Table 5.
Studies Involving Narrow Therapeutic Index Cardiovascular Drugs
| Source | Drugs Studieda | No. of Patients (Age Mean or Range, y)/Duration | Study Design | Population (Setting) | Jadad or Newcastle Ottawa Scoreb | Results | Source of Funding |
|---|---|---|---|---|---|---|---|
| Antiarrhythmic Agents | |||||||
| Amit et al,59 2004 | Rythmex vs propafenone | 119 (65)/18 mo | Retrospective cohort study (pre/post design without concurrent controls) | Patients with atrial fibrillation stable while receiving brand for ≥18 mo switched to generic (non-US) | 4 | Generic use associated with slight reduction in total ED discharges and ED visits for chest pain (P < .01); no significant differences in clinic visits, admissions, cardioversions, and rate of use of other cardiovascular medications (P > .05) | Generic manufacturer |
| Kasmer et al,60 1987 | Pronestyl vs procain-amide | 10 (62)/6 doses of each separated by 1 wk of prior therapy | Bioequivalence study: single-blind RCT with crossover | Patients with ventricular dysrhythmias (US) | 1 | No significant change in type or frequency of VPBs on telemetry (P > .05) | Generic manufacturer, National Institutes of Health |
| Warfarin Anticoagulant | |||||||
| Handler et al,61 1998 | Coumadin vs warfarin | 57 (71)/4 wk of Coumadin and then 8 wk of warfarin vs 4 wk of warfarin and then 8 wk of Coumadin | Double-blind RCT with crossover | Outpatients with arrhythmia (US) | 5 | No significant differences in INR (P = .40), dose adjustments, adverse events (P > .05) | Generic manufacturer |
| Pereira et al,62 2005 | Coumadin vs warfarin | 7 (63)/Five 3-wk periods of each | Double-blind RCT with crossover | Outpatients with indications for anticoagulation (US) | 4 | No significant differences in INR measurements or variation (P = .98) | Not listed |
| Paterson et al,63 2006 | Coumadin vs 1 of 2 versions of warfarin | 36 724 (≥66)/40 mo before, 1 mo of transition, and 9 mo following switch | Population-based, cross-sectional time-series analysis | Elderly outpatients with numerous indications for anticoagulation taking Coumadin (non-US) | 5 | No significant differences in INR testing (P = .93) or hospitalization for hemorrhage (P = .89) or thromboembolism (P = .97) | Government |
| Lee et al,64 2005 | Coumadin vs warfarin | 35 (52)/4 wk of Coumadin and then 8 wk of warfarin vs 4 wk of warfarin and then 8 wk of Coumadin | Single-blind RCT with crossover | Patients with mechanical heart valves who received Coumadin for ≥2 mo (non-US) | 3 | Dose changes were rare; no significant differences in pooled INRs or frequency of adverse effects (P > .05) | Unknown |
| Halkin et al,65 2003 | Coumadin vs warfarin | 975 (70)/6 mo before and 6 mo after switch | Retrospective observa-tional study (pre/post design) | Outpatients with numerous indications for anticoagulation taking Coumadin (non-US) | 5 | After the switch, INR values were lower and warfarin doses prescribed were higher, especially in those who were subtherapeutic when receiving Coumadin (P < .01) | Not listed |
| Witt et al,66 2003 | Coumadin vs warfarin | 2299 (69)/3 mo before and 3 mo after switch | Retrospective cohort study | Outpatients with numerous indications for anticoagulation taking Coumadin (US) | 4 | More INR values below therapeutic range with generic (P < .001); overall average INR decreased by 0.13 after switch; no significant differences in hospitalizations, ED use, outcomes (bleeding or thromboembolism) | Not listed |
| Warfarin Anticoagulant | |||||||
| Milligan et al,67 2002 | Coumadin vs warfarin | 182 (75)/8 mo before and 10 mo after switch | Retrospective cohort study | Outpatients with numerous indications for anticoagulation taking Coumadin (US) | 5 | No significant differences in INR (P = .3), dose adjustments (P = .41), adverse events | Insurance company |
| Weibert et al,68 2000 | Coumadin vs warfarin | 113 (70)/4 wk before and 10 wk after switch | Multicenter double-blind RCT with crossover | Outpatients with atrial fibrillation who received Coumadin for 1 mo (US) | 4 | No significant differences in daily dose (<0.5 mg/d), average INR difference (P < .08), adverse events (P = .24 for hemorrhagic) | Generic manufacturer |
| Swenson and Fundak,69 2000 | Coumadin vs warfarin | 210 (78)/8 wk | Prospective observa-tional cohort study | Outpatients with indications for anticoagulation receiving Coumadin for ≥3 mo switched to warfarin (US) | 6 | No significant differences in INR between groups (P = .15); changes in INR of > 1.0 were rare; no adverse effects or adverse events | Not listed |
| Neutel and Smith,70 1998 | Coumadin vs warfarin | 39 (70)/3 wk of Coumadin and then 6 wk of warfarin vs 3 wk of warfarin and then 6 wk of Coumadin | Single-blind RCT with crossover | Outpatients with arrhythmia stably treated with Coumadin for 6 wk (US) | 2 | Changes in INR after switching were small and not significant (P > .05); no differences in adverse effect profiles between drugs | Not listed |
| Richton-Hewett et al,71 1988c | Coumadin vs warfarin | 55 (57)/3 mo of warfarin and then 4 mo of Coumadin | Retrospective cohort study | Outpatients with indications for anticoagulation switched to warfarin in a single hospital (US) | 5 | Higher rate of INR out of range (P < .001), dose changes (P < .05), clinic utilization (P < .03) with generic group; no significant differences in morbidity/mortality | Not listed |
Abbreviations: ED, emergency department; INR, international normalized ratio; RCT, randomized controlled trial; VPBs, ventricular premature beats.
a
Rythmex is manufactured by Knoll Pharmaceuticals, Delkenheim, Germany; Pronestyl, E. R. Squibb & Sons, New Brunswick, New Jersey; and Coumadin, DuPont Pharmaceuticals, Wilmington, Delaware.
b
The Jadad score range is 1–5 for RCTs; the Newcastle-Ottawa score range, 1–9 stars for observational studies.
c
Although conducted in the United States, this study did not involve a bioequivalent generic.