WASHINGTON – On December 6, 2018, the Journal of the American Heart Association (JAHA) published a meta-analysis by Katsanos et al ⁽¹⁾ that revealed an increase in long-term mortality with paclitaxel-coated balloons and paclitaxel-eluting stents. Briefly, the study evaluated 28 randomized control trials across 12 devices for the treatment of femoropopliteal disease.

Study findings:

• At one year, with 4,432 patients, there was no difference between the paclitaxel-eluting arm and the control arm for all-cause mortality (2.3 vs. 2.3%, RR 1.06, 95% CI 0.72–1.61).
• At two years with 2,316 patients (n=12 studies), there was a sharp increase in all-cause mortality with paclitaxel-eluting devices compared to control (7.2% vs. 3.8%, RR 1.68, 95% CI 1.15–2.47).
• At five years with 863 patients (n=3 studies), there was a persistently higher risk of all-cause mortality for paclitaxel-eluting devices compared to control (14.7% vs. 8.1%, RR 1.93, 95% CI 1.27–2.93).
• Risk was fairly stable in various sensitivity analyses: drug-eluting stents (DES) vs. drug-coated balloons (DCB). Interestingly, trials with a higher dose of paclitaxel had a higher risk ratio (highest with a 3.5 mg dose). This dose response was confirmed on meta-regression with 0.4% increased risk for every paclitaxel mg-year.

Experts from the Society for Cardiovascular Angiography and Interventions (SCAI) Vascular Disease Council have reviewed this meta-analysis and have concluded that the methods are appropriate and within constraints of trial-level meta-analysis. However, it is important to note that SCAI believes the associations are hypothesis-generating and require further investigation with patient-level data.

Study limitations:

• There is no mechanistic explanation for the study findings.
• A post-hoc analysis did not include patient-level data to adjust for clinical and angiographic differences between those who died and those who did not.
• There is evidence of discrepancy in some of the reported numbers.
• The study findings could be by chance — a type-1 error due to multiple testing.
• Less than 50 percent of the trials report data beyond one year and only three percent at five years.
• The equation to assess the paclitaxel dose/time relationship may have overestimated drug exposure and its effect over time.

On January 17, 2019, the U.S. Food and Drug Administration (FDA) issued a letter to alert physicians of these findings. At this time, FDA has asserted that the benefits of paclitaxel-coated devices outweigh the risks when used as indicated. However, FDA urged healthcare providers to report any adverse events or suspected adverse events with paclitaxel-eluting devices through its MedWatch program.

On January 22, 2019, investigators from several device trials presented new patient-level data at the Leipzig Interventional Course (LINC). Data from these trials show comparable mortality rates among patients treated with paclitaxel-coated or -eluting devices compared to angioplasty or bare metal stents.

• A pooled analysis of 1980 patients from the IN.PACT DCB program demonstrated that at five years, there was no statistically significant difference in all-cause mortality between the DCB and the control arm (9.3% vs. 11.2% respectively, p=0.399) ⁽²⁾.
• RANGER SFA randomized trial three-year data from 105 patients showed no significant difference in all-cause mortality between DCB and control (13.8% vs. 10.7%, respectively) ⁽³⁾.
• Five-year data from 479 patients enrolled in the ZILVER PTX randomized trial showed no statistically significant difference in all-cause mortality between ZILVER PTX and the control group (18.7% vs. 17.6% respectively, p=0.53) ⁽⁴⁾.
• A three-year pooled analysis of 2521 patients from RCTs and non-RCTs from the Stellarex DCB program (2351 DCB and 170 controls), showed no statistically significant difference in all-cause mortality between Stellarex and the control groups (7.9% vs. 9.9% respectively, p=0.78) ⁽⁵⁾.
• Five-year data from 1189 patients in the Levant 2 Trial within the LUTONIX DCB program showed no statistically significant difference in all-cause mortality between DCB and the control group (14.1% vs. 10.6% respectively, p=0.22) ⁽⁶⁾.

We expect further details from these meta-analyses to be examined in peer reviewed journals in the near future. Additional patient-level analyses are underway by FDA, independent physicians, and industry, and SCAI is closely monitoring this evolving situation.

“At present, SCAI concurs with FDA that the benefits of paclitaxel devices continue to outweigh any potential risks,” says David A. Cox, M.D., MSCAI, SCAI President.  “However, we strongly encourage our members to discuss the findings of the meta-analysis with their patients and to report any safety concerns to FDA.”

References:

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;7:24.

2. Schneider PA. DCBs over the long-term: Are they safe for our PAD patients? Insights from the IN.PACT DCB program. Presented at: LINC 2019. January 22, 2019. Leipzig, Germany.

3. Gray WA. Patient safety in the Eluvia DES and Ranger DCB program. Presented at: LINC 2019. January 22, 2019. Leipzig, Germany.

4. Dake MD. Long-term safety information on paclitaxel-eluting stents: insights from the Zilver PTX program. Presented at: LINC 2019. January 22, 2019. Leipzig, Germany.

5. Lyden S. Long-term safety data from the Stellarex DCB program. Presented at: LINC 2019. January 22, 2019. Leipzig, Germany.

6. Scheinert D. Long-term safety data of the Lutonix DCB formulation. Presented at: LINC 2019. January 22, 2019. Leipzig, Germany.

Update: On January 25, 2019, the Society for Cardiovascular Angiography and Interventions (SCAI) released a statement related to the potential association between paclitaxel devices used in the peripheral arteries and mortality. At that time, The U.S. Food & Drug Administration (FDA) and SCAI's Vascular Disease Council felt that the benefit associated with paclitaxel devices outweighed any potential risk. However, on March 15, 2019, the FDA released a second notification alerting physicians of a potential signal at five years in the three randomized clinical trials that were evaluated by the FDA.

At the present time, SCAI recommends that members follow FDA's recommendations until further data become available.