The aim of this study was to compare 5-year cost-effectiveness and clinical outcomes of patients with oral rapamycin (OR) plus bare-metal stent versus the drug-eluting stent (DES) strategy. During 2006 to 2007, a total of 200 patients were randomized to OR (n = 100) and DES (n = 100). Primary end point was to compare costs of initial procedure and cost-effectiveness of both revascularization strategies. Safety was evaluated by the composite of death, myocardial infarction, and cerebrovascular accident. Efficacy was assessed by target vessel and target lesion revascularizations. The 2 groups had similar baseline demographic, clinical, and angiographic characteristics. In the DES group, paclitaxel-, zotarolimus-, and sirolimus-eluting stents were used. Five-year clinical follow-up was accomplished in 99% patients. The DES group had significantly higher procedural (p <0.001), discharge to first-year (p = 0.02), and 1- to 5-year costs (p <0.001) compared with the OR group. At 5 years, the composite end point of death, myocardial infarction, and cerebrovascular accident (12% in the OR group vs 25% in the DES group, p = 0.01) was significantly less in the OR group. Target vessel revascularization (14.5% in the OR group vs 21% in the DES group, p = 0.16) and target lesion revascularization (10% in the OR group vs 17.6% in the DES group, p = 0.05) were not significantly different. In conclusion, a strategy of OR plus bare-metal stent was cost saving than a first-generation DES.
The Oral Rapamycin in ARgentina (ORAR) 3 trial is an investigator-driven randomized trial, which aimed to assess the cost-effectiveness of oral rapamycin (OR) plus bare-metal stent (BMS) versus drug-eluting stent (DES) in patients with de novo coronary lesions. One- and 3-year results have been published previously. This study reports the final 5-year clinical outcomes and the cost analysis of both revascularization strategies.
Methods
From January 2006 to September 2007, patients undergoing coronary stent implantation at the catheterization laboratories of 3 centers in Buenos Aires, Argentina (Sanatorios Otamendi, Las Lomas, and Clinica IMA) were evaluated, and those meeting the study clinical and angiographic inclusion criteria were asked to consent to the study.
Patients were randomized 1:1 to either the OR plus BMS or the DES arm. The study design and 1- and 3-year follow-up results have been previously reported. Patients were eligible for the study if they had clinical indication for myocardial revascularization, age >18 years, de novo severe stenosis suitable for stenting (≥70% visual estimation), reference vessel size from 2.5 to 4.0 mm by visual estimation, and were also suitable for coronary bypass surgery. The exclusion criteria were an acute myocardial infarction (MI) in the preceding 24 hours, in-stent restenosis, previous percutaneous coronary intervention (PCI) in the last 6 months, chronic total occlusion of the target vessel, rapamycin allergy, clopidogrel or aspirin intolerance, significant bleeding in the last 6 months, stroke or transient ischemic attack in the last 12 months, major blood dyscrasias including thrombocytopenia, patients with poorly controlled dyslipidemia, participation in another trial that did not allow long-term clopidogrel treatment, short life expectancy, or patients with infectious diseases.
The protocol of this study was approved by the ethics committees of the participating centers and the Argentina National Regulatory Agency for Drug, Food and Medical Technology. The study was conducted by a nonprofit organization (Centro de Estudios en Cardiología Intervencionista), and an independent safety clinical events committee blindly monitored and adjudicated all clinical adverse events ( Supplementary Material . All the patients signed a written informed consent for participation in this trial. The trial was registered in the ClinicalTrials.gov registry ( NCT00552669 ).
All eligible patients were randomized to OR plus BMS or DES. The randomization process in each center was performed in a blinded manner. In the OR arm, patients received a loading dose of 10 mg, the day before the stent implantation, followed by 3 mg/day for a total of 14 days.
PCI was performed using standard techniques. In the BMS group, various commercially available stents were used according to the operators’ preference. In the DES group, patients received one of the 4 commercially available stents: TAXUS (Boston Scientific, Natick, Massachusetts), Endeavor (Medtronic Vascular, Santa Rosa, California), Cypher (Cordis, Warren, New Jersey), and EucaTAX (Eucatech AG, Germany).
All patients received 325 mg/day of aspirin indefinitely, clopidogrel as a loading dose of 300 mg in the day of the procedure, and 75 mg/day thereafter for 1 month in the OR arm and for 1 year in the DES arm and after that according to physicians’ criteria. Statins were given to all patients indefinitely.
A clinical interview after hospital discharge was required twice for the first month of treatment and monthly thereafter up to 6 months with additional interviews at 9 months during the first year. Subsequently, at 2, 3, 4, and 5 years, patients were contacted in person or by telephonic interview, and in case of any reported cardiovascular event, a complete record of the event was obtained by the trained staff from the coordinating center of the study.
The primary end point of the study was to compare overall costs (in-hospital, follow-up, and cumulative) of the 2 revascularization strategies (OR and DES) at 1, 3, and 5 years of follow-up. This end point was selected on the hypothesis that both strategies would have similar efficacy.
Costs (expressed in US dollars) included hospitalization, medications (procedural and follow-up), and procedural resources (initial and follow-up). Professional fees during PCI procedures were estimated according to the national fees. All costs, procedural, in-hospital, and follow-up, were calculated from the perspective of third party payers based on the Argentinean medical tariff. All direct costs were converted to US dollars. Specific costing was done for each patient. The same stent list prices were used for all patients. Cost of oral sirolimus was added to initial procedure costs.
At 5 years, costs associated with new adverse events during follow-up were added if related to the initial procedure or with progression of coronary artery disease. Secondary end point included a safety end point defined by a composite of death from any cause, MI, and cerebrovascular accident (CVA) and was included in major adverse cardiovascular events (MACEs) definition. Target vessel failure (TVF) was defined as cardiac death, MI, and target vessel revascularization (TVR).
TVR and target lesion revascularization (TLR) were analyzed separately as efficacy end points not included in the MACE definition and were only clinically driven. Stent thrombosis (ST) was defined according to a previous definition. At 5 years, occurrence of malignancies, major bleedings, and incidence of adverse events according to age (≥or <65 years) were also analyzed. All end points were examined by the intention-to-treat principle.
The sample size of the study was calculated on the basis of a test for trend analysis. According to our previous data with oral sirolimus and DES, it was predicted that the incidence of TVR would be similar with both revascularization therapies. Therefore, sample size estimation was calculated according to cost differences and effectiveness between both revascularization strategies, with a statistical power of 90%. Taking into account both strategies would have similar events; cost variances will be driven by cost differences in DES and BMS designs and also by requirements of long-term dual antiplatelet therapy.
In view of that both revascularization procedures share indirect costs, we only analyzed direct costs and cost differences between the 2 strategies using the microcosting method.
A 1-tailed noninferiority test was performed using a predetermined noninferiority threshold level of 15%, with an overall α <0.05. A noninferiority test was selected under the hypothesis of equivalence in clinical efficacy between both strategies of OR and DES. The hypothesis was that the average DES cost minus the average cost of OR plus BMS was greater than the prespecified noninferiority threshold level, and as a consequence, DES would not be cost-effective compared with the OR plus BMS. A bootstrap method was used to validate the noninferiority cost test and was applied to patients having adverse events at follow-up.
Continuous variables are expressed as mean ± SD and categorical variables as percentage. Continuous variables were compared using analysis of variance with Bonferroni correction. Categorical variables were compared using chi-square analysis or Fisher’s exact test.
Kaplan-Meier survival plots were obtained for the evaluation of the primary end point and other adverse events and compared by the log-rank test. Cox regression curve was used to analyze the incidence of MACE.
Univariate and multivariate Cox regression analyses were performed using SPSS, version 17.0 (SPSS Inc., Chicago, Illinois), to determine independent predictors of outcome at follow-up. Variables of statistical significance after univariate analysis and clinically relevant covariates including all demographic, clinical, angiographic, and procedural variables were included into the model. A p value of <0.05 was considered significant.
Results
From January 2006 to September 2007, a total of 1,274 patients underwent coronary angiography, from which 200 patients were randomized. One hundred patients were included in the OR plus BMS group (131 vessels and 158 lesions) and 100 in the DES group (142 vessels and 170 lesions). A total of 347 stents were implanted, 171 in the OR and 176 in the DES groups. Baseline demographic, clinical, and angiographic characteristics of the 2 groups were similar ( Table 1 ). In the DES group, 97.2% of the DESs were TAXUS, Endeavor, or Cypher.
| Variable | OR + BMS (n = 100) | DES (n = 100) | p |
|---|---|---|---|
| Age (yrs) | 62.1 ± 10.1 | 63.4 ± 10.6 | 0.307 |
| Patients ≥ 65 yrs | 40 | 48 | 0.31 |
| Men | 83 | 81 | 0.99 |
| Hypertension ∗ | 69 | 72 | 0.93 |
| Dyslipidemia † | 71 | 81 | 0.61 |
| Current smoker | 21 | 17 | 0.67 |
| Diabetes mellitus | 24 | 33 | 0.36 |
| Left ventricular ejection fraction <50% ‡ | 11 | 6 | 0.20 |
| Previous MI | 26 | 33 | 0.51 |
| Chronic renal failure | 4 | 6 | 0.74 |
| Body mass index >25 kg/m 2 | 25 | 30 | 0.42 |
| Previous CVA | 2 | 2 | 1.00 |
| Previous PCI | 12 | 13 | 0.98 |
| Unstable angina pectoris | 62 | 56 | 0.74 |
| EuroSCORE | 3.63 ± 2.7 | 3.41 ± 2.6 | 0.56 |
| Multiple-vessel disease | 48 | 51 | 0.90 |
| Left main coronary disease | 10 | 7 | 0.44 |
| No. of treated vessels | 131 | 142 | 0.70 |
| No. of treated lesions | 158 | 170 | 0.75 |
| No. of lesions per patient | 1.6 ± 0.7 | 1.7 ± 0.8 | 0.34 |
| No. of vessel per patient | 1.3 ± 0.5 | 1.4 ± 0.6 | 0.20 |
| No. of stent deployed | 171 | 176 | 0.94 |
| Overlapping stents per patient | 31 | 21 | 0.28 |
| Reference diameter (mm) | 2.8 ± 0.5 | 2.8 ± 0.4 | 1.0 |
| Reference diameter ≤2.5 mm, per lesion (%) | 57 (36) | 48 (28) | 0.32 |
| Lesion length (mm) | 13.8 ± 5.5 | 14.4 ± 5.9 | 0.34 |
| Stent length (mm) | 19.1 ± 4.3 | 21.4 ± 5.2 | 0.001 |
| Stent diameter (mm) | 2.78 ± 0.4 | 2.76 ± 0.4 | 0.66 |
| Target coronary artery (%) | |||
| Right | 33 (21) | 39 (23) | 0.82 |
| Left anterior | 71 (45) | 82 (48) | 0.79 |
| Left circumflex | 49 (31) | 44 (26) | 0.51 |
| Left main | 5 (3) | 5 (3) | 0.83 |
| Plaque type A/B1 § (%) | 61 (39) | 55 (32) | 0.4 |
| Plaque type B2/C § (%) | 97 (61) | 115 (68) | 0.9 |
∗ Hypertension was defined as arterial blood pressure ≥140/90 mm Hg.
† Dyslipidemia was defined as total cholesterol serum levels >200 mg/dl.
‡ Measured by ventriculography and/or echography.
§ According to the American Heart Association classification.
Succinctly, in the OR group, 24% of patients developed minor side effects linked to the drug intake including gum sores (14%) and diarrhea (12%), 4% required drug discontinuation, none of them with hospitalization, and all of them had complete relief of the symptoms when the drug was stopped. The details of baseline characteristics, PCI strategy, and hospital results have been described elsewhere.
At 1 and 3 years, cumulative cost was significantly higher with DES strategy (p <0.001), and patients included in both groups had a similar clinical outcome, although MACE at 3 years was higher in the DES group (p = 0.07).
All patients had a minimum 5 years of follow-up, and excluding patients who died before scheduled long-term visit, the follow-up rate in both groups was 99%. At 5 years, 40% of patients in the DES arm and 18% of the OR arm were on clopidogrel treatment (p <0.001).
Table 2 and Figure 1 summarizes the in-hospital, follow-up, and cumulative costs per patient in each group. As we can see in Table 2 , the DES group had significant higher procedural (p <0.001), discharge to first-year (p <0.02), and 1- to 5-year costs (p <0.001). At 5 years, cumulative costs were significant higher in the DES group compared with the OR group ($12,011.5 ± 6,090.1 and $7,516.1 ± 2,734.3, respectively, p <0.001). One-tailed noninferiority testing showed that the DES therapy failed to be cost-effective compared with OR. To be cost-effective, DES strategy should be associated with a 16.6% decrease in the cost of the initial procedure, a 49% cost decrease during follow-up, and a 34.2% cumulative cost decrease at 5 years. Cost differences in treatment strategies reflect the initial differences in the cost of DES and BMS, the higher numbers of TVR beyond the first year in the DES group ( Tables 2 and 3 ), and longer requirement of clopidogrel therapy in the DES group (p <0.001). In addition, the average follow-up cost per patient with adverse cardiac events was significantly higher in the DES group than the OR group ($10,727.7 ± 5,400.1 and $6,588.7 ± 3491.7, respectively, p <0.001); as a result of all these disparities, 5-year cost was 37.5% higher in DES than the OR strategy. Figure 2 shows the results of factoring in the costs of patients with new adverse cardiac events and generating 100 sample costs of patients with reposition using the bootstrap method at 5-year follow-up; the patients in the DES group with complications had significantly higher in-hospital costs than the patients in the OR group.
| US Dollars | OR + BMS (n = 100) | DES (n = 100) | p |
|---|---|---|---|
| Initial procedure | |||
| PCI | 970.5 ± 43.7 | 973.9 ± 52.9 | 0.35 |
| Stent (BMS or DES) | 596.3 ± 304.6 | 2,623.7 ± 1,397.4 | <0.001 |
| Drugs ∗ | 761.0 ± 14.9 | 54.7 ± 1.2 | <0.001 |
| Professional fees | 603.5 ± 17.2 | 605.2 ± 19.0 | 0.52 |
| Hospital fees | 1,502.9 ± 637.0 | 1,459.5 ± 1,199.3 | 0.74 |
| Overall initial costs plus taxes † | 5,365.5 ± 876.0 | 6,921.5 ± 2,251.4 | <0.001 |
| Follow-up | |||
| Out of hospital to 1 yr | 883 ± 2,111.8 | 1,594.5 ± 2,338.2 | 0.02 |
| 1–5 yrs | 6,633 ± 2,138.1 | 10,417 ± 5,361.2 | <0.001 |
| 0–5 yrs ‡ | 7,516.1 ± 2,734.3 | 12,011.5 ± 6,090.12 | <0.001 |
∗ Including OR treatment during 14 days.
† According to legislation from Argentina, 21% of final costs.
| Years | OR (n = 100) | DES (n = 100) | RR | 95% CI | p | |
|---|---|---|---|---|---|---|
| Inferior | Superior | |||||
| Death | ||||||
| 0–1 | 3 | 7 | 2.33 | 0.62 | 8.76 | 0.16 |
| 1–5 | 3 | 9 | 3.00 | 0.83 | 10.75 | 0.06 |
| 0–5 | 6 | 16 | 2.66 | 1.08 | 6.53 | 0.02 |
| Cardiac death | ||||||
| 0–1 | 1 | 4 | 4.00 | 0.45 | 35.16 | 0.38 |
| 1–5 | 2 | 5 | 2.5 | 0.49 | 12.58 | 0.22 |
| 0–5 | 3 | 9 | 3.00 | 0.83 | 10.75 | 0.06 |
| Acute MI | ||||||
| 0–1 | 6 | 9 | 1.5 | 0.55 | 4.05 | 0.63 |
| 1–5 | 0 | 3 | 4.0 | 0.45 | 35.16 | 0.36 |
| 0–5 | 6 | 12 | 2.33 | 0.93 | 5.82 | 0.10 |
| Death + acute MI + CVA | ||||||
| 0–1 | 9 | 15 | 1.66 | 0.76 | 3.63 | 0.34 |
| 1–5 | 3 | 10 | 3.33 | 0.94 | 11.75 | 0.08 |
| 0–5 | 12 | 25 | 2.08 | 1.10 | 3.91 | 0.01 |
| TVF | ||||||
| 0–1 | 21 | 23 | 1.09 | 0.64 | 1.84 | 0.73 |
| 1–5 | 5 | 13 | 2.6 | 0.96 | 7.02 | 0.08 |
| 0–5 | 26 | 36 | 1.38 | 0.90 | 2.11 | 0.08 |
| TVR (%) | ||||||
| 0–1 | 14/131 (10.6) | 15/142 (10.5) | 0.98 | 0.49 | 1.96 | 0.86 |
| 1–5 | 5/131 (4) | 15/142 (10.5) | 2.78 | 1.04 | 7.46 | 0.02 |
| 0–5 | 19/131 (14.5) | 30/142 (21) | 1.45 | 0.86 | 2.45 | 0.16 |
| TLR (%) | ||||||
| 0–1 | 11/158 (7.0) | 14/170 (8) | 1.18 | 0.55 | 2.52 | 0.84 |
| 1–5 | 5/158 (3) | 16/170 (9.4) | 2.95 | 1.10 | 7.87 | 0.03 |
| 0–5 | 16/158 (10) | 30/170 (17.6) | 1.74 | 0.98 | 3.07 | 0.05 |
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