Outcomes and Cost Savings of an ACE Inhibitor Therapeutic Interchange
OBJECTIVE:
To determine the cost-effectiveness and outcomes of a therapeutic interchange from captopril, enalapril, or lisinopril to quinapril for 36 patients with mild-to-moderate hypertension.
DESIGN:
A three-month, open-label, nonrandomized therapeutic interchange trial performed from September 1995 through July 1996.
SETTING:
University-affiliated outpatient clinics.
RESULTS:
Outcomes at minimum follow-up of three months indicated that 35 of 36 patients (97%) were successfully switched to quinapril with similar blood pressure control. Four of the 36 patients (11%) complained of a cough while on quinapril; however, these patients also experienced coughing on their previous ACE inhibitor therapy. At the same time, three other patients who had side effects on their previous ACE inhibitor therapy did not have a recurrence of side effects on quinapril. A cost savings of $4,956 per year for these 36 patients during the first year of follow-up was projected.
CONCLUSION:
Switching patients with mild-to-moderate hypertension stabilized on captopril, enalapril, or lisinopril to quinapril is cost-effective. However, therapeutic interchange programs involving other drug classes with indications in other disease states must be evaluated individually to assess their cost-effectiveness.
J Managed Care Pharm 1997; 3:219-23.
In drug classes with multiple agents having similar mechanisms of action and benefit-risk profiles, the tendency to select the lowest-cost drug is great.1-3 Managed care organizations sometimes switch patients to less expensive products.4-6 This approach may be economically sound, but it should be evaluated by looking not only at the acquisition costs of drugs but also the costs of repeat clinic visits, diagnostic and/or any laboratory tests required, titration of drug doses or addition of other drugs, and the evaluation and/or treatment of adverse reactions.7 The objective of this study was to evaluate the outcomes and costs of patients switched to quinapril from captopril, enalapril, or lisinopril. The results of this study can contribute to decisions about formulary and drug product selection recommendations concerning ACE inhibitors in the management of hypertension.
METHODS
Patients
Thirty-six patients stabilized on ACE inhibitor therapy (captopril [n=12], enalapril [n=12], and lisinopril [n=12]) for hypertension with or without a diuretic comprised the study population. Eligible patients had to be between 35 and 70 years of age. There were no restrictions with regard to gender or race. Diastolic blood pressure (BP) before starting drug therapy had to be between 90 and 110 mmHg with a systolic BP of less than 180 mmHg. Patients had to be controlled (diastolic BP<90 mmHg) on stable doses of captopril, enalapril, or lisinopril for at least three months prior to being switched to quinapril. Eligible patients were restricted to those whose diastolic BP was controlled on no more than 150 mg/day of captopril, 40 mg/day of enalapril, or 40 mg/day of lisinopril. There were no restrictions with regard to concomitant disease states other than end-stage renal disease, which was a reason for exclusion from the study.
Study Design
Only four patients underwent tapered discontinuation regimens for prior ACE inhibitor therapy. Patients generally were asked to initiate quinapril the day following the discontinuation of their previous ACE inhibitor. However, in six patients, a lapse of 3-8 days without any ACE inhibitor therapy occurred because of an administrative error.
Quinapril was initiated at 10 mg/day and increased to 20 or 40 mg/day at two- to three-week intervals, depending on response and prior ACE inhibitor dose (see Table 1). Loss of BP control after the switch was defined as a rise in diastolic BP to >95 mmHg, a greater than 5 mmHg increase in diastolic BP, or a greater than 10 mmHg increase in systolic BP during quinapril therapy as compared to BP readings during the previous ACE inhibitor therapy. Patients not having adequate BP control on 40 mg/day of quinapril, or those developing dose-limited side effects on any dose of quinapril, were returned to their original ACE inhibitor. Patients with continued BP control who did not develop dose-limiting side effects were followed for a minimum of three months.
Table 1. Targeted quinapril doses following conversion from other ACE inhibitors
| QUINAPRIL mg/day | CAPTOPRIL mg/day | ENALAPRIL mg/day | LISINOPRIL mg/day |
| 10 | <= 50 | <= 5 | <= 5 |
| 20 | >50 to <= 100 | >5 to <20 | >5 to <20 |
| 40 | >100 to 150 | <= 20 to 40 | <= 20 to 40 |
| not accepted | >150 | >40 | >40 |
Cost Analysis
Costs evaluated in this analysis include the comparative acquisition costs of captopril, enalapril, lisinopril, and quin-april. Acquisition costs used in this study represent the actual average cost of these drugs at six pharmacies enrolled in three local managed care plans in Omaha, Nebraska. Also included were the costs of additional clinic visits, laboratory monitoring, emergency room visits, and hospitalizations, as well as the costs of managing side effects that patients experienced follow-ing the switch to quinapril.
Data Analysis
Comparability of demographic and baseline characteristics among baseline ACE inhibitor groups (captopril, enalapril, and lisinopril) were assessed using one-way analysis of variance for continuous variables and Pearson's chi-square for dichotomous and categorical data. Mean treatment costs among drug therapy groups were compared using one-way analysis of variance. A modified least-significance multiple range test was used for multiple comparisons. Continuous data were presented as the mean ± SD. For all analyses, a P value of <0.05 was considered statistically significant.
RESULTS
Thirty-six patients were switched from captopril (n=12), enalapril (n=12), or lisinopril (n=12) to quinapril. Outcomes are detailed in Tables 2, 3, and 4. Baseline demographics and clinical characteristics were not significantly different between the captopril, enalapril, and lisinopril groups, with the exception of the duration of initial ACE inhibitor therapy. All patients switched to quinapril were dosed on a once-a-day basis. No attempt to discontinue diuretic therapy was made in the eight patients receiving an ACE inhibitor in conjunction with a diuretic.
Thirty-five patients (97%) had continued blood pressure control and tolerated quinapril for a minimum of three months after the switch. The remaining patient, who had been controlled on enalapril 40 mg/day, experienced an increase in blood pressure after the switch to quinapril. Following the conversion, four of 36 patients (11%) complained of a cough. However, this side effect also had occurred during these patients' previous ACE inhibitor therapy. In fact, seven of 36 patients (19%) had suffered an adverse effect on their previous ACE inhibitor, while three patients who had side effects on their previous therapy had no recurrence of adverse events on quinapril.
The total cost savings resulting from the quinapril switch in these 36 patients was $4,956 ($138 per patient). See Table 5 for details. The major cost advantage of switching patients to quinapril is its lower acquisition cost compared to other ACE inhibitors. The major sources of costs associated with the switch were additional clinic visits, laboratory tests, and side-effects management. Patients switched to quinapril averaged 2.5 clinic visits through the end of follow-up. Laboratory monitoring primarily included electrolyte and renal function assessments. Emergency room visits were very few; only two patients visited the emergency room for suspected side effects, and these ultimately were determined to be unrelated to quinapril. If these non-drug-related emergency room costs were eliminated, the projected savings would be $5,441 in the first year. There were no hospitalizations during follow-up, also adding to the cost benefits.
Table 5. Cost analysis of ACE-inhibitor switch
| Projected Annual Costs | Initial ACE Inhibitor | Quinapril | Difference |
| Acquisition Cost of ACE Inhibitor | $14,685 | $7,344 | $7,341 |
| Additional Antihypertensive Therapy | $432 (8 on diuretics) | $432 (8 on diuretics) | 0 |
| Laboratory Monitoring | - | $326 | $-326 |
| Clinic Visits | - | $1,210 | $-1,210 |
| ER Visits | - | $485 | $-485 |
| Hospitalizations | - | 0 | 0 |
| Costs of Managing Side Effects | - | $364 | $-364 |
| TOTALS | $15,117 | $10,161 | $4,956 |
DISCUSSION
ACE inhibitors, with their low incidence of overall side effects and favorable risk-benefit profile in patients with diabetes mellitus, renal dysfunction, and heart failure, are a commonly used class of drugs for the initial treatment of hypertension.8 However, when compared to diuretics and beta-blockers, this drug class may have a relatively high acquisition cost.9 Further, the availability of a large number of ACE inhibitors, the relevance of tissue ACE activity, and the absence of long-term outcomes data make product selection difficult.8,9 However, a growing number of providers are using formularies to contain prescription costs.10-14 And the tendency to choose a single preferred agent in drug classes such as ACE inhibitors makes good fiscal sense. Many managed care organizations have used therapeutic interchange or switch programs to convert patients stabilized on one drug to another product with similar efficacy but at a lower cost. These conversions typically are within, rather than across, drug classes. Although such switch programs have received widespread criticism, they continue to be used on a regular basis.5,6 Therapeutic interchange, if performed properly, can be advantageous, as the literature is beginning to show. Therapeutic interchange programs have been reported previously for cephalosporins,1 calcium channel blockers,3 H2 receptor antagonists,15 and selected ACE inhibitors.16,17 Two published ACE inhibitor switch programs involved conversions from enalapril to lisinopril with very similar pharmacologic profiles.18 In the study by McDonough et al.,17 BP control was not established prior to or following the switch. As a result, no conclusions about dose proportionality or clinical outcomes could be reached. In the study by Lindgren-Fumaga et al.,16 94 of 141 patients switched between products were excluded from the study, a situation that raises concern about selection bias. Although BP control was evaluated following the switch, patients were followed for only one month. Despite these methodological concerns, both studies concluded that cost savings could be realized by the ACE inhibitor interchange. However, the results of therapeutic interchange programs require additional study.
Limitations of this study include the lack of blinding, failure to introduce an intervening placebo baseline period, lack of a randomized crossover, and a relatively short duration of follow-up. However, while the lack of blinding may have implications with regard to the observed frequency of side effects, it should have little impact on BP outcomes. The lack of an intervening placebo baseline period and a failure to employ a randomized crossover design may ultimately have allowed the inclusion of patients who may not have had a rise in BP to pretreatment levels. Ultimately, however, the switch protocol design parallels the clinical practice of managed care organizations. The minimum three-month follow-up may have been too short to detect late onset side effects or late treatment failures with quinapril. Further follow-up is needed to identify the impact of late adverse reactions or late treatment failures.
CONCLUSION
The study reported here demonstrates that a successful therapeutic interchange with ACE inhibitors in patients with mild-to-moderate hypertension is possible. Switching patients to quinapril from captopril, enalapril, and lisinopril resulted in an excellent rate of success, few adverse outcomes, and cost savings of $138 per patient during the first year of the switch. The acquisition cost savings associated with quinapril were projected to be $7,341 for all 36 patients. This amount was reduced by the additional costs of clinic visits, laboratory monitoring, and side effects.l These costs must be considered in the evaluation of switch program.
References
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Authors
DANIEL E. HILLEMAN, PHARM.D., is Professor and Chair, Department of Pharmacy Practice, Creighton University School of Pharmacy, Omaha. SYED M. MOHIUDDIAN, M.D., is Director, Division of Cardiology, Creighton University School of Medicine. RICHARD L. WURDEMAN, PHARM.D., is Clinical Pharmacist, Cardiac Center, Creighton University. E. CHUMA WADIBIA, PHARM.D., M.B.A., is Research Fellow, Cardiac Center, Creighton University.
Correspondence: Daniel E. Hilleman, Pharm.D., Creighton University Schools of Medicine and Pharmacy and Allied Health, 2500 California Plaza, Omaha, NE 68178.
Copyright © 1997, Academy of Managed Care Pharmacy, Inc. All rights reserved.