Impact of the cost of prescription drugs on clinical outcomes in indigent patients with heart disease.

STUDY OBJECTIVE: To measure the impact that economic relief for prescription drugs to indigent patients with cardiovascular disease has on indicators of disease control. DESIGN: Prospective cohort study. SETTING: University inner-city outpatient clinic. PATIENTS: One hundred sixty-three indigent patients with heart disease who were uninsured or whose insurance plan did not provide prescription drug coverage and who had baseline data. INTERVENTION: Patients were assisted in obtaining prescription drugs, free of charge, in an attempt to improve adherence to their drug regimens. MEASUREMENTS AND MAIN RESULTS: The primary end point was to determine if cardiovascular outcome measures (i.e., international normalized ratio [INR], blood pressure, low-density lipoprotein [LDL] cholesterol, and hospitalizations) and drug adherence improved in all patients after 6 months of prescription assistance compared with a 6-month baseline period. In patients receiving warfarin, mean INR increased from 2.44 +/- 0.64 at baseline to 2.61 +/- 0.53 at 6 months (p<0.05). In patients with hypertension, mean blood pressure decreased from 138 +/- 20/80 +/- 11 mm Hg at baseline to 138 +/- 19/78 +/- 12 mm Hg at 6 months (p<0.05 for diastolic blood pressure only). The mean LDL level for patients on lipid-lowering drugs significantly decreased from 126 +/- 39 mg/dl at baseline to 108 +/- 38 mg/dl at 6 months (p<0.001). For each disease measure, the improved disease control seen at 6 months persisted throughout 24 months of follow-up. Hospitalizations for the entire cohort decreased from 85 at baseline to 49 at 6 months. Patient drug adherence improved from 48.5% at baseline to 72.7% at 6 months (p<0.001). CONCLUSIONS: Drug adherence and clinical outcomes improved, and the number of hospitalizations declined when cardiovascular drugs were obtained for patients who could not afford to pay for them. Health care insurance plans that do not provide coverage for cardiovascular prescription drugs may be more costly secondary to poor disease control and increased hospitalizations.

Analysis of the use of digoxin immune fab for the treatment of non-life-threatening digoxin toxicity.

BACKGROUND: Studies indicate that digoxin toxicity often results in lengthy hospitalizations and considerable costs, both of which may be decreased through the routine use of digoxin immune Fab (FAB). METHODS: A computer-based decision analysis model was developed to compare the treatment of non-life-threatening digoxin toxicity with either FAB or standard therapy from the hospital perspective. A cost-minimization analysis was then performed to compare overall total costs (primary endpoint) for each treatment branch. A secondary endpoint of length of hospital stay (LOS) was also compared between the 2 groups. Clinical variables (serum digoxin concentration [SDC], creatinine clearance [Clcr], and body weight), event probabilities, and other model-specific variables were varied in univariate and multivariate sensitivity analyses. RESULTS: FAB was associated with an incremental cost of $54 compared with standard therapy ($2,784 vs. $2,730, respectively) but reduced LOS by 1.5 days (1.5 days vs. 3.0 days, respectively). Sensitivity analyses show that FAB is less costly at SDC > 3.5 ng/mL and Clcr < 22 mL/min. FAB reduced LOS at SDC > 2.3 ng/mL. Monte Carlo simulation revealed that FAB was less costly in 37% of the cases and reduced LOS 72% of the time compared with standard therapy. CONCLUSIONS: The abbreviated LOS associated with the use of FAB in patients with non-life-threatening digoxin toxicity may translate into lower treatment costs in many clinical scenarios, making it a cost-saving alternative to standard therapy in patients with high SDC and renal dysfunction.

Rationale, development, and clinical outcomes of a multidisciplinary amiodarone clinic.

OBJECTIVES: To review the rationale and development of a multidisciplinary amiodarone clinic, and document the clinical outcomes resulting from its implementation. METHODS: A clinic was established to provide an ambulatory setting in which patients receiving amiodarone could be followed according to published guidelines by a multidisciplinary team of cardiovascular health care specialists. Patients receiving amiodarone were referred to the clinic by their primary physicians. A data base containing each patient's medical history, current drug therapy, and baseline laboratory values was developed during the initial visit. Liver function tests, thyroid function tests, and chest radiographs were performed every 6 months, and pulmonary function tests were scheduled on an annual basis. Dosage adjustments were performed in select patients. RESULTS: Since November 1996, 60 patients have been referred to the amiodarone clinic. Mean length of follow-up before and after referral was 16.3+/-25.5 and 9.2+/-5.5 months, respectively. Laboratory tests were performed according to accepted guidelines in 14 (23%) patients before referral compared with 54 (90%) patients after enrollment (p<0.001). Previously unrecognized adverse events were detected in 21 (35%) patients, including pulmonary fibrosis, QT prolongation, liver enzyme elevation, hypothyroidism, hyperthyroidism, and asthma exacerbation. Amiodarone was discontinued in six patients, four of whom had suspected pulmonary toxicity. The dose of amiodarone was adjusted in 29 (48.4%) patients. CONCLUSION: Many patients receiving amiodarone are not being followed according to published recommendations. Implementation of a specialized, multidisciplinary amiodarone clinic improves outcomes by monitoring for early detection of drug-related toxicities and by facilitating proper dosage modifications.

Prolongation of the QT interval related to cisapride-diltiazem interaction.

Cisapride, a cytochrome P450 3A4 (CYP3A4) substrate, is widely prescribed for the treatment of gastrointestinal motility disorders. Prolongation of QT interval, torsades de pointes, and sudden cardiac death have been reported after concomitant administration with erythromycin or azole antifungal agents, but not with other CYP3A4 inhibitors. A possible drug interaction occurred in a 45-year-old woman who was taking cisapride for gastroesophageal reflux disorder and diltiazem, an agent that has inhibitory effect on CYP3A4, for hypertension. The patient was in near syncope and had QT-interval prolongation. After discontinuing cisapride, the QT interval returned to normal and symptoms did not recur. We suggest that caution be taken when cisapride is prescribed with any potent inhibitor of CYP3A4, including diltiazem.

Comparison of intravenous diltiazem and verapamil for the acute treatment of atrial fibrillation and atrial flutter.

STUDY OBJECTIVES: To compare the efficacy and safety of intravenous diltiazem and verapamil in controlling ventricular rate in patients with atrial fibrillation or flutter, and to evaluate the effects of these agents on left ventricular systolic function. DESIGN: Prospective, randomized, double-blind, crossover study. SETTING: University-affiliated hospital and Veterans Administration hospital. PATIENTS: Seventeen men with atrial fibrillation or flutter with a ventricular rate of 120 beats/minute or higher and a systolic blood pressure of 100 mm Hg or greater. INTERVENTIONS: Patients received up to two intravenous boluses of either diltiazem or verapamil, followed by an 8-hour continuous infusion if a therapeutic response was achieved (phase I). After a washout period, patients who responded were crossed over to receive the other drug in a similar fashion (phase II). MEASUREMENTS AND MAIN RESULTS: At the end of each infusion, the patient's ejection fraction was assessed by gated angiography. Of the 17 men initially randomized, 8 successfully completed both phases I and II. In these patients, baseline mean (+/- SD) ventricular rates before treatment with intravenous diltiazem and verapamil were 138 +/- 15 and 132 +/- 9 beats/minute, respectively (NS). At 2 minutes after the initial bolus dose, the mean ventricular rate decreased to 100 +/- 13 beats/minute in the diltiazem group compared with 114 +/- 17 beats/minute in those receiving verapamil (p < 0.05). Mean ventricular rates of 96 +/- 11 and 97 +/- 9 beats/minute were maintained during the 8-hour continuous infusion of diltiazem and verapamil, respectively (NS). On completion of the bolus dose(s) and during continuous infusions, there were no significant differences in blood pressures between the groups. Mean ejection fractions were 35.6 +/- 13.6% and 35.5 +/- 15.4% in the diltiazem and verapamil groups, respectively (NS). For the 17 patients, the mean maximum percentage decreases in blood pressure were not significantly different between groups. However, three patients developed symptomatic hypotension, all of whom were randomized to receive verapamil initially. CONCLUSION: Intravenous diltiazem and verapamil are comparable in terms of efficacy and effect on systolic function in patients with rapid atrial fibrillation and flutter. However, hypotension may limit therapy with verapamil in some patients.

Evaluation of two forms of sustained release nifedipine using 24 h ambulatory blood pressure monitoring.

Therapeutic interchange between the available forms of sustained release nifedipine (osmotic-pump and coat-core forms of nifedipine) is a matter of controversy. This study was initiated to determine whether there is a difference in clinical outcomes when there is interchange between the two forms of sustained release nifedipine when used for the treatment of hypertension. A total of 43 patients with a history of stage I hypertension who were receiving stable doses of the osmotic-pump form of nifedipine for > 3 months with controlled blood pressures (< 150/90 mm Hg) were enrolled. Patients were then switched to the same dose of the coat-core form of nifedipine and were followed for 3 months. In the 36 patients who completed the study, mean trough serum nifedipine concentrations were significantly higher with the osmotic-pump from (46.5 +/- 35.0 ng/mL) of nifedipine compared with the coat-core form (27.2 +/- 20.4 ng/mL) (P < .05). However, blood pressure control as determined by the indices of 24 h ambulatory blood pressure monitoring, trough blood pressures and load blood pressures were similar between the osmotic-pump and coat-core forms of nifedipine. The coat-core form of nifedipine was discontinued in four patients for possible side effects. In this group of patients with mild hypertension, there were no clinically relevant differences in blood pressure control between the two forms of nifedipine. Some patients on the coat-core form of nifedipine may need to discontinue therapy due to intolerable side effects.

Economic impact of digoxin toxicity.

The costs of digoxin toxicity to the US healthcare system have not been previously reported. Therefore, the 1994 database of US University Health-System Consortium (UHC) was searched for cases of digoxin toxicity using the International Classification of Diseases (9th edition) [ICD-9] codes. In addition, the medical records of 17 patients admitted to the University of Illinois Hospital from September 1994 to July 1995 with a diagnosis of digoxin toxicity were also reviewed. Of the 17 patients, 14 were admitted with a primary diagnosis of digoxin toxicity. Causes of digoxin toxicity were worsening renal function (6 patients), excessive dosage prescribed (4 patients), excessive dosage self-administered (2 patients), multiple prescriptions (2 patients), accidental ingestion (1 patient), drug-drug interaction (1 patient) and unknown (1 patient). Digoxin toxicity could have been prevented in 9 (53%) of the 17 patients. The mean length of stay in the hospital as a result of digoxin toxicity was 3.3 +/- 1.2 days. The mean laboratory cost associated with digoxin toxicity was $US275.54 +/- $US106.57 and the mean hospital bed cost was $US3781.92 +/- $US2572.22. The mean overall cost associated with digoxin toxicity was $US4087.05 +/- $US2659.76. There was a significant correlation between the total cost associated with digoxin toxicity and the serum digoxin concentration on admission (r = 0.73, p < 0.01). From the UHC database, a total of 836 cases of digoxin toxicity in 56 hospitals were identified. This represented the occurrence of digoxin toxicity in 0.07% of all patients admitted to these US academic hospitals. Digoxin toxicity results in considerable costs to the healthcare system. Most cases can be considered readily preventable with proper patient counselling and education.

Postabsorption concentration peaks with brand-name and generic verapamil: a double-blind, crossover study in elderly hypertensive patients.

The pharmacokinetic actions, bioequivalence, and cardiovascular effects of two verapamil products were studied in a randomized, double-blind, crossover study in eight elderly hypertensive patients (median age, 69.5 years; range, 60-79 years) given brand-name or generic immediate-release verapamil in 120-mg twice-daily doses for 14 days. Blood pressures, heart rates, P-R intervals; and serum concentrations of R-/S-verapamil and norverapamil were measured multiple times in patients during the last day of each therapy. Median blood pressure decreased more with generic verapamil than with the brand-name drug, with the largest difference occurring at 0.5 hours (137/74 mmHg versus 144.5/80.5 mmHg; P = 0.05 and 0.091, respectively). Pharmacokinetic parameters were not different for the two products (P < 0.01). However, the generic product, compared with the brand-name drug, had mean area under the concentration-time curve (time 0 to 12 hours) ratios (90% CI) of 1.09 (0.78-1.52), 1.16 (0.87-1.55) and 1.11 (0.81-1.52) for R-, S-, and total verapamil. Seventy concentration peaks (31 with the brand-name drug, 39 with the generic drug) appeared between 8 and 24 hours. Median percentages of increase of these peaks, compared with those of previous concentrations, were 48.3% and 36.3% for brand-name and generic drugs, respectively. Fifty of the 70 peaks (71%) were associated with a stereospecific concentration peak of norverapamil and, temporally, with meals. Our findings suggest that whereas the two verapamil products may not be bioequivalent by Food and Drug Administration criteria, the observed differences in effects were not clinically significant in this elderly population. Multiple concentration peaks after absorption were observed in all patients with both verapamil products and were perhaps related to enterohepatic recirculation.

Class III antiarrhythmic agents: the next wave.

Class III antiarrhythmic agents are characterized by their ability to prolong action potential and increase refractoriness. The use of these drugs namely, sotalol hydrochloride and amiodarone hydrochloride, is rising. Both agents are effective for treating a range of ventricular arrhythmias, and amiodarone in particular has been linked with improved mortality in certain patient populations compared with class I agents. Sotalol and amiodarone have individual, complex pharmacologic profiles. As a result, there are also differences in their side effects and proarrhythmic actions. Sotalol is associated with side effects related to beta-adrenergic blockade and an incidence of proarrhythmia similar to that of class Ia agents. Amiodarone is associated with pulmonary toxicity and other adverse events, but rarely induces torsades de pointes. These agents must be differentiated from pure class III potassium channel blockers, such as the dextro isomer form of sotalol, which is linked to increased mortality compared with placebo in post-myocardial infarction patients with reduced ventricular function or a history of heart failure.

Racial and gender differences in endothelin-1.

In summary, ET-1 levels were significantly increased in black men compared with white men. This racial difference could have important research implications if increased ET-1 levels are linked to left ventricular hypertrophy and other cardiovascular diseases, and it may serve as a foundation for future studies.

Pharmacologic profile of survivors of acute myocardial infarction at United States academic hospitals.

Optimal drug therapy for patients with acute myocardial infarction (AMI) is well described in the medical literature. However, data on the actual pharmacologic management of patients surviving AMI at academic hospitals is unavailable. The purpose of this study was to document treatment profiles in 500 patients surviving AMI at 12 academic hospitals in the United States. These profiles were compared with established guidelines and were evaluated for trends. Overall, thrombolytics (streptokinase > or = tissue-type plasminogen activator) were administered in 29% of the patients, with a greater proportion of patients receiving beta-blockers than calcium channel antagonists in the initial 72 hours (61% vs 40%; p < 0.005) and at discharge (51% vs 35%; p < 0.005). Further, women were less likely than men to receive thrombolytic therapy (odds ratio [OR] = 0.61; confidence interval [CI], 0.54 to 0.69) or beta-blocker therapy within the first 72 hours (OR = 0.61; CI, 0.55 to 0.67) or at hospital discharge (OR = 0.53; CI, 0.48 to 0.58). Overall, improvements could still be made in the number of patients who receive thrombolytic and acute and chronic beta-blocker therapies after AMI, particularly in women. Changes in treatment profiles may be a reflection of the publication of large clinical trials.

Serum nifedipine concentrations and response of patients with pulmonary hypertension.

In patients with primary pulmonary hypertension who respond to nifedipine during acute drug testing, there is a significant linear correlation of serum nifedipine concentration with pulmonary artery pressure and resistance. Although most demonstrate an initial response at readily attainable nifedipine concentrations with conventional dosages, a subset of patients seem to display delayed or incomplete oral absorption; these results may facilitate the clinical use of nifedipine in patients with primary pulmonary hypertension.

Cocaine concentration-effect relationship in the presence and absence of lidocaine: evidence of competitive binding between cocaine and lidocaine.

UNLABELLED: To better understand the interaction between cocaine and lidocaine, we studied the cocaine's concentration-effect relationship for action potential duration (APD) and the rate of rise of phase 0 of the action potential (Vmax) of canine papillary muscle in the presence and absence of lidocaine. We measured APD and Vmax during programmed stimulation and superfusion with normal Tyrode's, 30 microM cocaine and 30 microM cocaine + 30 microM lidocaine. Using two microelectrodes, we simultaneously recorded action potentials from two sites during programmed stimulation and measured the conduction velocity and effective refractory period during exposure to normal Tyrode's, cocaine and cocaine + lidocaine. Cocaine with or without lidocaine delayed the plateau of the APD restitution curve. At 1000 msec cycle length, the addition of 30 microM lidocaine to the superfusate containing 30 microM cocaine shortened the time constant for reactivation of Vmax from 514 +/- 63 to 234 +/- 28 msec (P < .01). Lidocaine also improved the conduction velocity decreased by cocaine, but did not significantly change the effective refractory period. The configuration of cocaine concentration-effect curve for APD was biphasic. For cocaine concentrations < 100 microM, APD progressively shortened prolonged with increasing concentrations. As cocaine concentrations increased > 100 microM, APD progressively shortened. The addition of lidocaine to the superfusate with cocaine > 100 microM tended to attenuate the progressive APD shortening due to cocaine. Lidocaine shifted the curve correlating cocaine concentration and reduction of Vmax rightward, but preserved Emax at cocaine concentration > 225 microM. These findings suggest competitive antagonism between cocaine and lidocaine at a single sodium channel receptor. CONCLUSION: lidocaine displaces cocaine from the sodium channel receptor through competitive binding. Lidocaine may prove to be beneficial in reversing cocaine-induced slowing of ventricular conduction.

QT interval prolongation and torsades de pointes due to erythromycin lactobionate.

STUDY OBJECTIVES: To discern the frequency of torsades de pointes and QT prolongation in patients receiving intravenous erythromycin lactobionate; to examine the degree of QT prolongation and QT dispersion due to intravenous erythromycin in a typical clinical setting; and to identify any concurrent factors that might predispose patients to excessive QT prolongation or torsades de pointes while receiving intravenous erythromycin. DESIGN: Retrospective cohort trial. SETTING: A university teaching hospital. PATIENTS: All inpatients who received intravenous erythromycin lactobionate during a 1-year period. MEASUREMENTS AND MAIN RESULTS: The records of 278 consecutive patients were analyzed, of whom 49 had 12-lead electrocardiograms while receiving and not receiving erythromycin. The dosages of erythromycin ranged from 18-83 (42 +/- 18) mg/kg/day. Of the 49 patients, the baseline QTc was 432 +/- 39 msec, compared with 483 +/- 62 msec during erythromycin therapy (p < 0.01). In 30 of 49 patients with heart disease, the increase in QTc due to erythromycin was 15 +/- 11%, compared with 8.6 +/- 10% in the 19 patients without heart disease (p < 0.05). The degree of QTc dispersion was 34 +/- 16 msec at baseline, compared with 80 +/- 35 msec with erythromycin (p < 0.01). Overall, 19 (39%) of 49 patients had a moderate to severe delay in ventricular repolarization (QTc > or = 500 msec). Of the 278 patients prescribed intravenous erythromycin over the year, it caused torsades de pointes in just one (< or = 0.4%). CONCLUSION: Erythromycin lactobionate-induced torsades de pointes is rare, although QT prolongation is common. Some patients may be at risk for suffering torsades de pointes due to this agent, particularly if heart disease or other factors that may further delay ventricular repolarization are present.

Prescribing trends and pharmacoeconomic considerations in the treatment of arrhythmias. Focus on atrial fibrillation and flutter.

Considerable progress has been made regarding the treatment of atrial fibrillation and atrial flutter. However, controversies still exist with respect to the therapy of choice for ventricular rate control, requirements for long term preventive therapy, and the place of surgical and ablation alternatives. Surrounding these controversies also lies a paucity of pharmacoeconomic studies, which limits delineation of the most cost-effective therapy for patients with atrial fibrillation and atrial flutter. This article reviews prescribing trends in the US for antiarrhythmic agents, and the available pharmacoeconomic studies that have specifically addressed the treatment of atrial fibrillation and atrial flutter.

Effective use of magnesium for acquired torsade de pointes in a 4-month-old infant.

We report a 4-month-old infant with torsade de pointes secondary to procainamide treatment. The infant presented with atrial flutter and converted to normal sinus rhythm with intravenous procainamide. Oral procainamide therapy was initiated as the infusion was tapered, and the patient subsequently developed incessant torsade de pointes. Once the proarrhythmia was recognized, procainamide was withheld, and intravenous magnesium was administered. The torsade de pointes resolved after one bolus of magnesium sulfate. An infusion regimen of magnesium was given until the procainamide and N-acetylprocainamide concentrations became undetectable. Intravenous magnesium should be administered to newborns with acquired torsade de pointes; dosing guidelines for its use are suggested.

Reversal of the electrocardiographic effects of cocaine by lidocaine. Part 2. Concentration-effect relationships.

Ventricular arrhythmias due to cocaine may be related to its ability to slow ventricular conduction or prolong repolarization. We previously showed that lidocaine reversed QRS prolongation due to cocaine. The purposes of these experiments were to characterize cocaine's concentration-effect relationship on both ventricular conduction and repolarization, and to determine the effects of lidocaine on these relationships. The effects of lidocaine on cocaine-induced electrocardiographic changes were studied in 20 isolated, Tyrode-perfused guinea pig hearts. Variables at cocaine concentrations ranging from 3-195 microM were measured and repeated in the presence of a fixed concentration of lidocaine 30 microM. Using nonlinear regression analysis, the sigmoid Emax and simple Emax models were fit to cocaine concentration versus percentage change in QRS plots. Measures of best fit indicated that this relationship was best described by the sigmoid Emax model. Compared with cocaine alone, the curve for cocaine with lidocaine showed a greater EC50 (concentration at 50% of maximum effect) (59 vs 100 microM) but similar Emax (371 vs 367%), consistent with competition. Similar values were obtained from the linear transformation of the data. Cocaine concentration versus percentage change in the JTc interval showed a biphasic effect: concentrations below 65 microM prolonged JTc, but those above 65 microM had no effect or decreased JTc. In contrast to changes in QRS, addition of lidocaine increased the effects of cocaine on JTc: area under the concentration-effect curve for cocaine alone was 720 versus 859 microM% for cocaine with lidocaine. Lidocaine reverses cocaine-induced slowed ventricular conduction through competition for binding, but it appeared to increase cocaine-induced prolongation of repolarization.(ABSTRACT TRUNCATED AT 250 WORDS)