Study Highlights Disparity Between Pre-, Postmarket Study Outcomes for DES

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Postmarket surveillance of zotarolimus-eluting stents (ZES) shows similar efficacy compared with premarket studies despite differences in patient populations but finds higher risk of myocardial infarction (MI), according to a paper published online June 9, 2014, ahead of print in the American Journal of Cardiology.

The results, researchers say, bolster the notion that postmarket surveillance studies are “essential for the detection of safety signals” that might otherwise go unnoticed.

Methods

Moshe Vardi, MD, of the Harvard Clinical Research Institute (Boston, MA), and colleagues evaluated differences in clinical profile and long-term outcomes of patients receiving Endeavor ZES (Medtronic; Minneapolis, MN) using patient-level data through 3 years from the:

  • ENDEAVOR program of premarket studies including ENDEAVOR PK, I, II (trial and continued access registry), III, and IV (n = 2,132)
  • PROTECT randomized trial, conducted after US Food and Drug Administration approval (n = 4,375)
Many baseline patient and angiographic characteristics differed between the 2 cohorts. Premarket studies had greater prevalence of women and patients with a history of hypertension, hyperlipidemia, MI, and family history of CAD. The postmarket study had more patients with history of smoking and a higher number of lesions treated per subject. Unstable angina was a more common presentation in the premarket group, while MI was more prevalent in the postmarket group.


At 3 years, unadjusted rates of MACE (all-cause death, MI, clinically driven TLR, and emergent CABG), MACCE (stroke added to MACE), and target vessel failure (cardiac death, MI, and clinically driven TVR) were equivalent between the pre- and postmarket groups.

However, premarket studies had a higher rate of clinically driven TVR and the postmarket trial had increased rates of MI and definite/probable stent thrombosis (table 1).

Table 1. Unadjusted 3-Year Outcomes

 

Premarket
(n = 2,132)

Postmarket
(n = 4,375)

P Value

Clinically Driven TVR

11.2%

8.4%

< .001

MI

2.8%

4.3%

.005

Definite/Probable Stent Thrombosis

0.7%

1.5%

.016


Even after propensity score adjustment and accounting for the effects of protocol-mandated repeat angiography, differences remained in:

  • Clinically driven TVR (adjusted HR 1.45; 95% CI 1.04-2.04; P = .031)
  • MI (adjusted HR 0.53; 95% CI 0.30-0.91; P = .021)

Landmark analyses indicated that the disparity in TVR occurred only within the first 270 days (P = .021) and not thereafter (P = .220). The higher rate of MI in the postmarket trial, meanwhile, was driven not by periprocedural events (P = .390) but by those occurring after 48 hours (P = .008).

Take Some Data ‘With a Grain of Salt’

Interventionalists are hopefully aware that outcomes for new products may not be quite as good after they move from the trial setting into actual use, Dr. Vardi told TCTMD in a telephone interview. “For most [coronary stents], there is no real-life data, so you have to deal with what you have,” he said. “I think the uniqueness of this study is that it’s the first that I know of to actually quantify these differences.”

Clinicians need to consider the effect of the trial setting, Dr. Vardi advised. When interpreting large studies with results that seem too good to be true, he suggested, “you should take them with a grain of salt,… read them carefully, and think about how they apply to your clinic.”

Dr. Vardi commented that the differences can be attributed to “a mix of clinical presentation, patient [characteristics], and real-life use vs strict protocol-guided use under premarket trial definitions, which are very, very robust.” Importantly, postmarket studies must adhere to on-label use and as such, may still present too rosy a picture, he added.

Postmarket May Not Go Far Enough

The paper outlines some downsides to both pre- and postmarket studies.

“Premarket trials typically do not include the full range of patients treated in a ‘real-world’ or even an ‘on-label’ setting, posing a limitation of generalizability of results. Furthermore, even within the selection criteria imposed, investigators tend to enroll healthier subjects into clinical trials and impose other selection biases related to age and gender. Infrequent events are also hard to detect in the settings of premarket studies,” the researchers write.

In postmarket surveillance, they continue, “case selection based on requirements to adhere to the device’s instructions for use may also impair patient representation. In addition, [PROTECT], being a randomized trial, is even less representative of routine clinical practice than a truly unselected [postmarket surveillance] study.

“To better understand differences in outcomes between clinical trials and the ‘real world,’ analyses of data generated from nonvoluntary registries (eg, Cath-PCI) and from electronic health record[s] are warranted,” Dr. Vardi and colleagues conclude. “It is likely that safety signals may have been even stronger in a less selected population.”

 


Source:
Vardi M, Perez J, Griffin PJ, et al. Usefulness of postmarket studies to evaluate long-term safety of coronary eluting stents (from the ENDEAVOR and PROTECT programs). Am J Cardiol. 2014;Epub ahead of print.

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Disclosures
  • The paper contains no statement on potential conflicts of interest for Dr. Vardi.

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