teaser
Since its introduction into clinical practice, coronary angioplasty has faced an incredible rate of change not comparable to any other medical technology
Fabrizio Clementi
Giuseppe Sangiorgi
EMO Centro Cuore
Columbus
Milan
Italy
The introduction of drug-eluting stents[1] (DES) has revolutionised the way interventional cardiologists treat coronary atherosclerosis. Due to lower rates of restonosis compared with baremetal stents, interventionalists now are able to treat more complex anatomy and extensive coronary disease encompassing, in recently published trials[2] and reports,[3] treatment of left main and three vessel diseases. Among them, the SYNTAX trial, one of the landmark studies in the history of interventional cardiology, is the first randomised, controlled clinical trial to compare PCI using a drug-eluting stent (Taxus; Boston Scientific) with CABG in patients with left main disease and three vessel disease.
Altogether, the trial enrolled 1,800 patients in its randomised arm from 62 EU sites and 23 US sites. Results showed that the 12-month primary endpoint rates for MACCE (Major Adverse Cardiovascular or Cerebrovascular Event rate, including all-cause death, stroke, MI and repeat revascularisation) were 17.8% for PCI and 12.1% for CABG (p=0.0015). However, outcome in the trial’s secondary endpoint (the combined rate of all-cause death, stroke and MI, with revascularisation removed) was 7.6% for PCI and 7.7% for CABG (p=0.98).
The rate of stroke was 0.6% for PCI and 2.2% for CABG (p=0.003). Other findings from the 12-month data showed that the rate of symptomatic graft occlusion was 3.4% in the CABG group, and the rate of stent thrombosis in the PCI group 3.3% (p=0.89). Despite the fact that the primary endpoint of non-inferiority was not met, the Syntax trial has shown that among patients without diabetes or patients with isolated LM disease or LM + 1 vessel disease PCI is comparable to CABG. Moreover, the Syntax committee developed a score, based on coronary lesion complexity, able to stratify patients’ risk of 12-month MACCE. Patients with a Syntax score less than 32 had comparable results with both PCI and CABG.
Since the observation of possible increased risk of stent thrombosis with DES,[4] the cardiology community has focused attention on safety[5] with the recommendation of a more appropriate on-label usage of DES[6] and prolonged double antiplatelet therapy[7] for at least 12 months (especially with first-generation DES such as Cypher and Taxus stents). Different randomised trials and real-world registries have clearly demonstrated that the rate of early and late stent thrombosis does not differ between BMS and DES. DES are related to an increased risk of stent thrombosis of 0.6% per year, and there is a slight increase incidence of very late (over 2 years) stent thrombosis.[8] Issues related to the increased incidence of very late stent thrombosis are late stent malapposition, incomplete strut coverage and stent underexpansion.[9] Recently reported results of the ODESSA trial confirmed this finding by optical coherence tomography imaging technique (OCT).
With three different DES, Cypher, Taxus and Endeavor, compared with BMS, the ODESSA trial observed a rate of non-covered struts and late malapposition after 6 months significantly increased in the DES group. The authors found a difference in the rate of non-covered struts and malapposed segments among different DES and among DES and BMS (8.2%, 4.3%, 0.02% and 0.9% for Cypher, Taxus, Endeavour and BMS respectively). The results correlated well with the observed neointimal growth, with the Cypher stent having the lowest degree of neointimal obstruction and the BMS having the highest. However, the ODESSA trial was not powered to observe differences in stent thrombosis, so any correlation will be possible among this late phenomenon and strut non coverage/malapposition.
More than 12 different DES have received the CE mark in Europe and different drugs have been tested (paclitaxel, sirolimus, everolimus, tacrolimus, zotarolimus, biolimus). Reflections of the widespread development of new devices are evident in daily practice; interventional cardiologists have now the opportunity to choose between many different platforms, each of them characterised by a specific safety and efficacy profile, with the possibility to improve treatment options and results in different patient subsets. Nowadays the choice for the optimal device is balanced between optimal efficacy in terms of restenosis prevention and optimal safety in terms of stent thrombosis risk.
Different pathological and animal studies analysing DES interaction with the vessel wall have confirmed the presence of an inflammatory response to the drug-retaining polymers of DES.[10] This observation has led industry to develop newer stent designs and solutions for drug delivery to reduce the inflammatory response of the vessel wall and increase the biocompatibility of the stent to allow complete tissue coverage of the stent struts from the bloodstream.[11]
[[Fig 4]]
A new stent platform (the biolimus-eluting Biomatrix stent; Biosensor inc) with a bioabsorbable drug-retaining polymer that completely disappears after three months, and an abluminal coating (only toward the vessel wall), is now available on the market. Results of the first phase III clinical trial[12] recently published (LEADERS) have shown non-inferiority of this new device in comparison with the Cypher stent in terms of 9-month MACCE (9% vs 11% respectively; p for non-inferiority = 0.003, p for superiority = 0.39) and in the in-stent percentage diameter stenosis (20.9% vs 23.3%; p for non-inferiority = 0.001, p for superiority = 0.26) among a population of more than 1,500 patients with chronic stable disease and acute coronary syndromes.
A subset analysis has included 46 patients who underwent OCT imaging at 9 months. In total, the investigators have examined 11,068 struts in 64 lesions. At nine months, 39.4% of lesions treated with Cypher had more than 5% non-covered struts, as compared with only 3.6 % of lesions that received the Biomatrix stent (p=0.005). In addition, lesions treated with Cypher were more than 10 times more likely to have more than 5% malapposition (9.7% vs 0.9%, p=0.06).
These data confirm the role of vessel wall hypersensitivity versus stent polymer in delayed healing of stent struts and late malapposition. Indeed, previous observation from the ODESSA trial has led to a correlation between late loss and the ratio of non-covered/malapposed struts in four different stent platforms (Cypher, Taxus, Endeavor and BMS), raising the possibility that more efficacious antiproliferative drugs may indeed reduce neointimal growth but at the same time may increase the rate of non-covered/malapposed struts. Conversely, evidence from the OCT substudy of the LEADERS trial has shown for the first time that a more potent antiproliferative drug (in-segment late loss 0.08 vs 0.15 with Biolimus vs Sirolimus; p=0.15) was associated with a lower rate of non-covered/malapposed struts, suggesting an important role of vessel wall hypersensitivity due to drug-releasing polymer.
The last technological frontier is now represented by absorbable stents. Initial reports on this new platform are awaited with great expectation among the interventional cardiology community. If this technology can demonstrate its efficacy it would be a major revolution in interventional cardiology leading to the possibility of even more extensive coronary treatment strategies including small vessel disease and end-stage coronary atherosclerosis, which currently are orphans in terms of efficacious treatment.
References
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12. Windecker S, et al. Lancet 2008 Sep 27;372(9644):1163-73.
