Dissolving Coronary Stents: The Fog of Hype
The recent approval by the US Food and Drug Administration (FDA) of the Absorb GT1 bioresorbable vascular scaffold (BVS) system (Abbott Vascular) got me thinking about a modern-day medical problem: the tension between progress and safety.
Precarious is the balance between embracing the new and sticking with the tried and tested—pioneer vs Luddite. Interventional cardiologists are known for their pioneering spirit. By definition, a pioneer takes risks and sometimes suffers consequences.
We allow novel devices leeway because future iterations of a new device often prove beneficial. In general, current-generation drug-eluting stents (DES) perform better than the original versions.
But newer is not always better. The heart-rhythm community, including me, in my gullible days, accepted low-profile implantable cardioverter-defibrillator (ICD) leads, such as Medtronic's Sprint Fidelis. This embrace had disastrous consequences for patients.
Hindsight is sharp, but in the case of low-profile ICD leads, I assign some of the blame for this mistake on our susceptibility to industry marketing. We let our guard down. The bulkier ICD leads we were using at the time (and now) were performing well.
Do We Need a New Stent?
Performing well is how most interventional cardiologists would describe current-generation DES. Sure, the problem of neoatherosclerosis at the site of metal stent deployment continues to dog long-term results of PCI. But less than one in 500 patients suffers from late-stent thrombosis with standard DES. That makes for a tough comparison of any new stent—dissolving or not.
Approval of a disappearing stent has created great excitement—among both patients and doctors. The Wall Street Journal covered the first US implant of BVS. The patient said he "really liked the idea that the stent was going to dissolve and be out of there." He and his doctor were drawn to the potential benefit of this new technology. The keyword in that sentence—and in the entire BVS story—is potential.
Before delving into the actual BVS evidence, let's review the case for placing any coronary stent in patients with stable coronary artery disease. It is a short story. The highest-quality evidence shows that PCI in this setting does not reduce the chance of MI or death, and, by 3 years, there's no advantage in relief of angina.
BVS vs DES Evidence
ABSORB III : Approval of BVS hinged on this large US study. In this multicenter (193 sites) randomized trial, more than 2000 patients with stable or unstable angina received either a BVS (n=1322) or standard DES (n=686). The primary end point was target-lesion failure, defined by cardiac death, target-vessel infarction, or ischemia-driven target lesion revascularization at 1 year.
ABSORB III limited enrollment to patients with relatively stable symptoms and uncomplicated coronary lesions. It also used an arguably lenient noninferiority margin of 4.5 percentage points for the risk difference between the two stents.
Numerically more target lesion failure occurred in the BVS group (7.8%) vs the DES group (6.1%). This delta of 1.7% fell within the 95% confidence interval [CI] for noninferiority (−0.5 to 3.9, P=0.007).
Stent thrombosis occurred in 1.5% of patients in the BVS group vs 0.7% in the DES group. The authors note that the study was underpowered for low-frequency events such as stent thrombosis, but their observation of a higher risk of subacute scaffold thrombosis (>24 hours <30 days) has been seen in other data sets (0.9 vs 0.1, P=0.04).
Lancet Meta-analysis: German and Japanese investigators performed a meta-analysis of six trials of 3738 patients who underwent PCI with either the BVS or DES. They found similar rates of target lesion failure, revascularization, and death. The most concerning observation was a near-doubling of the risk of stent thrombosis and a tripling in subacute stent thrombosis (OR 3.11; 95% CI 1.24–7.82, P=0.02).
Systematic Review and Meta-analysis: Investigators from the Medstar Cardiovascular Research Network performed a systematic review and meta-analysis of patients treated with the BVS for various indications including ACS. This larger study also included registry and retrospective studies for a total of more than 10,500 patients (8351 treated with BVS and 2159 with DES). Similar to the Lancet meta-analysis, treatment with the BVS resulted in a doubling of the rate of stent thrombosis (OR 2.06; 95% CI 1.07–3.98).
In the real world, BVS is even less impressive.
ISAR-ABSORB Registry: Clinicians from Munich, Germany studied 419 consecutive patients who had BVS implanted at two high-volume centers. At 12 months, they found that the rate of death, MI, or target lesion revascularization was 13.1%. Definite stent thrombosis occurred in 2.6%—almost twice that observed in the clinical trials. Their conclusions exude wisdom: "Further study with longer-term follow-up and larger numbers of treated patients is required before we can be sure of the role of these devices in clinical practice."
German/Swiss Registry: At two German and two Swiss hospitals, 1305 consecutive patients received 1870 BVS devices. Investigators observed stent thrombosis in 42 patients, 40 of whom presented with ACS or sudden death. The incidence for stent thrombosis was 1.8% at 30 days and 3% at 12 months.
A novel part of this case-control study was adoption of a BVS-specific implant strategy partway through the series to address the issue of incomplete scaffold expansion. This adjustment led to a decrease in stent thrombosis from 3% to 1%; however, the authors acknowledge the limits of this implant-technique analysis, including the possibility of confounding and imbalances of clinical characteristics in the groups.
Proponents of BVS technology cite potential benefits. A disappearing stent could reduce neovascularization at the stent site and restore normal artery motion. These good things might translate to improved clinical outcomes. Animal models suggest complete resorption occurs at 36 months. The problem is that we don't have clinical data (published in peer-reviewed journals) with much more than 1-year follow-up. This, despite the fact that BVS has been approved in Europe since 2011.
The other argument BVS proponents make is that it is an early-generation device. It will improve. Maybe. Maybe not.
The reasons for concern are many.
First is the published evidence. Every study I read shows numerically more complications with BVS, including a higher incidence of myocardial infarction. Although, technically, the BVS system will be called "noninferior" to DES, the pattern is striking. And, if you add its "noninferiorness" to the lack of compelling evidence for PCI in stable CAD, any increase in complications is significant.
Then there is the matter of stent thrombosis. The combination of intense marketing, therapeutic optimism, and the pioneering spirit of cardiologists tempts one to skim over the words "stent thrombosis." This is medical speak for creating an acute heart injury in a patient with a chronic disease. You can accuse me of hyperbole, but the authors of the German/Swiss registry called stent thrombosis a "particularly malignant" condition.
The second problem with BVS is that it's a more complicated implant procedure. Patient and lesion selection will be key—as will staying true to inclusion criteria from the clinical trials. The fact that registry studies of real-world data show higher complication rates than clinical trials is ominous.
The third problem is cost. This is 2016; like it or not, new devices and drugs will have to "cross the fourth hurdle" of cost-effectiveness. Not only is BVS priced higher than regular DES, but a more complicated implant procedure, combined with the likely need for advanced imaging, such as optical coherence tomography, will further increase cost.
Finally, a comment on device approval in the US: I'm not sure we are doing it right. The FDA advisory committee was highly supportive of BVS. Some of these supposedly impartial judges even made enthusiastic comments. I'm baffled; how could they look at the data and be so positive? Enthusiasm is fine when the data show superiority.
I am not against innovation. I understand that pioneering means making miscues. BVS has immense potential. But it's unproven and thus far does not look especially good.
To me, a middle ground between progress and safety is possible. I'd propose that until novel devices like BVS are shown to deliver better outcomes, approval should come with three requirements: a controlled prospective registry, a full informed consent about the uncertainty, and discount (not premium) pricing.