David S. Roffman

Outpatient dobutamine and dopamine infusions in the management of chronic heart failure: Clinical experience in 21 patients

Dobutamine (and dopamine) are potent positive inotropic drugs which are frequently given to treat decompensated congestive heart failure. This study reports on the use of ambulatory dobutamine (and dopamine) infusions in 21 outpatients with advanced congestive heart failure. Each patient was initially hospitalized, and hemodynamic and clinical efficacy to dobutamine (and dopamine) was assessed. These 21 patients were carefully selected from a larger population of approximately 40 patients referred for this therapy. Chronic venous access was established and a drug infusion pump was supplied. Patients and family members were trained in the use of these devices. Eleven patients were treated with intermittent dobutamine infusions for 48 consecutive hours weekly, six patients with continuous (i.e., 24 hours daily) dobutamine infusions, and four patients with continuous, daily dobutamine and dopamine infusions. Significant (p less than 0.001) increases in cardiac index (1.8 +/- 0.6 to 2.7 +/- 0.7 L/min/m2) occurred during the initial dobutamine titrations. Functional classification (3.8 +/- 0.4 to 2.8 +/- 0.7) also improved significantly (p less than 0.01) during the 1.8 to 24 (mean 7.8) months of outpatient infusion therapy with dobutamine (and dopamine). Complications during outpatient therapy included drug tolerance (two instances), infection (two with bacteremias, eight with exit site infections), drug extravasation (three instances), and pump malfunction (two instances). Twenty patients have died: eleven from heart failure, four suddenly (one of them 9 months after dobutamine was stopped), and five from noncardiac causes. Our data suggest that outpatient dobutamine (and dopamine) infusions may be an effective form of therapy for selected patients with severe congestive failure who are refractory to more conventional treatment or who are awaiting cardiac transplantation.

The effects of diuresis on the pharmacokinetics of the loop diuretics furosemide and torsemide in patients with Heart failure

PURPOSE To evaluate the pharmacokinetics of furosemide and torsemide before and after diuresis in patients presenting with marked fluid overload. SUBJECTS AND METHODS We studied 44 patients with New York Heart Association class III or IV heart failure, ejection fraction < or =40%, and an estimated excess fluid body weight > or =6.8 kg. Oral furosemide or torsemide was administered before and after diuresis. Pharmacokinetic parameters were assessed before and after diuresis. RESULTS Following diuresis, maximum plasma concentration increased from 11.0+/-5.0 microg/mL to 13.9+/-6.8 with torsemide (P <0.05) and from 3.1< or =1.5 to 3.9+/-1.9 with furosemide (P=0.16). Maximum concentration increased by more than 30% in only one third of the patients. Total absorption (by area under the curve method) increased 6% among patients on torsemide (P=0.38) and 7% among patients on furosemide (P=0.63) and increased >30% in only 1 torsemide and 2 furosemide patients. The time to maximum concentration decreased from 1.40+/-.82 h to 0.81+/-0.36 with torsemide (P <0.01). There were no differences between furosemide and torsemide in the effects of edema on absorption. CONCLUSION Marked diuresis altered the pharmacokinetics of both furosemide and torsemide in only a small percentage of patients. The use of adequate doses of oral diuretics in edematous patients may be successful, thereby permitting home treatment with oral diuretics and avoiding the cost of hospitalizations or home intravenous administration services.

High- Versus Low-Dose ACE Inhibitor Therapy in Chronic Heart Failure

OBJECTIVE To discuss the controversy associated with the optimal dosing of angiotensin-converting enzyme (ACE) inhibitors in the management of patients with systolic heart failure; specifically, to review data related to the use of high-dose ACE inhibitors related to both neurohormonal and clinical outcomes associated with doses similar to, lower than, and higher than those used in the large, randomized clinical trials. DATA SOURCES Primary, review, and meta-analysis articles were identified by MEDLINE search (1987–September 2002) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION All of the articles identified from the data sources were evaluated, and all information deemed relevant was included in this discussion. All available comparative dose trials, both prospective and retrospective, were evaluated for clinical and neurohormonal outcomes. DATA SYNTHESIS The majority of data comparing the effect of high- with low-dose ACE inhibitors on neurohormonal outcomes demonstrate dose-related reduction in various neurohormonal measurements including plasma ACE, aldosterone, atrial natriuretic peptide, B-type natriuretic peptide, and interleukin-6 levels. Clinical endpoints including New York Heart Association class and heart failure—related hospitalizations were reduced by higher doses, but a dose-related survival benefit has not been demonstrated. Differences in duration of therapy and study design may account for variability in neurohormonal and morbidity results among various studies. CONCLUSIONS Despite documented underutilization in clinical practice of doses of ACE inhibitors demonstrated in large controlled trials to improve morbidity and mortality, clinicians should attempt to reach these target doses if possible in patients with heart failure. Higher doses may improve surrogate markers for heart failure without impacting survival.

Digitalis and other positive catecholamine-like inotropic agents in the management of congestive heart failure

Positive inotropic agents are used to improve the impaired cardiac contractility that characterizes chronic heart failure. Digitalis is the traditional drug given for this purpose. However, there is controversy about the effectiveness of digitalis in chronic heart failure. Analysis of the available data indicates the efficacy of digoxin in mild heart failure (i.e., New York Heart Association functional classes I and II) and the relative lack of efficacy in advanced heart failure (i.e., NYHA functional class IV). Further, digoxin can be stopped in a substantial number of patients without recurrence of congestive heart failure. In selected patients whose condition no longer responds to digoxin, the long-term administration of dobutamine may be an effective alternative approach.

Digoxin pharmacokinetics in congestive heart failure.

Abstract: The steady‐state pharmacokinetics of oral digoxin in eight hospitalized patients was compared upon their admission with marked right‐sided congestive heart failure and later when they were compensated. Large intersubject variations in the serum digoxin concentration profiles were observed. However, over a 24‐hour dosing interval, digoxin concentrations in each patient studied during heart failure were either similar or higher than those observed when the patient became compensated. There were no significant differences in digoxin half‐life of elimination between the two states. In contrast, the mean ratio of the fraction of digoxin dose absorbed to its apparent volume of distribution was increased by 37 per cent (P < 0.05) in heart failure. Contrary to the prevailing notion, we found that the oral administration of supplemental doses of digoxin only on the basis of its reduced serum concentration in patients with congestive heart failure is unwarranted.

Incident depression increases medical utilization in Medicaid patients with hypertension.

Hypertension is an important risk factor for cardiovascular disease and occurs disproportionately among patients with depression. Few studies have rigorously examined outcomes specifically among hypertensive patients with newly diagnosed comorbid depression. Aim: We hypothesized that incident depression would exacerbate hypertensive disease and that this would be evident through greater utilization of medical services than would otherwise occur in the absence of depression. Methods: Claims data for hypertensive patients enrolled in Maryland Medicaid (2005–2010) were used to estimate the change in annualized utilization following incident depression, compared to a matched cohort of hypertensive patients never diagnosed with depression. Multivariate regression was used to adjust for changes in antihypertensive medications, adherence and comorbidity that followed depression onset. Results: While medical utilization increased after incident depression, additional encounters tended to be for nonacute medical care and there was no significant increase in encounters specifically for cardiovascular or hypertension-related conditions. Discussion: The results contribute to the discussion on the relationship between depression and cardiovascular disease and will inform future studies that aim to look at longer term outcomes in patients with hypertension.

Pharmaceutical Restrictions Possible Effect on Patient/Physician Buy-In of Disease Management Programs

Restrictions on the use of pharmaceuticals (such as those for low molecular weight heparins) are commonly imposed by healthcare organizations to combat rising health care costs. These restrictions can be system-based which are established by imposing specific coverage policies by insurance companies and payors or can be patient-based which are those that limit certain therapeutic agents to specified patient populations.Disease management (DM) programs are implemented by healthcare organizations to improve patient care while utilizing resources efficiently. From a payor perspective, restricted use of pharmaceuticals would conform to the goals of DM. However, from a practitioner’s perspective, restrictions on the use of medications could sometimes be viewed as conflicting with their goal of providing appropriate patient care. Formularies and prior-authorization programs may sometimes impede physicians’ clinical autonomy and may hinder physicians’ willingness to participate in DM protocols with such drug restrictions. Furthermore, direct-to-patient advertisements and patient education are encouraging patients to participate actively in the drug selection process. When pharmaceutical restrictions prevent patients from receiving their drug of choice, patients may perceive that their treatment is suboptimal and unfavorable.Despite implementing a fine disease management protocol, imposing rigid drug-use restrictions could hinder physicians’ and patients’ buy-in of DM programs.

BETA BLOCKERS IN THE· ELDERLY

Adrenergic blocking drugs have become one of the most widely prescribed groups of agents in the current armamentarium of drugs for the treatment of a variety of cardiovascular and noncardiovascular disorders. Because diseases such as hypertension, angina, myocardial infarction, and arrhythmias are so prevalent among the elderly, beta blockers are commonly used in this population. There is, however, a significant amount of controversy involving the need to treat some of these problems in the elderly and additional doubt as to whether geriatric patients are less sensitive to the therapeutic effects of these drugs or are at greater risk of toxicity from this class of agents. The purpose of this chapter is to review the evidence documenting the efficacy of β-adrenergic blocking agents in the elderly as well as the data that quantitate the altered pharmacokinetics of beta blockers in the geriatric population. In addition, we will discuss methodology that is most appropriate to study β-blocking drugs in the elderly.