Interventional Cardiology in 2011 - A Look Back

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Five years ago we were given a mission to predict what the future would hold for interventional cardiology. We waxed of days past when angioplasty and bypass surgery were the only options and medical therapy was pedestrian for acute myocardial infarction (AMI), chronic angina and heart failure.

By 2006 stents had evolved into portable pharmacies, delivering a variety of drugs to the target site. This offered not just mechanical support for the vessel, but also a cerebral cocktail of molecular weapons to prevent restenosis. At the time there were only two drug-eluting stents (DES) on the market: the first being the sirolimus-eluting (Cypher®) stent (Cordis Corporation, Bridgewater, NJ) and later the paclitaxel-eluting (Taxus®) stent (Boston Scientific, Natick, MA). The Cypher stent by then had an excellent track record with three years of follow-up and excellent safety and efficacy data; the Taxus stent, which had entered the market more recently, was not far behind.1–3 We predicted that the slotted tube design would remain the fundamental building block for all stents and this has proved to be true. Since then two new stents have been approved by the Federal Drug Administration (FDA) in the US: the everolimus-eluting (Xience®, Promus®) stent (Abbott Vascular, Abbott Park, IL and Boston Scientific, Natick, MA) and the zotarolimus-eluting (Endeavor®) stent (Medtronic, Minneapolis, MN). Both have enjoyed success and share the bulk of the market. Data from all the stents look strikingly similar to Cypher with no obvious advantages emerging.4 Despite some negative reports in Europe in 2006 about DES being unsafe and a panic rush back to bare metal stents (BMS), further careful analysis proved that the initial reports were flawed owing to blurry registry data and a lack of rigorous randomization.5 DES have made a vigorous comeback and remain center-stage as a first line of defense for intervention with over 70 % of patients receiving them.6

In a surprising move, Cordis Corporation has temporarily abandoned the coronary stent market as it regroups around its next product into the marketplace, the Nevo®, which will probably be launched in Europe first. This stent still incorporates the slotted tube platform but has added multiple holes that act as drug reservoirs so that higher concentrations of drugs can be loaded as well as multiple drugs in a bidirectional pattern. Initial data look promising.7

We predicted the evolution of the bioabsorbable stent. Indeed, Abbott Laboratories has made considerable progress. Initial clinical data from Serruys et al. have been presented and look interesting.8,9 Nonetheless, approval and widespread acceptance still appear to be some way off in the future as more data are needed. Stent thrombosis and restenosis remain challenges to this platform.

We were optimistic that multiple new drugs would be available as stent coatings but, alas, the regulatory pathway has become stifling, discouraging new innovation. More progress has been made with barriers than with new drugs and it seems unlikely that any new platform or drug will be approved in the future. We predicted progress with nanotechnology, which has made some headway, but it will be years before a nanoparticle-eluting stent enters the market.10
With the regulatory slowdown, we have achieved neither our optimistic 0.5 % thrombosis rate nor the 1–3 % restenosis rate we predicted. We have hit a wall of 1–2 % thrombosis and 7–10 % restenosis, which is unlikely to change much in the next five to ten years. We have learned that off-label use of DES in more complex patients has higher restenosis rates than expected.11 Perhaps new customized systemic drugs or platelet reactivity testing will teach us which patients are more likely to clot or restenose than others and treatment can be tailored accordingly.12,13

We predicted that custom bifurcation stents would be available to use in selected cases. Although they have enjoyed success in Europe they are still not approved in the US.14 Again, regulatory paralysis has prevented early approval and acceptance here.

In 2006, peripheral atherectomy devices (i.e. Silverhawk®, EV3, Plymouth, MN) were being studied and the early data looked promising enough to encourage us to predict that the technology would transfer to the coronaries within five years for selected cases.15 To date, there has been minimal movement toward the coronary circulation because the usual hurdles of delivery, inadequate debulking, perforation and restenosis remain.16

Progress in AMI has been more pharmacologic than device related. Large randomized trials have shown the superiority of DES over BMS for restenosis but long-term follow-up clearly shows late events and attrition of benefit.17 This needs to be studied more closely in the future. The Harmonizing outcomes with revascularization and stents in acute myocardial infarction (HORIZONS)-AMI trial showed the surprising benefit of bivalirudin in AMI compared with heparin, suggesting that smarter pharmacology may improve survival post MI.18

Although hyperbaric oxygenation for AMI reduction looked exciting in 2006, multiple technical and procedural setbacks in Europe have changed the timeline for approval in the US by several years.19 Focus has now moved more toward cell therapy for AMI, with promising results in several large trials. Several approaches have evolved as we predicted, including autologous unselected bone marrow, autologous adipose-derived stem cells (Cytori Therapeutics Inc., San Diego, CA), allogenic angioblasts (Angioblast), and cardiospheres from right ventricular biopsies.20,21 Early results look promising that some sort of cell therapy will be appropriate following AMI. However, countless questions remain regarding which cell type, what dose, what method of delivery and timing of treatment.
For chronic angina and angiogenesis we were hopeful that gene therapy would be approved and mainstream by 2011. Unfortunately, despite encouraging Phase I and II data using vascular endothelial growth factor (VEGF), the much anticipated Phase III randomized GENASIS trial (Corautus Genetics Inc., Atlanta, GA) failed to meet the primary endpoint: treadmill time (unpublished data). This was most likely due to several tactical errors in the study design and execution, plus a flawed injection catheter rather than the product itself. Nonetheless, this failure effectively derailed further investment in gene therapy for angina in favor of cell-based therapies. It is unlikely that this discipline will be resurrected for cardiovascular disorders, disappointing many in the field who still feel that the therapy works.

Stem cells for heart failure looked promising in 2006 based on the early data using skeletal myoblasts; however, these trials disappointed once again with only marginal early results and then financial woes from a severe recession preventing small companies from raising enough money to complete the trials.22 Work in this important area is being carried out worldwide and even though companies have emerged with commercial products and profits there is a paucity of convincing data showing that stem cells improve left ventricle function in either ischemic or non-ischemic cardiomyopathy. Studies continue to be hampered not just by the regulatory environment but also by the complexity of the study design and by a lack of agreement on primary endpoints.

On the brighter side, even though we missed the mark regarding VEGF there has been progress using adult stem cells for angina relief with the completion of the Phase II Autologous cellular therapy CD34-chronic myocardial ischemia (ACT34-CMI) trial (Baxter, unpublished).23 In this important study, it was shown for the first time that autologous adult stem cells can be safely injected into the myocardium of ischemic ventricles in no-option patients with refractory angina, and result in subjective improvement in angina and objective improvement in treadmill time, which were both statistically significant.

A pivotal Phase III trial is planned and is awaiting FDA approval to begin. There is reason to be optimistic that this is one of our predictions that might come true. However, given the size of the trial and the regulatory delays, it will be eight to ten years before it will be available for general use, if positive.

The one prediction that exceeded our expectations is percutaneous valve replacement. Thanks to intense competition and clever engineering, two viable prototypes are being tested and are advancing rapidly. By identifying a large population in need, i.e. inoperable patients with severe aortic stenosis, credible data are appearing daily for both the SAPIEN transcatheter heart valve (Edwards Lifesciences, Irvine, CA) and the CoreValve® (Medtronic, Minneapolis, MN). Each has its own advantages and disadvantages but early data suggest that both can serve this niche patient population well. Hurdles remain regarding the size of the devices, vascular access, a fairly high stroke rate, and the requirement for post-operative pacemakers.24,25 It remains to be seen whether this technique can be applied to a younger, healthier patient population that could easily be treated with conventional open surgical replacement where mortality and morbidity is quite acceptable. Eventually, the hope is that a non-inferiority trial will be performed to prove that percutaneous aortic valve replacement is ‘as good’ as surgery, which would open the door for wider use.

Although computed tomography (CT) imaging continues to improve, we had hoped that by now it would have advanced sufficiently to replace angiography. Resolution is quite good but not quite good enough in our experience to make decisions about severity of disease. It is superb for defining congenital anomalies of the coronary circulation but is only mediocre for measuring stenoses accurately enough to make clinical decisions, particularly in the presence of stents or dense calcium. An additional concern is the high radiation dose needed for adequate studies.26

By contrast, MRI imaging has progressed quickly to become an essential diagnostic tool, not as much for ischemia but for viability. Late gadolinium enhancement has become the standard for determining whether akinetic myocardium is dead or alive as well as deciphering the various types of cardiomyopathies.27

Robotics and remote surgical procedures have met our predictions and expectations. There is a great interest in performing hybrid procedures in patients with unprotected left main disease by using less invasive robotic left internal mammary artery to left anterior descending artery (LIMA-to-LAD) grafting and then staged stents to the left main and circumflex with single stents. This gives the patient the best of all worlds by achieving total revascularization without vein grafts or bifurcation stents and with the best surgical graft, the LIMA, and large single stents. More critical studies will need to be conducted as we learn more about these techniques and will involve a sizable learning curve; reports of unexplained lung injury have been noted.28

Although breakthroughs in innovation in the peripheral circulation have been sparse, there is as we had hoped some exciting news in peripheral intervention. There have been several studies using stem cells that have shown some success in patients with severe peripheral artery disease (PAD). One of these is an interesting small Phase I study by Losordo et al. (unpublished) that showed a significant reduction in amputation rates at six months in patients with limb at risk peripheral disease treated with autologous CD34+ cells compared with patients who received placebo. A Phase II study is planned and is eagerly anticipated.29
The long-awaited Carotid revascularization endarterectomy versus stenting trial (CREST) is now complete comparing percutaneous stenting with surgical endarterectomy in patients with carotid stenosis and showed equivalence between the two procedures but emphasized the importance of patient selection to minimize complications.30

We predicted accurately that percutaneous abdominal aortic aneurysm repair will be commonplace and, with many new designs, success rates are higher and complications lower than in 2006.31

In these brief five years, exciting new technology has emerged that we did not predict. Initial data for radiofrequency ablation neurectomy of the renal arteries for refractory hypertension has shown surprising success.32 Larger studies are planned for this novel approach and there is great optimism that it could be a permanent solution for what is a serious problem in some patients.

Finally, a revolutionary groin access device for percutaneous interventions was recently approved by the FDA (Arstasis, Redwood City, CA). It has been approved for diagnostic 5 and 6 French sizes: the device enters the artery in such a way as to create a self-sealing flap, such that upon removal, simple manual pressure for between three and five minutes is all that is needed to obtain complete hemostasis as the arterial pressure naturally closes the flap. Patients can ambulate at one to two hours resulting in early discharge. The obvious benefit is that the procedure can be performed without leaving any foreign material behind such as collagen, sutures, or biogels. Studies are being conducted to look at larger French sizes in patient populations such as intervention cases where the patient is fully anticoagulated with either heparin or bivalirudin (Angiomax®, The Medicines Company, Parsippany, NJ). This exciting new technology may replace all others in selected patients if future studies confirm its safety and efficacy.

In conclusion, these past five years have produced a mixture of both success and failures. On balance there is great cause for optimism as we continue to innovate and progress. The efforts remain tireless and undaunted in the face of great challenges both financial and regulatory. The dreams of Andreas Grüntzig remain alive, to be able to work in the coronary arteries in the conscious patient using percutaneous techniques. I am sure that if he were alive today he would be proud of the discipline that he spawned.


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