case Summary: A 47-year-old male with a history of heart failure with New York Heart Association class III—IV symptoms presented to our institution with ventricular fibrillation and ventricular tachycardia storm. Torsade de pointes secondary to a combination of doletilide and hypokalemia was determined to be the etiology. Upon stabilization, the patient was initiated on dronedarone 400 mg orally twice daily by the electro physiology service for atrial fibrillation. The patient had a questionable history of amkxtaroπe intolerance. By hospital day 9 (day 4 of dronedarone therapy), the patient demonstrated a clinical picture consistent with acute renal and hepatic failure possibly due to worsening heart failure. Dronedarone was discontinued on hospital day 10. He was subsequently transferred to an outside hospital where he required milrinone therapy for cardiogenic shock. Laboratory markers of renal and hepatic function improved over the remainder of his hospitalization and he was discharged on hospital day 20. Discussion: Dronedarone is a newly approved antiarrhythmic agent with multichannel blocking properties similar to amiodarone. Use of the Naranjo probability scale determined that this patients worsening heart failure leading to acute renal and hepatic failure was possibly caused by dronedarone. The implication from the ANDROMEDA trial as well as our experience in this case is that dronedarone should be used cautiously in patients with heart failure and avoided in patients specifically outlined in the product labeling. Conclusions: This case report, to our knowledge, represents the first published postmarketing report of worsening heart failure complicated by multiorgan dysfunction in the setting of dronedarone initiation. Dronedarone use must be approached with caution in patients with a history of heart failure.