ENDEAVOR IV: A zotarolimus-eluting stent versus a paclitaxel-eluting stent in a randomized clinical trial

What is unique about the Endeavor stent?

All drug-eluting stents are multi-component systems, consisting of a stent, a carrier vehicle and a drug. The Endeavor stent demonstrates unique properties in each of these components. The stent is the recently introduced Medtronic Driver cobalt alloy stent with thin struts and an edgeless design. This stent is extremely flexible and deliverable. From a physician operator standpoint, the Endeavor stent can be delivered more easily to portions of the coronary tree that would be difficult to access with earlier generation DES. The drug carrier system is a biocompatible hydrophilic polymer called phosphorylcholine, which is modeled using biomimicry to look like the surface of a red blood cell. Animal studies have indicated that this polymer is non-inflammatory with a very favorable healing response. The polymer carrier is also extremely thin compared to Cypher and Taxus polymer carriers, only one micron in thickness after drug elution, which may contribute to its biocompatibility. The therapeutic agent is zotarolimus, a sirolimus analog which has equal anti-proliferative potency compared to sirolimus, but is slightly more lipophilic. This means that zotarolimus has a longer tissue residence time once it is eluted from the stent into the vessel wall. Zotarolimus from the Endeavor stent is eluted quickly over the first two weeks, with small amounts of drug retained in the tissue for slightly longer than a month. The rapid elution of the drug may be important in helping to explain rapid healing of the stent surface The Endeavor drug-eluting stent system has been designed with safety in mind. It is our hope — but of course we need more clinical data to be conclusive — that this device will have safety properties similar to a bare metal stent, while retaining clinical anti-restenosis efficacy similar to a first generation drug-eluting stent.phosphorylcholine, is a biocompatible carrier which is modeled using the process of biomimicry to look like the surface of a red blood cell. It is very biologic, in the sense that it is not viewed as a foreign object by the body and as such, we think that there will be a very favorable healing response to the carrier system. The way it is incorporated with the drug, zotarolimus, is also interesting. Zotarolimus is a sirolimus analog, with a tetrazole macrocycle (?) in a substitution position. This gives it essentially equal efficacy or potency compared to sirolimus, but zotarolimus is slightly more lipophilic, which means it has a longer tissue retention time once it is eluted from the stent into the tissue. The drug is eluted quickly over the first two weeks, with some drug retained in the tissue for as long as a month. The rapid elution of the drug is important, because it helps the entire surface to heal very rapidly. While the rapid elution of zotarolimus induces specific biologic effects, it probably does not impair the early healing responses after implantation. The stent system has been designed with safety in mind. It is our belief — but of course we still need more clinical data — that this device will have safety properties similar to a bare metal stent but the clinical efficacy of a first-generation drug-eluting stent. the surface of a red blood cell. Animal studies have indicated that this polymer is non-inflammatory, with a very favorable healing response. The polymer carrier is also extremely thin compared to the polymer carriers of the Cypher and the Taxus stents, only one micron in thickness after drug elution, which may contribute to its biocompatibility. The therapeutic agent is zotarolimus, a sirolimus analog which has equal anti-proliferative potency compared to sirolimus, but is slightly more lipophilic. This means that zotarolimus has a longer tissue residence time once it is eluted from the stent into the vessel wall. Zotarolimus from the Endeavor stent is eluted quickly over the first two weeks, with small amounts of drug retained in the tissue for slightly longer than a month. The rapid elution of the drug may be important in helping to explain rapid healing of the stent surface. The Endeavor drug-eluting stent system has been designed with safety in mind. It is our hope — but of course we need more clinical data to be conclusive — that this device will have safety properties similar to a bare-metal stent, while retaining clinical anti-restenosis efficacy similar to a first-generation drug-eluting stent.

What was the ENDEAVOR IV trial design?
ENDEAVOR IV was a large pivotal randomized clinical trial, conducted at 80 sites in the U.S., involving 1,548 patients with obstructive native coronary lesions. The patients were equally randomized to the Endeavor stent or Taxus paclitaxel-eluting stent. The primary endpoint of ENDEAVOR IV was target vessel failure, a composite endpoint consisting of cardiac death, myocardial infarction, and target vessel revascularization at nine months. The secondary endpoint was in-segment late loss, determined by angiographic follow up at eight months in a small subgroup of patients. ENDEAVOR IV has been completed and the primary endpoint of target vessel failure at nine months was 6.6% for Endeavor versus 7.2% for Taxus. Endeavor clearly fulfilled its non-inferiority primary endpoint. Importantly, target lesion revascularization was also statistically indistinguishable between Endeavor and Taxus, especially if we focus on the 80% of patients who did not have angiographic follow up. The angiographic endpoint, in-segment late loss, was increased with Endeavor compared to Taxus, as was binary restenosis.

Endeavor’s higher in-segment late loss at angiographic follow up sparked a great deal of discussion when you presented the trial data at TCT.
This is complex and interesting issue. Angiographic results, like in-segment late loss, are meant to be surrogate endpoints. Of course, what physicians care about most when we implant a bare-metal or drug-eluting stent is whether that patient is going to have a clinical recurrence at the treatment site that requires repeat revascularization. The best study endpoint to determine the need for repeat revascularization is target lesion revascularization. If you interpose systematic angiographic follow up into a study, it is common for revascularization events to occur at a higher rate. This phenomenon is called the ‘oculostenotic reflex’which means that the presence of a follow-up angiogram influences clinical decision-making about whether the physician performs a repeat revascularization. Since there is a higher late loss and percent diameter stenosis at follow up with Endeavor stents compared with Taxus stents, the oculostenotic reflex is especially important, as physicians react disproportionately to Endeavor stents, which have more frequent intermediate stenoses that are clinically unimportant. In the ENDEAVOR IV trial, the 20% of patients with angiographic follow up had a greater difference in target lesion revascularization between Endeavor and Taxus stents, than in the 80% of patients with only clinical follow up. In the clinical follow-up cohort, the 12-month target lesion revascularization rates were 3.6% for Endeavor stents versus 3.3% with Taxus stents, obviously no difference. Our group and others have shown that there is not a linear relationship between late loss and the probability of target lesion revascularization. This means that at late loss levels below or around 0.6 millimeters, we still see slowly rising target lesion revascularization rates in the mid-single digits, whereas when late loss climbs to 0.8 or 1.0 millimeters, usually observed with bare-metal stents, target lesion revascularization increases at a steeper slope, to several-fold higher values.

If during all angiographic follow up in clinical trials we used a pressure wire (physiologic measurement to determine whether a lesion actually requires treatment), what effect might that have?
That’s a great question. If you used a pressure wire and required that only lesions with documented physiologic obstruction be revascularized, the results would be much closer to the natural clinical state, where revascularization procedures are dictated by clinical symptoms or evidence of inducible ischemia on stress tests. In fact, in one of our earlier trial designs we proposed that an abnormal pressure wire response should be a requirement for repeat revascularization, but we couldn’t get most of the operators to apply the technique consistently.

Why do you think that is?
Well, it’s not a standard technique, it involves using a different guidewire, and the methodology, although fairly simple, is generally not used routinely in the U.S. You are right, however; if we had physiologic assessments of stenosis severity as opposed to only visual estimates of stenoses from the angiogram, I think the clinical trials would more accurately reflect the “real world” clinical scenario, wherein recurrent symptoms or documented ischemia tend to drive revascularization decisions.

We don’t know if the increased late loss seen in angiographic follow up is due to “healthy re-endothelialization”?

People like to use that term; I’m not sure what it means, but certainly there is more homogenous and more equally distributed neo-intima seen on intravascular ultrasound imaging over an Endeavor stent than with other drug-eluting stents. Also, animal studies have demonstrated rates of early re-endothelialization with Endeavor which are more similar to bare-metal stents and further animal studies indicate that this new endothelium has normal functional attributes. We think this probably contributes to the observation in patients that Endeavor stents are similar in safety profile to bare-metal stents. What’s unique about the ENDEAVOR trial series? The ENDEAVOR series of clinical trials is very comprehensive. The suite of studies which were discussed with the FDA included ongoing trials and post-market surveillance trials totaling more than 25,000 patients. There has never been a drug-eluting stent subjected to this degree of clinical trial scrutiny in the immediate pre- and post-approval time-frame. We presented data from a blinded, randomized trial with Endeavor versus a bare-metal stent which showed similar efficacy to SIRIUS and TAXUS IV. We also presented two additional randomized studies which compared Endeavor to both commercially approved drug-eluting stents, Cypher and Taxus, including ENDEAVOR IV. This high density of data allowed us to pool studies with common definitions and perform appropriate statistical analyses to assess long-term safety of the Endeavor stent. We had 1,287 patients with long-term follow up at 2 years and 675 patients at 3 years. These data have indicated a very low frequency of late and very late stent thrombosis with Endeavor, by both protocol and ARC (Academic Research Consortium) definitions, results which are similar to a bare-metal stent and improved compared to current FDA-approved drug-eluting stents. Including the ongoing studies, Endeavor will be the most completely studied drug-eluting stent for both on-label and more ‘real world’ off-label indications. This should give interventional operators and patients a feeling of confidence and reassurance that there will be no efficacy and safety surprises with Endeavor in the future.

Do you think the ease of deliverability will favor an increased use of the Endeavor stent in more complex cases (which may also affect measured real-world outcomes)?

Yes, definitely. In most cases, you can ultimately deliver a Cypher or a Taxus stent, but as the operator, you often have to use stiffer guidewires, or predilate more aggressively, or use a larger guiding catheter for increased support in order to “muscle” the stent down the coronary tree. The experience of having to deliver out-of-date stiff drug-eluting stents will be gone with Endeavor. I think it will make things a lot easier for operators, much more analogous to putting in modern thin-strut and highly flexible bare-metal stents. This improved ease-of-use with Endeavor will likely result in its use in more complex and difficult to reach coronary lesions, such as calcified lesions or in situations of increased vessel tortuosity.

What lies ahead?
We still need more studies to address unanswered questions, especially the issues of long-term safety and the duration of dual anti-platelet therapy. The duration of dual anti-platelet treatment with Endeavor is going to be an interesting question, because we are not certain that patients will need the recommended full one year of therapy. In ENDEAVOR II, III and IV, dual anti-platelet therapy was either 3 or 6 months. Until more data are available, we expect that the Endeavor instructions for use will still conform to the American College of Cardiology/American Heart Association guidelines, where dual anti-platelet therapy is recommended for one year for all drug-eluting stents. Experimental studies with Endeavor indicating healing properties close to bare-metal stents and preliminary clinical data also suggesting comparable safety to bare-metal stents, leaves open the possibility that Endeavor may allow shorter-term dual anti-platelet regimens. Of course, carefully planned clinical trials will be required to prove that Endeavor is truly safe from the standpoint of stent thrombosis, despite only one, two or three months of clopidogrel therapy.
In addition, the Endeavor stent has been expanded to include the Resolute platform. The CE mark approved Resolute drug-eluting stent, compared with Endeavor, is the same stent, same balloon catheter, same drug and drug dose, but has a different drug carrier vehicle. This custom biostable hydrophilic polymer is called BioLinx and dramatically extends the drug elution time. Rather than eluting very quickly over the first few weeks, BioLinx elutes the drug slowly over a three-month period. Early clinical studies outside the U.S. indicate very low late loss with Resolute, comparable to the best sirolimus and everolimus-eluting stents. With the Resolute platform, you will have an extremely effective drug-eluting stent from the standpoint of low late loss, but the question now is, will it be as safe as the parent Endeavor platform from the standpoint of stent thrombosis? These are certainly interesting questions for future clinical trials.

With respect to clinical scenarios in which Endeavor should be used after FDA approval, obviously this is rather subjective and will vary depending on operator preferences and the kinds of patients and lesions treated. Clearly, difficult to reach coronary lesions would be a good group of cases for Endeavor, as it is highly deliverable. Also, due to the improved safety margins, many of the patients currently treated with bare-metal stents due to concerns about long-term clopidogrel use might also be good candidates for Endeavor. I would certainly not be surprised if Endeavor becomes among the most widely used drug-eluting stents in the U.S. over the next year.
Finally, I would like to note that several key individuals have contributed importantly to the Endeavor clinical program, including Dr. Laura Mauri from the Brigham and Women’s Hospital, Dr. Jeffrey Popma, the director of the core angiographic lab, and Dr. Peter Fitzgerald, the director of the core intravascular ultrasound lab.