Cost effectiveness of outpatient anticoagulant prophylaxis after total hip arthroplasty.

Guidelines for deep venous thrombosis (DVT) and pulmonary embolism (PE) prophylaxis have been developed for patients undergoing total hip arthroplasty (THA). Studies suggest that risk for developing these complications may exist for as long as 3 months following surgery. Cost-effectiveness analyses were performed on three pharmacoprophylaxis regimens administered over a 30-day period using literature-reported values for incidences of DVT and PE in patients postdischarge following THA. A cost savings of $21,466.89 will occur for each thromboembolic event avoided if low-dose warfarin daily is used routinely compared to enoxaparin 40 mg daily. Additionally, a cost savings of $18,618.10 is experienced if enoxaparin 40 mg daily for 4 days plus low-dose warfarin daily is administered versus enoxaparin 40 mg daily. Clinicians may choose to continue prophylaxis postdischarge with enoxaparin 40 mg daily for 4 days in combination with warfarin for 30 days in these patients until results of more definitive studies become available.

Prevention of venous thromboembolism: adherence to the 1995 American College of Chest Physicians consensus guidelines for surgical patients.

BACKGROUND: The American College of Chest Physicians addressed the dilemma of identifying optimal therapy for venous thromboembolism (VTE) prophylaxis and published their Fourth Consensus Conference on Antithrombotic Therapy in 1995, with recommendations for prophylactic therapy. Despite these recommendations, appropriate VTE prophylactic therapy is underused. OBJECTIVES: To examine routine practices in the prevention of VTE in high-risk surgical patients and to determine the extent of adoption of grade A prophylactic therapies as recommended by the American College of Chest Physicians. METHODS: Retrospective medical record review in 10 teaching or community-based hospitals located in the United States. Medical charts of 1907 patients were randomly selected for review from the population of patients who underwent high-risk major abdominal surgery, total hip replacement, hip fracture repair, or total knee replacement between January 1, 1996, and February 28, 1997. RESULTS: Of 1907 patients, VTE prophylaxis was used in 89.3%; use was 93.7% in each of the 3 orthopedic surgery groups and 75.2% in the high-risk major abdominal surgery group. The percentage of patients receiving grade A therapy was highest in the hip replacement group (84.3%) vs. the other groups (knee replacement, 75.9%; hip fracture repair, 45.2%; abdominal surgery, 50.3%). CONCLUSIONS: The use of grade A prophylaxis was related to the type of surgery, with the highest use seen in total hip replacement and the lowest in hip fracture repair. One in 4 patients who underwent high-risk major abdominal surgeries failed to receive any form of VTE prophylaxis. Publication of consensus statements alone may be insufficient to ensure the incorporation of important new clinical information into routine practice.

A pharmacoeconomic assessment of enoxaparin and warfarin as prophylaxis for deep vein thrombosis in patients undergoing knee replacement surgery.

This paper examines the relative cost-effectiveness of enoxaparin and warfarin as prophylactic therapy for the prevention of deep vein thrombosis (DVT) in patients undergoing knee replacement surgery in a managed care setting. Although enoxaparin is more expensive than warfarin, it is also more effective in the prevention of DVT after knee replacement surgery. To date there has been no comprehensive assessment of the cost-effectiveness of the alternative agents used for this purpose. This evaluation is undertaken using a decision model that contrasts enoxaparin and warfarin regimens. The model takes explicit account of the incidence of proximal DVT, distal DVT, pulmonary embolism (PE), and major bleeds. The probabilities of clinical events are taken from data from a published randomized, controlled, clinical trial. Key assumptions are that PEs derive only from asymptomatic proximal DVTs and that a false-positive diagnosis of DVT is made in 10% of cases. Unit resource cost data are taken from pharmacoeconomic studies of DVT prophylaxis in hip replacement surgery. The analysis focuses on the actual or expected cost of prophylactic treatment using enoxaparin as opposed to warfarin and, as appropriate measures of cost-effectiveness, the cost per DVT event avoided and the cost per incidence of PE avoided. The expected cost of warfarin prophylaxis is $105 less per patient than that of enoxaparin. In terms of expected cost per DVT event avoided, enoxaparin prophylaxis is $2525 less than for warfarin; in terms of expected cost per PE avoided, it is $87,201 less. Enoxaparin is more cost-effective than warfarin in terms of both DVT events and PEs avoided in patients who have undergone knee replacement surgery.

Pharmacoeconomic model of enoxaparin versus heparin for prevention of deep vein thrombosis after total hip replacement.

The costs of heparin and enoxaparin to prevent deep vein thrombosis (DVT) after total hip replacement in the U.S. treatment environment were compared. A decision model was used in a pharmacoeconomic comparison of subcutaneous enoxaparin and subcutaneous heparin, each given for seven days, for the prophylaxis of DVT. In the model, three outcome pathways could follow prophylaxis: proximal DVT, distal DVT, and no DVT (but with a possible false-positive clinical diagnosis of DVT). Probabilities of thromboembolic events and major bleeding were derived from three randomized clinical trials. Account was also taken of the effects of pulmonary embolism (PE). Pharmacoeconomic studies and expert opinion were relied on for the model's principal resource-use categories and costs for DVT prophylaxis, clinical diagnosis of DVT and PE, and DVT and PE treatment. The outcome of choice for the model was the number of DVT events avoided. Regardless of the trial data used, the total mean cost of enoxaparin prophylaxis ($3336 to $3380) exceeded the cost of heparin prophylaxis ($3292 to $3330). However, enoxaparin was more cost-effective in avoiding DVT than heparin, irrespective of the trial on which the analysis was modeled. A sensitivity analysis involving length of hospital stay and length of prophylactic therapy showed the model to be robust and gave the advantage in all instances to enoxaparin in cost per DVT avoided. A model of enoxaparin versus heparin DVT prophylaxis after total hip replacement showed that enoxaparin was more costly than heparin in overall expected treatment costs but more cost-effective in the avoidance of DVT.

The expanding role of pharmacy and therapeutics committees. The 1990s and beyond.

Traditionally, pharmacy and therapeutics (P&T) committees have been responsible for overseeing the drug use process, using formulary systems to control drug costs. Primarily, these committees act in an advisory capacity as policy-recommending bodies within healthcare systems, for the specific purpose of promoting rational drug therapy. Methodologies utilised by these committees include drug use evaluation, medical staff education, continuous quality improvement, formulary restriction and therapeutic interchange. Future roles of P&T committees will include the evaluation of clinical outcomes information, including quality-of-life issues, to establish policies governing the use of drugs at all levels and in all types of healthcare.

A multi-center analysis of the use of enalapril and lisinopril in elderly hypertensive patients.

OBJECTIVE: To evaluate the clinical use and adverse effects of enalapril and lisinopril in elderly hypertensive subjects. DESIGN: A multi-center, retrospective, drug use evaluation survey. SETTING: Ambulatory care clinics at 14 VA and 14 academic medical centers. PATIENTS: 422 elderly (> 60 years of age) patients with hypertension and no clinical evidence of congestive heart failure. INTERVENTION: At least 3 consecutive months of anti-hypertensive therapy with either enalapril or lisinopril. MEASUREMENTS: Blood pressure, serum creatinine, serum potassium, concomitant disease states, concurrent medications, and documentation of any adverse event that might be related to ACE inhibitor therapy. RESULTS: There were no significant differences in systolic and diastolic blood pressures, serum creatinine, or serum potassium between enalapril- and lisinopril-treated patients at baseline and after 3 months of therapy. Both treatments resulted in a significant reduction in diastolic blood pressure. There was no significant difference in the incidence of adverse effects between the two treatments. Significantly more patients were dosed on a twice daily regimen of enalapril than lisinopril. CONCLUSION: The data from this retrospective study confirm the safe and effective use of enalapril and lisinopril, two long-acting ACE inhibitors, in elderly hypertensive patients.

Treating hypertensive emergencies. Controlled reduction of blood pressure and protection of target organs.

Diastolic blood pressure of 120 mm Hg or more is often cited as identifying a hypertensive crisis. However, the absolute level of blood pressure may not be as important as the rate of increase. One important feature that distinguishes hypertensive emergency from hypertensive "urgency" is the ongoing vascular damage that occurs with hypertensive emergency. When this is present, therapy should be initiated as soon as possible. The initial goal is to reduce mean arterial pressure about 15% to 25% within the first 48 hours. Overzealous or uncontrolled reduction in blood pressure may result in coma, stroke, myocardial infarction, acute renal failure, or death. Thus, a drug with titratable dosing (eg, intravenous nitroprusside sodium [Nipride, Nitropress]) is preferred in most situations. Patients with hypertensive urgency do not have evidence of vascular damage. Usually, they are asymptomatic, have no retinal lesions, and have a marked elevation in diastolic blood pressure. Hypertensive urgency does not require immediate normalization of blood pressure, but initiation of therapy and careful follow-up are critical.

Diuretics and hypertension in black adults.

A randomized controlled, single-blind trial was conducted to compare the effectiveness of a high-dose diuretic with a combination of a diuretic and metoprolol in black adults with hypertension. All subjects were first treated with 50 mg/d of hydrochlorothiazide for four weeks. Only subjects with a diastolic blood pressure of 95 mm Hg or higher at the end of this four-week period entered the randomized trial. We hypothesized that black patients with uncontrolled hypertension and low plasma renin activity on usual-dose hydrochlorothiazide therapy (ie, 50 mg/d) would respond better to higher doses of hydrochlorothiazide (ie, 100 to 150 mg/d) than to a usual-dose diuretic and metoprolol. Diuretic-metoprolol combination therapy was significantly more effective than high-dose diuretic therapy regardless of plasma renin status.

A comparative trial of digoxin and digitoxin in the treatment of congestive heart failure.

A randomized, crossover, single-blind study compared the efficacy and dosing accuracy of digoxin and digitoxin in 15 ambulatory patients wth congestive heart failure. Loading doses and maintenance doses were calculated according to published equations that adjust for sex, height, and lean body weight (for digitoxin), plus estimated creatinine clearance (for digoxin). At each 2-week visit, serum drug concentrations were measured and compliance with the prescribed regimen was assessed by tablet count. At the end of each study period, a congestive heart failure (CHF) score was determined in a blinded fashion by the same physician. Patient compliance was unusually high (greater than or equal to 80%) at every visit. Therapeutic concentrations were achieved with digoxin and digitoxin in 5 and 14 patients, respectively (p less than 0.05). During digitoxin therapy, CHF scores were lower than pretreatment values (p less than 0.05). The difference between CHF scores during the digoxin and digitoxin periods did not achieve significance (0.05 less than p less than 0.06). Therapeutic serum concentrations can be achieved more easily and frequently with digitoxin than digoxin without compromising the patient's CHF status.

Detection and characterization of Leishmania species and strains from mammals and vectors by hybridization and restriction endonuclease digestion of kinetoplast DNA.

Leishmania parasites from animals, man or insect vectors were characterized by the gel electrophoresis of restriction endonuclease enzyme-produced mitochondrial (kinetoplast) DNA (kDNA) fragments and/or by DNA-DNA hybridization with 32P-labelled cloned, or uncloned, kDNA fragment probes from type isolates. The electrophoretic separation of kDNA fragments is a sensitive method for detecting genetic similarities and differences among Leishmania. Parasites with similar kDNA restriction fragment patterns belong to the same schizodeme and schizodeme analysis is useful for studying Leishmania populations. Cloned, species-specific kDNA probes detected Leishmania in sandflies and in liver, spleen or blood preparations from infected animals. Cloned DNA probes also hybridized to immobilized kDNA from in vitro cultivated promastigotes and detected as few as 100 parasites in a species-specific manner. Sensitive DNA hybridization probes should be useful in research on the immunology, chemotherapy or epidemiology of animal and human leishmaniasis.

Practical value of a new serum digitoxin assay.

The purpose of this study was to evaluate a new fluorescence polarization immunoassay, TDx, for digitoxin by comparing the results of this assay with those of a radioimmunoassay (RIA). Thirty-three serum samples were obtained from 15 patients during, and for 4 weeks after, a 4-week course of digitoxin therapy. Each sample was separated by centrifugation, coded, and frozen until analysis. At the time of analysis, each sample was divided and analyzed simultaneously by TDx and RIA. Nine samples yielded results less than 2 ng/ml (limit of assay sensitivity) by one or both methods and were excluded from further data analysis. Linear regression analysis of the results of the remaining 24 paired samples (x = TDx, y = RIA) revealed a strong correlation coefficient of r2 = 0.95, slope = 0.95, and a y intercept of -0.99 (y = -0.99 + 0.95x). Additionally, the TDx results were lower than the RIA values in only five of 33 paired samples; and these occurred in four patients who had a significantly lower mean estimated creatinine clearance than that of the other 11 patients (39.0 +/- 9.1 ml/min/1.73 m2 vs. 63.3 +/- 11.8 ml/min/1.73 m2, p less than 0.01). The TDx system is a comparable alternative to the RIA method, but differences in specificity and sensitivity may exist and should be evaluated more thoroughly.

Population pharmacokinetics of racemic warfarin in adult patients.

The population pharmacokinetics of racemic warfarin was evaluated using 613 measured warfarin plasma concentrations from 32 adult hospitalized patients and 131 adult outpatients. Warfarin concentrations were measured in duplicate using a high-performance liquid chromatographic procedure. The pharmacokinetic model used was a one-compartment open model with first-order absorption (absorption rate constant set equal to 47 day-1) and first-order elimination. The extent of availability was assumed to be one. A linear regression model was used to evaluate the influence of various demographic factors on warfarin oral clearance. Age appeared to be an important determinant of warfarin clearance in this adult population. There was about a 1%/year decrease in oral clearance over the age range of 20-70 years. Smoking appeared to result in a 10% increase in warfarin clearance, while coadministration of the inducers phenytoin or phenobarbital yielded about a 30% increase in clearance. This study has yielded a predictive model that, when combined with appropriate pharmacological response data, may be useful in the design and adjustment of warfarin regimens.

Plasma protein binding of warfarin: methodological considerations.

Recent theoretical work has suggested that radiochemical impurities can significantly alter the binding results for highly protein-bound drugs. We compared protein binding of warfarin by ultrafiltration and equilibrium dialysis with 98% radiochemically pure [14C]warfarin. Ultrafiltration and equilibrium dialysis were performed at 37 degrees C and pH 7.45 on the plasma of patients receiving chronic warfarin therapy. Binding to plasma from seven patients were measured in duplicate by both a nonspecific radioisotopic technique and a specific HPLC technique. The nonspecific technique gave percentage of free warfarin values of 1.84 +/- 0.11 (mean +/- SD) and 1.59 +/- 0.14 for ultrafiltration and equilibrium dialysis, respectively. The HPLC procedure yielded a percentage of free warfarin by ultrafiltration of 0.969 +/- 0.203 and a value of 0.690 +/- 0.095 by equilibrium dialysis (p less than 0.05). The HPLC procedure for protein binding was performed on plasma samples from 12 additional patients and yielded a percentage of free warfarin of 1.01 +/- 0.69 by ultrafiltration and 0.44 +/- 0.34 by equilibrium dialysis (p less than 0.05). It can be concluded that radiochemical impurities may lead to significant overestimation of the percentage of free warfarin. Ultrafiltration yielded a higher percentage of free warfarin than did equilibrium dialysis, but the ability to distinguish binding differences among patients was similar.

Effect of diltiazem on warfarin plasma protein binding.

Previous work by Bloedow et al. evaluated the effect of warfarin on diltiazem binding. Unbound diltiazem remained constant (22.5 +/- 3.6 per cent) in the presence of warfarin. We studied 10 patients, 51 to 72 years old, who were receiving warfarin as an anticoagulant for valvular replacement, thrombosis, or embolus. Our study demonstrates that a single 120-mg oral diltiazem dose, sufficient to cause hemodynamic changes, does not displace warfarin from plasma binding sites.

Clinical pharmacy functions in ambulatory patient care.

A functional interpretation of clinical pharmacy as an implementing mechanism for extending the objectives and responsibilities of clinical pharmacology in ambulatory patient care is presented. Evidence is given to support the effectiveness of the clinical pharmacist in assisting primary care physicians with the design of optimal drug regimens and evaluating and managing patients on chronic drug therapy. Opportunities for the clinical pharmacist to carry out long-term drug trials and participate in the design and execution of epidemiological drug studies are also discussed. The clinical pharmacist can make important contributions to ambulatory patient care in areas of drug treatment and evaluation by working in concert with primary care physicians and clinical pharmacologists.

Rapid metabolism of phenytoin: a method of calculating proper dosage.

The optimal dosage of phenytoin can be accurately determined by a pharmacokinetic method. By plotting the rate of administration of phenytoin acid against the apparent plasma clearance rate, we estimated the maximum rate of metabolism and the serum concentration at which the rate of metabolism was one half the maximum rate for phenytoin and then applied the Michaelis-Menten equation to optimize the dosage of phenytoin in a 48-year-old man with uncontrolled idiopathic generalized seizures and increased metabolism of phenytoin. The patient became seizure free on a regimen of 650 mg of phenytoin daily and experienced no side effects of phenytoin over-dosage. The pharmacokinetic technique described is simple to use and can be applied in an outpatient clinic.