JOURNAL REVIEW

Year : 2015  |  Volume : 1  |  Issue : 2  |  Page : 182-184

Journal review: The BASKET PROVE II study

Suraj Khanal, Ramesh Patel
Department of Cardiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Correspondence Address:
Dr. Suraj Khanal
Department of Cardiology, 3rd Floor; Block-C; Advanced Cardiac Center, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/2395-5414.166314

Article

Background

• Polymers are drug carrier molecules and are large compounds consisting of repeating structural units typically connected by covalent chemical bonds
• It has been demonstrated that the coating of stents with inert polymers may reduce the surface reactivity and thrombosis ^[1]
• Both the first and the second-generation of drug-eluting stents (DES) are using a nonbiodegradable polymer such as polystyrene-b-isobutylene-b-styrene (Taxus) and fluoropolymer (Xience) to control the drug elution
• However, polymers by disintegration and absorption, may induce local inflammation, hypersensitivity reactions, neoatherosclerosis and very late stent thrombosis (VLST), myocardial infarction, or cardiac death ^[2]
• As nonbiodegradable polymers may lead to an inflammatory response, biodegradable polymers are being investigated such as polylactic acid (PLA) and polyglycolic acid
• The rationale postulated for biodegradable polymer DES was that they would reduce the risk of VLST or late clinical events related to stent thrombosis beyond the 1^st year, when the polymer has dissolved while remaining as effective as a second-generation durable polymer DES (DP-DES) and as safe >1-year as bare-metal stents (BMS)
• This particular study has used PLA-based biodegradable polymer.

Study Objectives

• The aim of this study was to evaluate the long-term performance profile of a biodegradable polymer DES compared with DP-DES for efficacy and safety, and comparison with thin-strut coated BMS for late safety on a background of dual antiplatelet therapy, including prasugrel
• The primary end point was major adverse cardiac events
• The main secondary end point, the safety end point, was a combination of definite or probable stent thrombosis, myocardial infarction, or cardiac death.

Study Design

• BASKET-PROVE II was a randomized, multicenter, single- and assessor-blind, noninferiority trial with primary end point assessment after 2 years
• Eligible patients were presented between April 1, 2010 and May 21, 2012
• Eight centers in Switzerland, Denmark, Germany, and Austria were contributed patients
• A total of 2299 patients were enrolled in the trial.

Methods

• Eligible patients with chronic or acute coronary artery disease requiring stenting with stents ≥3.0 mm in diameter by visual assessment
• Patients were randomized in a 1:1:1 ratio to either: Biolimus-A9–eluting biodegradable polymer stainless steel DES (Nobori), everolimus-eluting DP cobalt-chromium DES (Xience Prime), or a newest-generation thin-strut BMS coated with a biocompatible silicone-carbide layer (prokinetic)
• Eight hundred patients per group was the primary goal, expecting a loss to follow-up rate of 10%
• However, actual loss was only 2% and hence 765/arm were included
• All the patients were prescribed acetylsalicylic acid 75–100 mg daily for long-term
• A loading dose of 60 mg prasugrel with a maintenance dose of 10 mg daily, risk-adjusted to 5 mg in patients aged >75 years, or body weight <60 kg
• Prasugrel for 12 months after stenting with DES and for patients with acute coronary syndrome and for 4 weeks after elective stenting with BMS.

Statistics

• The sample size for the trial was estimated based on the findings of the BASKET-PROVE trial
• Based on the BASKET-PROVE results, a noninferiority margin of 3.8% absolute risk difference compared with the DES group was prespecified, considering a 50% relative excess of events or more in the biodegradable polymer biolimus-A9–eluting stent patients as inferior
• Baseline characteristics are reported as counts and percentages or means ± standard deviation
• All the analyses were performed on the intention-to-treat population
• Time-to-event analyses were carried out using the Kaplan–Meier estimator and Cox proportional hazards models, stratifying for the center
• All the analyses were performed by an independent statistical team using the Statistical Software System R, version 3.1.0 (NOBORI stent, Terumo Corp., Japan).

Results

• The primary end point occurred in 7.6% of patients receiving biodegradable polymer, 6.8% of those receiving DP, and 12.7% with BMS
• Noninferiority of the biodegradable polymer stent compared with the DP-DES was established with an absolute risk difference of 0.78% (95% confidence interval [CI], −1.93% to 3.50% P for noninferiority, 0.042)
• Biodegradable polymer stent was superior to the BMS regarding the primary end point after 2 years (absolute risk difference − 5.16, 95% CI, −8.32 to − 2.01, P + 0.0011)
• The combined safety end points were not significantly different among the three stent groups.

Discussion

• In the present study, the biodegradable polymer biolimus-A9–eluting stent proved to be as effective and noninferior by intention-to-treat to the best-in-class second-generation DP everolimus-eluting stent to prevent restenosis
• Biodegradable polymer DES did not further reduce the rate of VLST, myocardial infarction, or cardiac death beyond 1-year
• Stent thrombosis rates were very low with all three stents, possibly because of the prasugrel based dual antiplatelet therapy in this study
• Similar results in DES in 1^st year reflect similar antiproliferative efficacy of the different “limus” drugs
• The lack of a reduction of VLST with biodegradable polymer observed in this study seems to question the concept that DP are key in late stent thrombosis formation
• This study enrolled patients in need of large coronary stents ≥3 mm in diameter, a population expected to have lower restenosis rates and higher rates of myocardial infarction, and death related to stent thrombosis.^[3]

Limitations

• The trial was not powered for late safety, the main secondary end point
• Present results suggest that a trial of >20,000 patients would be required to demonstrate a significant benefit of biodegradable polymer DES given the observed differences in VLST
• Because the priori definition of a noninferiority margin is somewhat arbitrary, the authors based their assumptions on the results of the predecessor BASKET-PROVE trial with similar design
• Inconsistent findings for noninferiority depending on whether the intention-to-treat or the per-protocol set was used
• Finally, the fact that all the patients were treated with prasugrel-based dual antiplatelet therapy may question the generalizability, regarding VLST and ischemic end points.

Comments

• No trial evaluating biodegradable polymer versus DP second-generation stents had a primary outcome assessment beyond 1-year up to the present trial ^[4]
• Findings of four meta-analyses indicate that the biodegradable polymer DES are superior in efficacy and safety compared with the BMS and first-generation DES ^{[5],[6],[7],[8]}
• Three meta-analyses found the increased rates of stent thrombosis for biodegradable polymer stents within 1-year, and 2 found a higher myocardial infarction rate, whereas others described the biodegradable polymer stents as noninferior in these outcomes
• With respect to the events after 1-year, the conclusions remain vague in view of the lack of direct trial comparisons
• BASKET-PROVE II adds important new information: It is the first trial with a 2-year primary endpoint and the first with a BMS control arm.

Conclusion

• Apparent noninferiority of biodegradable polymer biolimus-eluting DES compared with DP everolimus-eluting DES in the intention-to-treat analysis confirms the similar findings of early 1-year outcomes and extends them to a 2-year primary assessment
• Present data do not offer any evidence, however, that VLST and related myocardial infarction or cardiac death may be reduced by the biodegradable polymer biolimus-eluting compared to the best-in-class DP everolimus-eluting stents
• These findings challenge the concept that the polymer should be a key in the perceived late deficiency of DP-DES (i.e. their propensity to VLST).

References

1.	Rogers C, Edelman ER. Endovascular stent design dictates experimental restenosis and thrombosis. Circulation 1995;91:2995-3001.
2.	Nebeker JR, Virmani R, Bennett CL, Hoffman JM, Samore MH, Alvarez J, et al. Hypersensitivity cases associated with drug-eluting coronary stents: A review of available cases from the Research on Adverse Drug Events and Reports (RADAR) project. J Am Coll Cardiol 2006;47:175-81.
3.	Elezi S, Kastrati A, Neumann FJ, Hadamitzky M, Dirschinger J, Schömig A. Vessel size and long-term outcome after coronary stent placement. Circulation 1998;98:1875-80.
4.	Smits PC, Hofma S, Togni M, Vázquez N, Valdés M, Voudris V, et al. Abluminal biodegradable polymer biolimus-eluting stent versus durable polymer everolimus-eluting stent (COMPARE II): A randomised, controlled, non-inferiority trial. Lancet 2013;381:651-60.
5.	Navarese EP, Tandjung K, Claessen B, Andreotti F, Kowalewski M, Kandzari DE, et al. Safety and efficacy outcomes of first and second generation durable polymer drug eluting stents and biodegradable polymer biolimus eluting stents in clinical practice: Comprehensive network meta-analysis. BMJ 2013;347:f6530.
6.	Kang SH, Park KW, Kang DY, Lim WH, Park KT, Han JK, et al. Biodegradable-polymer drug-eluting stents vs. bare metal stents vs. durable-polymer drug-eluting stents: A systematic review and Bayesian approach network meta-analysis. Eur Heart J 2014;35:1147-58.
7.	Palmerini T, Biondi-Zoccai G, Della Riva D, Mariani A, Sabaté M, Smits PC, et al. Clinical outcomes with bioabsorbable polymer- versus durable polymer-based drug-eluting and bare-metal stents: Evidence from a comprehensive network meta-analysis. J Am Coll Cardiol 2014;63:299-307.
8.	Bangalore S, Toklu B, Amoroso N, Fusaro M, Kumar S, Hannan EL, et al. Bare metal stents, durable polymer drug eluting stents, and biodegradable polymer drug eluting stents for coronary artery disease: Mixed treatment comparison meta-analysis. BMJ 2013;347:f6625.