A pharmacy-based approach to cholesterol management.

OBJECTIVE: To determine the clinical and economic impact of a pharmacy-based cholesterol management program in patients with cardiovascular disease. STUDY DESIGN: Demonstration project. PATIENTS AND METHODS: From January 1, 1999, through June 30, 1999, 300 patients with a documented history of cardiovascular disease were enrolled in a pharmacy-based cholesterol program. A similar group of 150 randomly selected patients receiving usual care during the same period served as the comparator group. The following were collected for both groups: patient demographics, comorbidities, fasting lipid profiles, cholesterol medication, cost of medication, and cardiovascular events. The McNemar symmetry chi2 test was used to compare appropriate laboratory monitoring, receipt of cholesterol medication, and achievement of target low-density lipoprotein cholesterol levels at baseline and 1 year for both groups. Kruskal-Wallis analysis of variance was used to compare the cost of therapy for both groups at baseline and follow-up. RESULTS: Mean +/- SD age of program and usual care patients was 67 +/- 10 and 69 +/- 11 years, respectively. At 1 year, >95% of program patients were receiving appropriate laboratory monitoring. In 1 year, the percentage of patients reaching target low-density lipoprotein cholesterol levels increased from 45% to 72% (P< .01) and from 33% to 43% (P = .26) in program and usual care patients, respectively. Despite increased medication use among program patients, their cost per patient per month was lower at 1-year follow-up vs baseline. CONCLUSION: Regular patient interaction and close patient monitoring allowed the pharmacy-based lipid management program to improve cholesterol management in patients with cardiovascular disease.

Acid-suppressive therapy use associated with antihypertensive agents.

Nitrates and calcium channel blockers (CCBs) have been shown to decrease lower esophageal sphincter pressure and theoretically may precipitate or aggravate gastroesophageal reflux. Thus, the authors hypothesized that patients who receive these agents would have greater use of acid-suppressive drug use, defined as histamine2 antagonists or proton pump inhibitors. A retrospective cohort design was used to assess the use of acid-suppressive drug use in hypertensive patients with respect to both nitrates and antihypertensive therapy. Of 15,662 treated hypertensive patients, 20% received acid-suppressive therapy. An increased use of acid-suppressive therapy was associated with nitrate (odds ratio [OR] = 1.71), CCB (OR = 1.46), and alpha 1 antagonist (OR = 1.32) treatment, which appeared to be additive when patients received two or more of the agents. Within the class of CCBs, there was no significant difference among the individual agents. As the clinical and economic burden may be substantial, further study is warranted.

Treatment of hypertension in a managed care setting.

BACKGROUND: Based on recommendations of the Fifth and Sixth Reports of the Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, Health Care Plan (now Univera Healthcare) Buffalo, NY, developed a clinical guideline to improve the management of patients with hypertension. To increase awareness and utilization, the guideline was distributed as hard copy reports and made available through our electronic information system. OBJECTIVE: To determine blood pressure (BP) control rates and adherence to guideline recommendations. STUDY DESIGN: Retrospective chart review. PATIENTS AND METHODS: We randomly sampled hypertensive patients seen during 1998 to evaluate hypertension management. Computerized medical and pharmacy records were reviewed for patient demographics, antihypertensive medications, comorbid conditions, and BP readings. Patient assessment was based on antihypertensive regimen and achievement of target BP according to the recommendations of the guidelines (< 140/90 mm Hg for the general population and < 130/85 mm Hg for special populations). In addition, we assessed control rates using traditional Health Plan Employer Data and Information Set (HEDIS) measures (< 140/90 mm Hg). RESULTS: Overall, 35% of patients achieved target BP and 68% were treated with agents recommended by our JNC-based guideline. In contrast, using traditional HEDIS measures, 41% of patients achieved BP control. Of 39 patients with compelling indications (primarily diabetic patients), 13% achieved BP target and 67% were treated with recommended agents. CONCLUSIONS: The impact of our clinical guideline is reflected through the relatively high utilization of recommended drugs. However, optimal BP control continues to be problematic. In particular, patients with diabetes warrant focused attention.

Containment of heart failure hospitalizations and cost by angiotensin-converting enzyme inhibitor dosage optimization.

Using our model relating angiotensin-converting enzyme (ACE) inhibitor dosing and outcomes in heart failure (HF), we designed a prospective intervention trial for patients with systolic dysfunction. A clinical pharmacist initiated or titrated ACE inhibitor therapy or adjusted other medications within an HF management program based on Agency for Healthcare Policy and Research guidelines. Entry into the protocol required the approval of the attending physician. All patients received dietary, nursing, rehabilitation, social service, and clinical pharmacy consultations. Treatment conformed to Agency for Healthcare Policy and Research guidelines in 25% of patients (group A). Suboptimal therapy (75% of patients) was usually due to failure to administer an ACE inhibitor (48%) or inadequate dosing of an ACE inhibitor (46%). In 62% of suboptimal cases, the attending physician agreed to follow the clinical pharmacist's recommendations (group B). Patients of physicians who declined pharmacist intervention served as a negative control (group C). On admission, mean enalapril-equivalent daily doses in groups A, B, and C were 30, 4, and 6 mg, respectively, and at discharge, 36, 18, and 6 mg, respectively. At 180 days, rehospitalization frequency and total charges were lower in groups A (31% and $5,600) and B (35% and $3,800) than in group C (63% [p <0.004] and $9,800 [p <0.04]). Thus, optimization of ACE inhibitor doses by a clinical pharmacist can greatly improve rehospitalization rates and significantly lower cost of care in an HF management program.

Potential interaction between troglitazone and atorvastatin.

BACKGROUND: Troglitazone is a CYP3A4 isoenzyme inducer known to decrease the plasma concentration of drugs metabolized by CYP3A4. Atorvastatin, a known substrate of the CYP3A4 pathway, is often used in combination with troglitazone for diabetic patients with dyslipidemia. AIMS: The purpose of this study was to investigate the clinical effects of troglitazone on the fasting lipid profiles of patients receiving atorvastatin. METHOD: We retrospectively reviewed the medical records of patients who received concomitant troglitazone and atorvastatin therapy during a 24-month period. Patients were included in the analysis if during the study period, complete laboratory data were available (fasting lipid profile and glycosylated haemoglobin), the dose of atorvastatin remained unchanged, there were no changes in the diabetic drug regimen, patients received at least 3 months of combination therapy and patients were adherent with their medication. RESULTS: Four out of 31 (13%) patients satisfied the inclusion criteria. All of these patients were male, with a mean age of 63. All patients were receiving insulin only for diabetes control when the troglitazone was added. There was an increase in LDL-cholesterol and triglycerides of 23.3% and 21.3%, respectively. CONCLUSION: The increase in LDL-cholesterol and triglycerides on atorvastatin and troglitazone combination therapy compared with atorvastatin mono-therapy is suggestive of a drug interaction. Further studies involving troglitazone and atorvastatin may be warranted to substantiate this interaction.

Homocysteine as a risk factor for atherosclerosis.

OBJECTIVE: To review the role of homocysteine as a risk factor in the pathogenesis of atherosclerosis and to provide recommendations for the treatment of hyperhomocysteinemia. DATA SOURCES: A MEDLINE search using key terms such as homocysteine, atherosclerosis, folic acid, vitamin B6, and vitamin B12 was conducted for the time period 1966 through January 1999. STUDY SELECTION: An article was selected for inclusion in this review if it assessed the relationship and proposed mechanisms of hyperhomocysteinemia on the vasculature, physiologic changes due to hyperhomocysteinemia, and outcomes due to hyperhomocysteinemia, such as morbidity and mortality. In addition, studies that assessed the treatment outcomes of hyperhomocysteinemia were evaluated. DATA SYNTHESIS: Studies of patients with cerebral vascular disease reveal elevated homocysteine concentrations in 30-40% of patients compared with controls. Many studies demonstrate a correlation between elevated homocysteine concentrations, risk of myocardial infarction, and mortality. In addition, hyperhomocysteinemia and decreased folic acid concentrations have been identified in end-stage renal disease (ESRD) and type 2 diabetic patients, while both concentrations remained normal in healthy controls. Studies using folic acid 650 microg/d reduced homocysteine concentrations to within normal therapeutic range after two weeks of treatment. Studies with vitamins B6 and B12 have demonstrated that the use of either alone is ineffective, but when combined or administered with folic acid, homocysteine concentrations return to normal. All therapies must be given for the lifetime of the patient. In addition, patients must use discretion in their diet, as common beverages, such as coffee, have a strong correlation with hyperhomocysteinemia, while foods high in folic acid, vitamin B6 and vitamin B12 may reduce homocysteine concentrations. Additional prospective studies are needed to determine effects of treatment of hyperhomocysteinemia and various diets on atherosclerotic morbidity and mortality. CONCLUSIONS: Studies demonstrate a positive correlation between hyperhomocysteinemia and atherosclerosis. The treatment of choice for hyperhomocysteinemia is folic acid. Although the optimal dose is not known, 650 microg/d is the minimum effective dose. To date, no studies have assessed the effects on morbidity and mortality when treating high homocysteine concentrations in atherosclerotic patients.

Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers.

OBJECTIVE: To determine whether there are gender-specific differences in the pharmacokinetics and pharmacodynamics of metoprolol enantiomers. METHODS: Twenty normal volunteers (10 men and 10 women) received 100 mg oral metoprolol tartrate twice daily for a total of nine doses. Pharmacokinetics and pharmacodynamics were studied after the last dose. Subjects also completed a control pharmacodynamic study; the order of drug and control studies was randomized. Measurements of heart rate and systolic blood pressure were obtained during peak submaximal bicycle exercise testing. (R)-Metoprolol and (S)-metoprolol concentrations were determined by stereospecific HPLC. The percentage difference in exercise heart rate and systolic blood pressure (metoprolol versus control), and (R)- and (S)-metoprolol plasma concentrations were comodeled. RESULTS: Men and women showed stereoselective pharmacokinetics; (S)-metoprolol concentrations were significantly greater than those for (R)-metoprolol for both groups. Women had greater drug exposure than men (higher maximum concentration and area under the plasma concentration-time curve). No differences were observed between genders with respect to elimination half-life. Females had a greater reduction in exercise heart rate and systolic blood pressure; however, the area under the effect curve was significantly greater for heart rate only. Pharmacodynamic data were best fitted by the Hill equation with the effect site in the central compartment. The fitted maximum effect and the concentration at one-half of the maximum effect for heart rate and systolic blood pressure did not differ between men and women (P > .20). CONCLUSIONS: Gender-related differences exist in the pharmacokinetics of metoprolol enantiomers, resulting in greater drug exposure in female subjects. However, concentration-effect relationships did not differ between men and women. Therefore the observed differences in drug effects were the result of gender-specific differences in metoprolol pharmacokinetics.

Underutilization of ACE inhibitors in heart failure.

Although the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in patients with ventricular systolic dysfunction are well documented, historically, a large proportion of patients have not received optimal therapy. Published studies to describe the trends in ACE inhibitor utilization and determinants of their use were reviewed. In recent years the number of patients treated with ACE inhibitors has increased; however, a relatively small proportion of these patients received adequate therapeutic dosages. Attention to factors that impair proper use of these agents is essential to realize improved outcomes in these patients.

Patterns of prescribing ACE inhibitors after myocardial infarction.

We attempted to determine physician prescribing patterns of angiotensin-converting enzyme (ACE) inhibitors in patients who experienced a myocardial infarction, stratified by left ventricular function. We retrospectively reviewed drug therapy at discharge in 534 patients to assess prescription of ACE inhibitor therapy, including dosage. Thirty-four percent of patients were discharged taking an ACE inhibitor, of whom only 11% received recommended dosages. The drugs were prescribed more often for patients who had an ejection fraction below 40% than for those with an ejection fraction of 40% or above (54% vs 28%, p<0.05). We conclude that ACE inhibitors are underprescribed for patients who experienced a myocardial infarction, illustrating the gap between clinical research and clinical practice, and the need for programs to ensure optimal medical management.

Reteplase: a new thrombolytic for the treatment of acute myocardial infarction.

OBJECTIVE: To summarize the published data on reteplase, the most recent thrombolytic agent approved by the Food and Drug Administration for use in the management of acute myocardial infarction in adults. DATA SOURCES: Published data on reteplase identified by MEDLINE searches (January 1985-June 1997), as well as other pertinent literature. DATA SYNTHESIS: Reteplase is a new thrombolytic agent derived from human tissue plasminogen activator. Its mechanism of action is similar to that of alteplase, but it differs in pharmacokinetic and pharmacodynamic properties. Certain structural changes contribute to differences in pharmacokinetic properties such as a prolonged half-life (15 min), which allows it to be administered as two 10-MU bolus injections. Reteplase has been shown to have fibrin specificity similar to that of alteplase, but with a lower binding affinity for fibrin. This enables reteplase to bind to the thrombus repeatedly and increases its fibrinolytic potential. In clinical trials, reteplase demonstrated more rapid and complete coronary patency compared with alteplase, without a significant increase in clinical adverse events. However, the improvement in coronary artery patency with reteplase versus alteplase did not result in a reduction in mortality in the GUSTO III trial. CONCLUSIONS: Despite evidence that use of reteplase results in an improved coronary artery patency rate versus accelerated infusion alteplase, an improvement in mortality rate with reteplase was not shown. Reteplase may have an advantage over alteplase due to a more rapid and simpler dosing regimen, but the significance of this difference is yet to be determined.