The calcium channel blocker felodipine attenuates the positive hemodynamic effects of the beta-blocker metoprolol in severe dilated cardiomyopathy--a prospective, randomized, double-blind and placebo-controlled study with invasive hemodynamic assessment.

BACKGROUND: In addition to standard therapy with ACE-inhibitors, digitalis and diuretics, beta-adrenergic receptor blockers have become a widely accepted strategy in the treatment of chronic heart failure. The role of calcium antagonists in CHF however remains controversial. To evaluate if a combination therapy of metoprolol and felodipine might improve hemodynamic parameters, a randomized and placebo-controlled study was designed. METHODS AND RESULTS: Sixty-three patients with DCMP, LVEF 3 months in NYHA II-III on standard medication were prospectively treated with either a) a combination of metoprolol+felodipine (MF group, n=20), b) metoprolol+felodipine-placebo (MP group, n=23), or c) metoprolol-placebo+felodipine-placebo (PP group, n=20). Compared to baseline, LVEF and LVEDD significantly improved after 6 months in the MP group (LVEF: 36+/-2% vs 29+/-2%, p<0.01; LVEDD: 68+/-3 mm vs 64+/-3 mm, p<0.05), whereas in the other treatment groups only minor changes were observed. A significant benefit in hemodynamic parameters as determined by right heart catheterization was noted also only in the MP group with a marked reduction in PAP mean (17 vs 24 mmHg, p<0.01), PCWP (10 vs 15 mmHg, p<0.001) resulting in a significant increase in cardiac and stroke volume index at rest with no marked changes in the MF and PP group. CONCLUSION: beta-blocker treatment in CHF patients improves left ventricular function and additionally invasive hemodynamic measurements both at rest and during exercise. In contrast, the combined therapy with the long-acting calcium antagonist felodipine neutralizes these beneficial effects of metoprolol therapy to almost placebo level, providing evidence based on hemodynamic measurements that this combination should be avoided in patients with CHF.

Dihydropyridines, felodipine, and PHARMAC.

Calcium antagonists have evolved as useful drugs in the treatment of hypertension and angina. Dihydropyridines are the largest subgroup and various products have been marketed. Safety concerns have largely been allayed by comparative outcome trials but concern remains over short-acting products. In New Zealand, many patients requiring fully subsidised dihydropyridines have had several changes of product imposed due to successive reference pricing and sole-supply arrangements, along with deregistering and reregistering of generic felodipine. Some narrowly avoided a complete loss of access to a suitable low dose of any dihydropyridine. Generic substitution and sole-supply arrangements may make useful savings but can leave the supply of key pharmaceuticals vulnerable and impose significant loss in quality of healthcare from multiple changes in pharmaceutical preparation.

Adherence to calcium channel blocker therapy in older adults: a comparison of amlodipine and felodipine.

The efficacy of dihydropyridine calcium channel blockers for treating hypertension appears to be similar, but a variety of factors, including patient characteristics, tolerability and pharmacokinetic properties, may influence treatment adherence and outcome. We aimed to evaluate treatment adherence in clinical practice among older hypertensive adults (50+ years) prescribed amlodipine or felodipine for the first time as part of the California Medicaid (Medi-Cal) program. We used a retrospective, matched, cohort-analysis design. Over 1 year, patients prescribed amlodipine were 21% less likely to discontinue study treatment than those prescribed felodipine. Discontinuation tended to occur early, with 20% and 30% of amlodipine and felodipine patients, respectively, discontinuing treatment after one prescription. A non-significant difference in favour of amlodipine was demonstrated for anti-anginal medication use among patients taking these drugs at baseline. This study suggests that use of amlodipine may be associated with improved adherence, compared with felodipine, among older out-patients in the Medi-Cal program.

A comparative analysis of amlodipine and felodipine in a military outpatient population: efficacy, outcomes, and cost considerations.

BACKGROUND: This retrospective study compared the efficacy, tolerability, and cost of two dihydropyridine calcium channel blockers. METHODS: Charts of patients who had been on continuous antihypertensive therapy with amlodipine or felodipine for at least 6 months were reviewed. Analyses include mean changes in blood pressure, percentage of patients achieving blood pressure (BP) < 140/90 mm Hg, average dose, and cost per day of the two calcium channel blockers, average cost of additional medication, total medication cost per day, and cost to achieve BP control. RESULTS: Eighty-seven percent of amlodipine-treated patients achieved BP control compared with 33% of felodipine-treated patients. Total medication cost to achieve BP control was 0.87 dollars per day for patients on amlodipine compared with 1.79 dollars per day for patients on felodipine. CONCLUSIONS: Amlodipine produced BP control in a greater percentage of patients than did felodipine at a lower total cost to achieve BP control. When evaluating the total cost of antihypertensive treatment, the cost of a drug alone can be misleading.

Health economics in the Hypertension Optimal Treatment (HOT) study: costs and cost-effectiveness of intensive blood pressure lowering and low-dose aspirin in patients with hypertension.

OBJECTIVES: To investigate the marginal cost-effectiveness of different targets for the reduction of blood pressure and the cost-effectiveness of adding acetylsalicylic acid (ASA) to the treatment of hypertension. DESIGN: Patients with hypertension were randomized to three target groups for blood pressure; < or =90, < or =85 and < or =80 mmHg. Patients were also randomly assigned ASA and placebo. The average follow-up time was 3.8 years. The direct costs for drugs, visits, hospitalizations, and side-effects were calculated and related to clinical outcome. SETTING: Resource utilization data from all the 26 countries in the study were pooled, and Swedish unit costs were applied to the aggregated resource utilization. SUBJECTS: A total of 18 790 patients, 50-80 years of age (mean 61.5 years), with a diastolic blood pressure between 100 and 115 mmHg (mean 105 mmHg). INTERVENTIONS: Antihypertensive treatment with the long-acting calcium antagonist felodipine was given to all patients. Additional therapy and dose increments in four further steps were prescribed to reach the randomized target blood pressure. Fifty per cent of the patients were randomized to a low dose, 75 mg daily, of acetylsalicylic acid. MAIN OUTCOME MEASURES: Direct health care costs, major cardiovascular (CV) events (myocardial infarction and stroke) and CV death. RESULTS: The average cost of drugs and visits increased with more intensive treatment. The increase in treatment costs was partly but not fully offset by a nonsignificant reduction in the cost of CV hospitalizations. For patients with diabetes there were no significant differences in total cost between the target groups. The cost of avoiding a major CV event was negative in the base case analysis, SEK -10 360 (CI: -78 195, 75 630), and SEK 18 450 (CI: -88 789, 192 980) in a sensitivity analysis. For patients on ASA, costs were slightly but significantly higher than for patients on placebo. The estimates of the cost of avoiding a major CV event varied between SEK 41 600 and SEK 477 400, with very wide confidence intervals. CONCLUSIONS: The treatment cost increases as the target for hypertension treatment is lowered. In patients with diabetes, intensive treatment to a lower target is cost-effective. Because of the nonsignificant difference in events, no conclusion can be made for all patients in the study. Furthermore, no conclusive evidence was found regarding the cost-effectiveness of adding ASA to the treatment of hypertension.

Efficacy and safety of a therapeutic interchange from high-dose calcium channel blockers to a fixed-dose combination of amlodipine/benazepril in patients with moderate-to-severe hypertension.

BACKGROUND: Recent hypertension trials have demonstrated the importance of achieving goal blood pressures to reduce the risk of target organ damage. In patients with moderate to severe hypertension, the use of high-dose monotherapy and/or combinations of drugs are necessary to achieve these goals. Fixed-dose combination products may be useful in these patients by reducing the number of daily doses required to control blood pressure. OBJECTIVE: The objective of the present study was to evaluate the efficacy and safety of a therapeutic interchange between high-dose calcium channel blocker therapy and a fixed-dose combination of amlodipine/ benazepril (Lotrel; Novartis Pharmaceuticals, USA) in patients with moderate to severe hypertension. METHODS: A total of 75 patients were switched from amlodipine (n = 25), felodipine (n = 25), and nifedipine-GITS (n = 25) to amlodipine/benazepril. Twenty-eight of the 75 patients (37%) were taking either a beta-blocker or a diuretic in addition to the high-dose calcium channel blocker prior to the switch. Blood pressure control, side effects and the cost of the therapeutic interchange were evaluated in the year following the therapeutic interchange. RESULTS: Sixty-six of the 75 (88%) patients were successfully switched with maintenance of blood pressure control and without the development of new dose-limiting side effects. Reasons for treatment failure after the therapeutic interchange included loss of blood pressure control in five patients and the development of new dose-limiting side effects in four patients. These side effects included cough in three patients and rash in one patient. After accounting for differences in drug acquisition cost and costs related to the switch (clinic and emergency room and laboratory tests), a cost savings of $16030 for all 75 patients was realised in the first year. The per patient-per year cost savings was $214. CONCLUSIONS: Our data indicate that a therapeutic interchange from selected high-dose calcium channel blockers to a fixed-dose combination of amlodipine/ benazepril can be successfully accomplished in the majority of patients.

Cost-effectiveness of felodipine-metoprolol (Logimax) and enalapril in the treatment of hypertension.

We present results from a Swedish retrospective cost-effectiveness analysis of felodipine-metoprolol (Logimax) and enalapril in hypertension. In the 8-week trial, the average reduction of diastolic blood pressure (DBP) and the share of patients reaching target DBP were both significantly greater in the felodipine-metoprolol group. Cost of treatment (costs of drugs and physician visits) was somewhat higher in the felodipine-metoprolol group. After 8 weeks, an extra 4.8 mmHg reduction and an additional 22% of patients reaching target DBP were achieved with felodipine-metoprolol at the extra cost of SEK 19 (Swedish kronor, $US I=SEK 7.90). The incremental cost per mmHg reduction and per patient reaching target DBP was calculated at SEK 4 and SEK 86, respectively. Average cost-effectiveness ratios showed that the costs per mmHg reduction and per patient reaching target DBP after 8 weeks were 40 and 34% lower in the felodipine-metoprolol group, respectively. In conclusion, felodipine-metoprolol is cost-effective in the treatment of hypertension.

Replacing short-acting nifedipine with alternative medications at a large health maintenance organization.

In response to recent evidence about the safety of calcium channel blockers, Group Health Cooperative of Puget Sound (GHC), a large health maintenance organization, implemented a plan in April 1996 to reevaluate the medications of 1349 patients who were taking short-acting nifedipine. Following the intervention, 79.8% of patients taking short-acting nifedipine discontinued use, and 45.6% switched to once-daily felodipine. By presenting physicians and patients with recent evidence about the safety of short-acting nifedipine, a large health maintenance organization was able to motivate broad-scale changes to safer alternative drug therapies.

Felodipine as an alternative to more expensive calcium antagonists in mild to moderate hypertension.

We studied the therapeutic substitution of a less expensive but equally effective antihypertensive agent and assessed patient outcome. The medication of 39 patients with hypertension was changed from once-daily diltiazem hydrochloride (Cardizem CD) or nifedipine (Procardia XL) to felodipine (Plendil). Titration to a final dose was based on home and office blood pressure measurements assessed over subsequent follow-up clinic visits. Self-administered questionnaires measured different aspects of well-being and symptoms before and after the change in medication. Eighty percent of the cohort switched successfully to felodipine. Office systolic and diastolic pressures improved after the medication change (systolic: 150 mm Hg versus 144 mm Hg; diastolic: 92 mm Hg versus 87 mm Hg). No statistically significant differences were found among the 39 symptoms measured. A yearly savings potential for our institution was estimated to be $72,000.