Meta-analysis: Everolimus-Eluting Stents Reduce Thrombosis vs. Other DES

Everolimus-eluting stents (EES) are less likely to result in stent thrombosis than other commonly used drug-eluting stents (DES), according to data from a large meta-analysis published online September 14, 2011, ahead of print in the Journal of the American College of Cardiology. The study also found that rates of myocardial infarction (MI) and target vessel revascularization (TVR) are likewise reduced with EES.

Investigators led by George D. Dangas, MD, PhD, of Mount Sinai Medical Center (New York, NY), reviewed online databases and searched conference proceedings, identifying 13 randomized trials involving 17,101 patients. The trials compared EES with other DES (excluding those with nonpermanent polymers) and reported clinical outcomes including stent thrombosis.

EES Against the Field

More patients received EES (Xience V, Abbott Vascular, Abbott Park, IL, or Promus, Boston Scientific, Natick, MA; n = 9,764) than other DES (n = 7,337) due to unbalanced randomization in some trials. The most common non-everolimus-eluting DES were the first-generation sirolimus-eluting Cypher (SES, Cordis, Miami Lakes, FL; 8 trials) and paclitaxel-eluting Taxus (PES, Boston Scientific, Natick, MA; 4 trials) stents and the second-generation zotarolimus-eluting Endeavor (ZES, Medtronic, Minneapolis, MN; 1 trial) stent.

All trials reported Academic Research Consortium-defined definite or probable stent thrombosis, but only the 11 trials in which that complication occurred were included in the endpoint analysis.

At a weighted mean follow-up of 21.7 months (range 9-48 months), EES reduced definite or probable stent thrombosis, as well as MI and TVR, compared with the other DES. Cardiac mortality, meanwhile, was similar between groups (table 1).

Table 1. Long-term Outcomes

 

 

EES

Other DES

RR (95% CI)

P Value

Definite/Probable Stent Thrombosis

0.7%

1.5%

0.55 (0.38-0.78)

0.001

MI

2.9%

3.9%

0.78 (0.64-0.96)

0.02

TVR

5.7%

7.7%

0.77 (0.64-0.92)

0.004

Cardiac Mortality

1.6%

1.9%

0.92 (0.74-1.16)

0.38

 
There was no evidence of heterogeneity across the studies for any endpoint except TVR. However, when the analysis was repeated after removal of the COMPARE trial, which showed the greatest reduction in TVR and the highest proportion of ACS patients, the heterogeneity disappeared.

In sensitivity analyses, the findings favoring EES were consistent for stent thrombosis, MI, and TVR regardless of clopidogrel duration (a minimum of 6 or 12 months) or duration of follow-up (up to or more than 1 year). The treatment effect, however, did vary by comparator DES for stent thrombosis (P for heterogeneity = 0.03), TVR (P for heterogeneity = 0.007), and MI (P for heterogeneity = 0.006). Risk reductions with EES were largest compared with PES, intermediate vs. ZES, and smallest vs. SES.

Moreover, in a regression analysis, the absolute benefit of EES increased with greater baseline risk of stent thrombosis (P < 0.001); a similar but weaker pattern was observed for MI and TVR.

Analysis showed no evidence that the findings were influenced by publication bias or small-study effects.

Quantifying the Patient Impact

According to the authors, the absolute reduction in stent thrombosis conferred by EES of 0.5%, translates into a number needed to treat of 200 (or 100 in high-risk patients) to prevent 1 episode of stent thrombosis. “Although modest, this level of protection is consistent with other commonly performed cardiac interventions,” they observe.

Contributing to the generalizability of the findings is the fact that most of the studies analyzed included a substantial proportion of patients with high-risk clinical or angiographic features, the investigators observe.

Several design features of the EES may account for its superior performance, the researchers say, including:

  • Elution of everolimus, a potent antiproliferative agent that reduces late loss and revascularization more than paclitaxel
  • A cobalt chromium platform enabling thin strut configuration; evidence suggests that thin struts minimize vascular injury and neointimal hyperplasia and permit more rapid endothelialization
  • A thin fluoropolymer coating that has been associated with reduced thrombogenicity, inflammation, and platelet activation

Powering Up to Assess Stent Thrombosis

Because most stent studies are geared toward efficacy endpoints like restenosis and TVR, it has been very difficult to aggregate enough patients to reliably evaluate rare events like stent thrombosis, Dr. Dangas told TCTMD in a telephone interview. “This is the first study to have sufficient statistical power to show a difference [among DES] in stent thrombosis,” he stressed.

“The meta-analysis is primarily a comparison of a next-generation stent with first-generation stents, but that is informative because it shows that stent technology has gotten safer as well as more effective,” said coauthor Somjot S. Brar, MD, of Kaiser Permanente (Los Angeles, CA), in a telephone interview with TCTMD.

Although the reduction in cardiac mortality with EES was not significant—likely because even with more than 17,000 patients the study was underpowered to detect a difference in that low-frequency endpoint—the MI rate tracks with that of stent thrombosis, “so the results have a certain consistency,” Dr. Brar noted.

The TVR advantage for EES is also important, Dr. Dangas added, but since TVR is a common event and stent trial endpoint, that was already well recognized.

Dr. Brar said it is reassuring that in each of the trials in the meta-analysis, increasing stent thrombosis rates in the control groups equaled progressively greater benefits imparted by EES. “EES seem to be more effective in people where you might be more concerned about stent thrombosis,” he noted.

Future studies will evaluate the comparative safety of EES in high-risk subgroups such as diabetics, Dr. Dangas added.

EES Success Due to Multiple Traits

Both authors agreed that no one element of EES design—drug, polymer, or thin struts—can be singled out as the primary reason for its superior performance. “My feeling is that this is a cocktail and all elements are important,” Dr. Brar said.

Whether the improved safety of EES might permit shortening the duration of dual antiplatelet therapy is an issue that definitely needs investigation, Dr. Brar added, noting that evidence for the current recommendation of 12 months of clopidogrel is weak. “In this paper the point estimates for 6 vs. 12 months of clopidogrel look essentially identical in favor of EES,” he observed. “That suggests that a shorter duration may be just as effective in preventing stent thrombosis. But [proving] that is going to require a dedicated randomized study.”

“For most [clinicians], the EES will be the predominant stent in the cath lab,” Dr. Brar predicted. “Clinically, it’s going to be the standard of care, and academically moving forward it will probably be the reference stent to which we compare newer technology.”

If future comparative stent trials assess the risk of stent thrombosis, they should use EES as the benchmark, Dr. Dangas agreed. But for practical reasons they are unlikely ever to be performed, he added.

 

Sources
  • Baber U, Mehran R, Sharma SK, et al. Impact of the everolimus-eluting stent on stent thrombosis: A meta-analysis of 13 randomized trials. J Am Coll Cardiol. 2011;Epub ahead of print.

Disclosures
  • Dr. Dangas reports receiving institutional support grants from Bristol-Myers Squibb/Sanofi-Aventis and The Medicines Company and consulting fees from Abbott Vascular, Astra-Zeneca, OrthoMcNeil, and Regado Biosciences; and serving as a clinical study investigator for Medtronic.
  • Dr. Brar reports no relevant conflicts of interest.

Comments