A recent meta-analysis of randomized clinical trials has identified a potential “signal” for increased long-term mortality in patients treated with paclitaxel-coated balloons (PCBs) and paclitaxel-eluting stents (PESs) in the peripheral arteries.1 This finding was both surprising and controversial, given the extensive body of evidence for paclitaxel use in the coronary arteries, where its track record of safety and efficacy is well-established. Nevertheless, given the potential implications of this meta-analysis, the FDA issued a warning letter to health care providers in January 2019 expressing potential concerns about the risk of paclitaxel-coated devices for the treatment of peripheral vascular disease and indicated that further study was needed.2 The FDA also acknowledged that a specific cause for potential increased mortality was unknown. No specific regulatory action was taken on FDA-approved or investigational paclitaxel-coated devices because it was believed that “the benefits continue to outweigh the risks.”

An FDA advisory panel was convened in June 2019, and again, although no definitive conclusions were reached, it was emphasized that the individual studies included in the meta-analysis required cautious interpretation, as there was a large amount of missing follow-up (up to 30% at 5 years), no clear mechanism identified for the mortality signal on review of animal and human studies, and poor correlations between paclitaxel dose and mortality.3 Nevertheless, a thoughtful discussion of the potential risks and benefits of paclitaxel-coated devices in patients with peripheral vascular disease was recommended.

These findings in patients with peripheral vascular disease prompted a retrospective review of patients treated with paclitaxel for coronary artery disease, which included substantially more patients, albeit at lower delivered paclitaxel dose. Although paclitaxel-coated coronary stents are no longer routinely used in current practice in the United States, there are a number of studies currently evaluating PCBs for native coronary artery disease and the treatment of in-stent restenosis (ISR).4-6 This article reviews the safety and efficacy profile of paclitaxel in patients with coronary artery disease (Table 1).4,7-20

PACLITAXEL MECHANISM OF ACTION

The commercial availability of bare-metal stents (BMSs) in the early 1990s was transformational for patients undergoing percutaneous coronary intervention (PCI), improving the safety of the procedure by treating coronary dissections associated with balloon-induced barotrauma and lessening the rate of late restenosis by 30% to 50%. Despite these beneficial effects, restenosis still occurred in 20% to 30% of patients treated with BMSs, particularly in those with diabetes mellitus, small vessels, and long lesions. A number of drug-eluting stents (DESs) were developed in the early 2000s to address the vexing process of restenosis. These DESs were composed of a metallic scaffold, durable polymer, and antiproliferative drug, most commonly sirolimus, another mTOR inhibitor analog, or paclitaxel.

Paclitaxel was originally isolated from the Pacific Yew tree (Taxus brevifolia) and is an antiproliferative agent that stabilizes intracellular microtubules and prevents mitosis in the Go-G1 and G2-M phases of the cell cycle.21 Paclitaxel was originally approved by the FDA in 1992 and has been used extensively in oncology, particularly for breast and ovarian cancer. Paclitaxel toxicity is well-characterized and includes neutropenia, neurotoxicity, and hypersensitivity reactions.22 Cardiac side effects are rare. Notably, the plasma levels of paclitaxel in oncology patients are 100 to 1,000 times higher than the cumulative doses of PESs. Highlighting its perceived safety, paclitaxel was deemed safe when given during pregnancy after organogenesis.23

PACLITAXEL-ELUTING CORONARY STENTS

Several DESs were developed to deliver paclitaxel to the coronary artery to inhibit arterial smooth muscle cell proliferation and reduce neointimal stenosis after stent placement (Table 1).7-15,24,25 The QuaDS-QP2 stent (Quanum Medical Corporation) provided a metallic scaffold, polymeric sleeve, and high quantities (up to 4 g) of paclitaxel.7 This stent had very brief clinical use, owing to high rates of vessel thrombosis, likely due to the very narrow efficacy-toxicity window with paclitaxel. The Jactax DES system (Boston Scientific Corporation) was a precrimped BMS that was coated on its abluminal aspect with an ultrathin (< 1 μm) one-to-one mixture of biodegradable polylactide polymer and paclitaxel applied as discrete microdots.8,26 The Achieve stent (Guidant Corporation) that released paclitaxel from a stainless steel stent without a polymer provided no significant benefit over BMS, likely due to the rapid elution of the paclitaxel.9

The predominant evidence base for PESs was developed with the TAXUS program studying Boston Scientific’s Taxus product line. These slotted-tube stainless steel stents included the Taxus NIRx stent (TAXUS I, II, and III studies),10-12 the Taxus Express stent (TAXUS IV, V, and VI studies),13-15 and the Taxus Liberté stent (ATLAS studies).27 Most clinical studies were performed with the slow-release (SR) formulation of the proprietary Translute polymer, which was designed to control paclitaxel release with an initial burst phase over the first 48 hours after implantation, followed by a low-level release phase for 10 days. The Taxus moderate-release (MR) device provided an eightfold higher 10-day drug release, and clinical studies showed no significant change in the antiproliferative effect but also no additional toxicity.15 Of the total loaded dose, approximately 90% remained sequestered within the SR polymer and 75% remained sequestered within the MR.

The TAXUS I study included 61 patients with de novo or restenotic coronary lesions who were randomized to receive a PES or BMS and showed a trend toward a decrease in restenosis in the PES group (0%) compared with the BMS group (10%).10 The TAXUS II trial evaluated PES in SR and MR formulations compared with BMS and showed a lower rate restenosis in the PES group.11 The TAXUS III trial was a small feasibility study of 28 patients with ISR treated with the PES.12

Figure 1. Five-year mortality pooled patient-level data from the TAXUS trials. Data from Stone GW, Ellis SG, Colombo A, et al. Long-term safety and efficacy of paclitaxel-eluting stents final 5-year analysis from the TAXUS clinical trial program. JACC Cardiovasc Interv. 2011;4:530-542.

The TAXUS IV study enrolled 1,314 patients with noncomplex coronary artery disease who were assigned treatment with a BMS, and 662 were assigned to receive treatment with an SR, polymer-based PES.13 Target lesion revascularization (TLR) was required in 3% of patients who received a PES and 11.3% of patients who received a BMS (relative risk, 0.27; 95% confidence interval [CI], 0.16–0.43; P < .001). The rate of angiographic restenosis was reduced from 26.6% to 7.9% with the PES (relative risk, 0.30; 95% CI, 0.19–0.46; P < .001). As a result, the FDA approved the Taxus stent based on a totality of clinical evidence, including the TAXUS IV study. In long-term follow-up at 1 and 5 years, the PES demonstrated superior efficacy with lower TLR and showed similar safety with no difference in major adverse cardiovascular events compared with a BMS (Figure 1).28,29 The TAXUS V study found similar results in patients with complex coronary artery disease.14 Shortly thereafter, the Taxus PES and sirolimus-eluting Cypher stent (Cordis, a Cardinal Health company) became standard of care in patients undergoing PCI. Within 10 months of approval, the Taxus stent had been implanted in over 1 million patients.30

Based on the safety and efficacy of PESs, despite the high rate of late lumen loss with the PESs compared with sirolimus-eluting stents,31 the Taxus stent became the comparator in a number of noninferiority stent versus stent trials that provided long-term clinical trial outcomes in a large number of patients treated with PESs.32,33

LATE STENT THROMBOSIS AND THE 2006 FDA ADVISORY PANEL MEETING

By the summer of 2006, DESs had become the default therapy for 80% to 90% of patients undergoing PCI due to the dramatic reduction in restenosis. Dual antiplatelet therapy was generally only continued for 1 year after the procedure. After a small series description of late stent thrombosis (> 1 year after the procedure),34 a meta-analysis of randomized trials showed higher late mortality in patients receiving either a sirolimus-eluting or paclitaxel-eluting coronary stent.35 As a result of these concerns, the FDA convened a meeting of the Circulatory System Devices Panel in 2006. This landmark advisory panel shed light on the limitations of the clinical trial design with DESs, including follow-up limited to 1 year, “off-label” use in patients with complex coronary disease (eg, bifurcation lesions, coronary artery bypass grafts, acute myocardial infarction, chronic total occlusion, and with overlapping stents), and variations in the definitions used for endpoint events.30 As a result of these analyses, it became apparent that there was an off-setting impact of the reduction of restenosis with the DES with the small but late risk of stent thrombosis.36 It was also believed that the type and amount of durable polymer also contributed to late stent thrombosis with early DESs, which could be lessened in part with the use of extended dual antiplatelet therapy. No particular toxicity related to paclitaxel or sirolimus was identified, but the overall use of DESs fell dramatically.

Newer-generation DESs were then developed with thinner stent filaments, lower polymer burden with more biocomparable polymers, and more effective antiproliferative agents. In a network meta-analysis that included 50,844 patients, the rates of 1-year definite stent thrombosis were significantly lower with cobalt-chromium everolimus-eluting stents (CoCr-EESs) compared with PESs, permanent polymer-based sirolimus-eluting stents, phosphorylcholine-based zotarolimus-eluting stents, and the Resolute zotarolimus-eluting stent (Medtronic).37 At 2-year follow-up, CoCr-EESs were still associated with significantly lower rates of definite stent thrombosis than BMSs and PESs. The beneficial effects of EESs over paclitaxel stents were mechanistically related enhanced efficacy with reduced TLR and stent thrombosis rather than toxicity related to paclitaxel.38 No late safety signals were detected in long-term follow-up of these studies with paclitaxel, but their availability was terminated due to lower efficacy compared with the latest-generation devices.

PACLITAXEL-COATED CORONARY BALLOONS

PCBs may have value in patients with ISR, small vessels, and those at high risk for bleeding. Scheller and colleagues reported a reduction in restenosis compared with balloon angioplasty alone in patients with ISR using early drug-coated balloon (DCB) technology.16 The superiority of PCBs in terms of target vessel revascularization persisted at 5-year follow-up. The PEPCAD II trial randomized 131 patients with ISR within BMSs to treatment with PCBs or PESs and showed that there was no difference in major adverse cardiac events in the two groups and no deaths at 12 months.17 The ISAR-DESIRE 3 trial demonstrated the noninferiority of DCB use compared with PES in percent diameter stenosis at 6 to 8 months.18

The first study investigating PCB use in small vessels was the PEPCAD I study, a single-arm trial investigating the SeQuent Please balloon (B. Braun Interventional Systems, Inc.), which showed that the DCB-only group had superior angiographic and clinical results at 6 months.19 Other randomized trials of DCBs in small vessels have been completed,20 and it appears that a DCB-only strategy with provisional BMSs might be a reasonable approach in this population.

A final subset of patients was evaluated in the DEBUT trial that randomized 208 patients with native coronary artery disease who were at high bleeding risk and were treated with a PCB or BMS. Patients treated with a PCB had a significantly lower rate of major adverse cardiac events compared with those in the BMS arm.4 A post hoc analysis showed that total mortality was higher in the BMS group.4 Additional studies with PCBs in these patient subsets are ongoing. No significant safety concerns have been identified to date.

CONCLUSION

Between the approval of PESs by the FDA in 2004 and the availability of next-generation DESs by 2010, millions of patients were treated with paclitaxel in coronary arteries. Because PESs were the default control stent in testing a number of new-generation DESs, extended follow-up to 5 years is available for thousands of patients. To date, there have been no late mortality signals in late cardiovascular or noncardiovascular deaths attributable to paclitaxel toxicity. PESs fell out of favor due to reduced efficacy compared with next-generation DESs rather than any identified paclitaxel toxicity. PCBs, which have not been approved in the United States, may have a particular benefit in patients with ISR, smaller vessels, or those at high risk for bleeding. Longer-term studies in larger numbers of patients with long-term follow-up should be performed.

1. Katsanos K, Spiliopoulos S, Kitrou P, et al. Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc. 2018;7:e011245.

2. US Food and Drug Administration. Treatment of peripheral arterial disease with paclitaxel-coated balloons and paclitaxel-eluting stents potentially associated with increased mortality—letter to health care providers. https://www.fda.gov/medical-devices/letters-health-care-providers/treatment-peripheral-arterial-disease-paclitaxel-coated-balloons-and-paclitaxel-eluting-stents. Published January 17, 2019. Accessed September 3, 2019.

3. US Food and Drug Administration. August 7, 2019 update: treatment of peripheral arterial disease with paclitaxel-coated balloons and paclitaxel-eluting stents potentially associated with increased mortality. https://www.fda.gov/medical-devices/letters-health-care-providers/august-7-2019-update-treatment-peripheral-arterial-disease-paclitaxel-coated-balloons-and-paclitaxel. Published August 7, 2019. Accessed September 3, 2019.

4. Rissanen TT, Uskela S, Eränen J, et al. Drug-coated balloon for treatment of de-novo coronary artery lesions in patients with high bleeding risk (DEBUT): a single-blind, randomised, non-inferiority trial. Lancet. 2019;394:230-239.

5. Unverdorben M, Vallbracht C, Cremers B, et al. Paclitaxel-coated balloon catheter versus paclitaxel-coated stent for the treatment of coronary in-stent restenosis: the three-year results of the PEPCAD II ISR study. EuroIntervention. 2015;11:926-934.

6. Vaquerizo B, Serra A, Miranda-Guardiola F, et al. One-year outcomes with angiographic follow-up of paclitaxel-eluting balloon for the treatment of in-stent restenosis: insights from Spanish multicenter registry. J Interv Cardiol. 2011;24:518-528.

7. de la Fuente LM, Miano J, Mrad J, et al. Initial results of the Quanam drug eluting stent (QuaDS-QP-2) Registry (BARDDS) in human subjects. Catheter Cardiovasc Interv. 2001;53:480-488.

8. Grube E, Schofer J, Hauptmann KE, et al. A novel paclitaxel-eluting stent with an ultrathin abluminal biodegradable polymer 9-month outcomes with the JACTAX HD stent. JACC Cardiovasc Interv. 2010;3:431-438.

9. Lansky AJ, Costa RA, Mintz GS, et al. Non-polymer-based paclitaxel-coated coronary stents for the treatment of patients with de novo coronary lesions: angiographic follow-up of the DELIVER clinical trial. Circulation. 2004;109:1948-1954.

10. Grube E, Silber S, Hauptmann KE, et al. TAXUS I: six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation. 2003;107:38-42.

11. Silber S, Colombo A, Banning AP, et al. Final 5-year results of the TAXUS II trial: a randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for de novo coronary artery lesions. Circulation. 2009;120:1498-1504.

12. Tanabe K, Serruys PW, Grube E, et al. TAXUS III trial: in-stent restenosis treated with stent-based delivery of paclitaxel incorporated in a slow-release polymer formulation. Circulation. 2003;107:559-564.

13. Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease.
N Engl J Med. 2004;350:221-231.

14. Stone GW, Ellis SG, Cannon L, et al. Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease: a randomized controlled trial. JAMA. 2005;294:1215-1223.

15. Colombo A, Drzewiecki J, Banning A, et al. Randomized study to assess the effectiveness of slow-and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions. Circulation. 2003;108:788-794.

16. Scheller B, Hehrlein C, Bocksch W, et al. Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. N Engl J Med. 2006;355:2113-2124.

17. Unverdorben M, Vallbracht C, Cremers B, et al. Paclitaxel-coated balloon catheter versus paclitaxel-coated stent for the treatment of coronary in-stent restenosis. Circulation. 2009;119:2986-2994.

18. Byrne RA, Neumann FJ, Mehilli J, et al. Paclitaxel-eluting balloons, paclitaxel-eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drug-eluting stent (ISAR-DESIRE 3): a randomised, open-label trial. Lancet. 2013;381:461-467.

19. Unverdorben M, Kleber FX, Heuer H, et al. Treatment of small coronary arteries with a paclitaxel-coated balloon catheter.
Clin Res Cardiol. 2010;99:165-174.

20. Cortese B, Micheli A, Picchi A, et al. Paclitaxel-coated balloon versus drug-eluting stent during PCI of small coronary vessels,
a prospective randomised clinical trial. The PICCOLETO study. Heart. 2010;96:1291-1296.

21. Giannakakou P, Robey R, Fojo T, Blagosklonny MV. Low concentrations of paclitaxel induce cell type-dependent p53, p21 and G1/G2 arrest instead of mitotic arrest: molecular determinants of paclitaxel-induced cytotoxicity. Oncogene. 2001;20:3806-3813.

22. Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncol. 2004;5:283-291.

23. Cardonick E, Moritz M, Armenti V. Pregnancy in patients with organ transplantation: a review. Obstet Gynecol Surv. 2004;59:214-222.

24. Axel DI, Kunert W, Göggelmann C, et al. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation. 1997;96:636-645.

25. Herdeg C, Oberhoff M, Baumbach A, et al. Local paclitaxel delivery for the prevention of restenosis: biological effects and efficacy in vivo. J Am Coll Cardiol. 2000;35:1969-1976.

26. Abizaid A, Costa JR Jr. New drug-eluting stents: an overview on biodegradable and polymer-free next-generation stent systems. Circ Cardiovasc Interv. 2010;3:384-393.

27. Ormiston JA, Charles O, Mann T, et al. Final 5-year results of the TAXUS ATLAS, TAXUS ATLAS Small Vessel, and TAXUS ATLAS Long Lesion clinical trials of the TAXUS Liberté paclitaxel-eluting stent in de-novo coronary artery lesions. Coron Artery Dis. 2013;24:61-68.

28. Ellis SG, Stone GW, Cox DA, et al. Long-term safety and efficacy with paclitaxel-eluting stents: 5-year final results of the TAXUS IV clinical trial (TAXUS IV-SR: Treatment of De Novo Coronary Disease Using a Single Paclitaxel-Eluting Stent). JACC Cardiovasc Interv. 2009;2:1248-1259.

29. Stone GW, Ellis SG, Colombo A, et al. Long-term safety and efficacy of paclitaxel-eluting stents final 5-year analysis from the TAXUS clinical trial program. JACC Cardiovasc Interv. 2011;4:530-542.

30. Pinto Slottow TL, Waksman R. Overview of the 2006 Food and Drug Administration Circulatory System Devices Panel meeting on drug-eluting stent thrombosis. Catheter Cardiovasc Interv. 2007;69:1064-1074.

31. Kedhi E, Stone GW. Everolimus-eluting stents: insights from the SPIRIT IV and COMPARE trials. Expert Rev Cardiovasc Ther. 2010;8:1207-1210.

32. Leon MB, Mauri L, Popma JJ, et al. A randomized comparison of the Endeavor zotarolimus-eluting stent versus the Taxus paclitaxel-eluting stent in de novo native coronary lesions 12-month outcomes from the ENDEAVOR IV trial. J Am Coll Cardiol. 2010;55:543-554.

33. Stone GW, Rizvi A, Newman W, et al. Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease. N Engl J Med. 2010;362:1663-1674.

34. Ong AT, McFadden EP, Regar E, et al. Late angiographic stent thrombosis (LAST) events with drug-eluting stents. J Am Coll Cardiol. 2005;45:2088-2092.

35. Nordmann AJ, Briel M, Bucher HC. Mortality in randomized controlled trials comparing drug-eluting vs. bare metal stents in coronary artery disease: a meta-analysis. Eur Heart J. 2006;27:2784-2814.

36. Stone GW, Ellis SG, Colombo A, et al. Offsetting impact of thrombosis and restenosis on the occurrence of death and myocardial infarction after paclitaxel-eluting and bare metal stent implantation. Circulation. 2007;115:2842-2847.

37. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet. 2012;379:1393-1402.

38. Dangas GD, Serruys PW, Kereiakes DJ, et al. Meta-analysis of everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease: final 3-year results of the SPIRIT clinical trials program (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions). JACC Cardiovasc Interv. 2013;6:914-922.

Mark K. Tuttle, MD
Clinical and Research Fellow, Harvard Medical School
Department of Internal Medicine (Cardiovascular Division)
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Disclosures: None.

Jeffrey J. Popma, MD
Director, Interventional Cardiology Clinical Services
Beth Israel Deaconess Medical Center
Professor of Medicine
Harvard Medical School
Boston, Massachusetts
jpopma@bidmc.harvard.edu
Disclosures: Receives institutional grants from Medtronic, Abbott Vascular, Boston Scientific Corporation, Cook Medical, Terumo, and Phillips; receives consulting fees from Boston Scientific Corporation for participating on a medical advisory board.