MedWire - ESC (Munich, Germany), August 31, 2008: Positive results from the first trial of a bevacizumab-eluting stent to prevent plaque neovascularization in patients with acute coronary syndromes (ACSs) were presented during an oral abstract session here on the second day of the European Society of Cardiology (ESC) congress. Also presented were data on the clinical use of intravascular ultrasound (IVUS) in placing drug-eluting stents (DESs) during percutaneous coronary intervention (PCI). Highlights of these two trials are reported here.
First-in-man use of bevacizumab-eluting stent: preventing plaque neovascularization
Dr. Konstantinos Toutouzas, First Department of Cardiology, Hippokration Hospital, Athens, Greece
According to data from the first human trial of a bevacizumab-eluting stent, [1] this approach is not only a feasible but also a well-tolerated means of preventing new blood vessel formation in the coronary arteries of patients with ACS. This is potentially important because neovascularization is associated with the destablization of atherosclerotic plaques.
“Bevacizumab-eluting stents seem to be safe for the treatment of non-culprit
de novo lesions in patients suffering from ACS,” said presenting author Dr. Toutouzas. He noted that minimal neointimal hyperplasia occurred and that, after long-term follow-up, there were no deaths or myocardial infarctions (MIs). In addition, there was no need for revascularization procedures.
Bevacizumab is a humanized monoclonal antibody that binds to vascular endothelial growth factor (VEGF), which is known to be involved in the growth of new blood vessels and tumorigenesis. Although data have shown that bevacizumab effectively inhibits VEGF and therefore both neovascularization and tumor growth, its effect on endothelialization and inflammation has not been fully studied in man.
Dr. Toutouzas and colleagues therefore set out to determine if the use of a bevacizumab-eluting stent could be of benefit in patients who had ACS and at least two or more clinically significant coronary artery stenoses on angiography. Previously, the team had shown that neovascularization can be prevented in rabbits with atherosclerotic-like disease. [2,3]
A Bio
divYsio™ drug delivery stent was used in the current study, and this had been soaked in a solution of bevacizumab three times for 5 minutes at a time and then allowed to air dry before being immediately placed in the coronary artery. Dr. Toutouzas noted that the stent consisted of a phosphorylcholine coating, which acts like a sponge to absorb the monoclonal antibody.
In total, 20 patients with a mean age of 64 years were recruited into the nonrandomized study. All had been diagnosed with ACS within the previous month. Two thirds of the population were male, 65% had hypertension, 45% were diabetic, and 55% had hypercholesterolemia. Half of the population had a family history of cardiovascular disease, and 50% were smokers.
Culprit lesions were treated at the discretion of the attending physician, and the bevacizumab-eluting stent was deployed in a non-culprit lesion. For stent placement to be considered, the non-culprit lesion had to be less than 20 mm in length and also had to result in significant (≥ 50%) stenosis, with a reference vessel diameter of ≥ 2.25 mm.
Post-PCI, all patients were given at least 6 months of dual antiplatelet therapy with aspirin and clopidogrel, with aspirin being continued indefinitely. Angiographic follow-up was undertaken at 12 months, with IVUS performed immediately after stent placement and again at 12 months. Clinical follow-up was at 24 months.
Dr. Toutouzas reported that all stents were successfully delivered - with a mean stent length of 13.5 mm and no malpostition - and that all patients were discharged without complication. At 2-year follow-up, no major adverse cardiovascular events (MACE) had occurred. These included death, MI and target lesion revascularization (TLR). In addition, no thrombotic events (acute, sub-acute or late) were seen, and systemic reactions to the stent were not observed. At 12 months, no restenosis (50% vessel narrowing) could be seen on either angiography or IVUS. Importantly, minimal neointimal hyperplasia was seen, with IVUS showing an average of only 0.7 mm in stented segments.
“We are now planning to use another stent,” Dr. Toutouzas concluded. This is a biodegradable polymer stent that already has bevacizumab on its surface, and the aim will be to assess the efficacy of this bevacizumab-eluting stent in patients with ACS.
Is routine IVUS helpful when placing drug-eluting stents?
Dr. Ron Waksman, Washington Hospital Center, Cardiovascular Research Unit, Washington D.C., USA
When placing a DES, using IVUS to guide its deployment is clinically useful and should be considered routinely, said Dr. Waksman. He presented the findings of a retrospective analysis of more than 4000 patients treated at the Washington Hospital Center between April 2003 and May 2006. [4]
“DESs are efficacious in reducing restenosis compared to bare metal stents (BMS),” Dr. Waksman commented. “Despite this, these stents are not free of restenosis and are limited by late stent thrombosis.” He added that IVUS studies have suggested that the primary reason for restenosis and thrombosis with DESs could be due to the stent not being placed properly. It is therefore possible that using IVUS would be of clinical benefit, because stents would be more likely to be deployed correctly.
To investigate, Dr. Waksman and colleagues looked at the development of definite stent thrombosis 12 months after DES placement using IVUS or angiography. They also examined the frequency of MACE. Of 4382 patients treated at their institution over the 3-year study period, 2801 had undergone IVUS-guided stent placement, and 1281 had undergoing angiographic-guided DES deployment.
“In order to make a fair comparison, we did a patient propensity-score matched analysis,” explained Dr. Waksman. This involved matching clinical and angiographic variables among the two groups of patients, including age, gender, cardiovascular risk factors, clinical presentation, left ventricular ejection fraction, and other angiographic features. This left 884 patients in each arm for analysis.
Summarizing the main findings, Dr. Waksman noted that definite stent thrombosis at 30 days occurred in four (0.5%) patients who underwent IVUS-guided DES placement and in 12 (1.4%) of those who underwent angiographic-guided DES placement (
p=0.045). Definite stent thrombosis was defined as angiographic or autopsy-proven partial or complete stent occlusion. Definite stent thrombosis at 1 year was 0.7% and 2.0% (
p=0.014), respectively, with probable stent thrombosis in 4.0% and 5.8% (
p=0.08), respectively. TLR was necessary in fewer patients who underwent IVUS-guided placement - at 5.1% and 7.2%, respectively - although this was not statistically significant (
p=0.06).
“No IVUS was a predictor of cumulative stent thrombosis at 12 months,” Dr. Waksman said, and this was “independent of DES type.” The hazard ratio for freedom from stent thrombosis with IVUS-guided placement at 12 months was 3.3 (95% CI: 1.25-10.00;
p=0.01). He also reported that patients undergoing IVUS-guided placement received longer stents and were more likely to undergo direct stenting, and there was more post-dilation in this group.
MACE occurred in 14.5% of IVUS patients and 16.2% of non-IVUS patients, although this was not a statistically significant difference (
p=0.32). Rates of death and Q-wave MI were similar in both groups.
Concluding, Dr. Waksman said, “IVUS-guided DES implantation has the potential to influence treatment strategy and reduce both DES thrombosis and the need for repeat revascularization.”
He therefore advocated that IVUS “should be considered for routine use during DES implantation,” when patients with ACS are at increased risk of these events.
References
- Toutouzas K, Stefanadi E, Karampelas J, et al. Long term results from the first-in-man application of bevacizumab-eluting stent: a novel approach for the inhibition of plaque neovascularization. Eur Heart J 2008;29:12 [Abstract 314].
- Stefanadis C, Toutouzas K, Stefanadi E, et al. Inhibition of plaque neovascularization and intimal hyperplasia by specific targeting vascular endothelial growth factor with bevacizumab-eluting stent: an experimental study. Atherosclerosis 2007;195:269-276.
- Stefanadis C, Toutouzas K, Stefanadi E, et al. First experimental application of bevacizumab-eluting PC coated stent for inhibition of vasa vasorum of atherosclerotic plaque: angiographic results in a rabbit atheromatic model. Hellenic J Cardiol 2006;47:7-10.
- Roy P, Steinberg DH, Sushinsky SJ, et al. The potential clinical utility of intravascular ultrasound guidance in patients undergoing percutaneous coronary intervention with drug-eluting stents. Eur Heart J 2008;29:1851-1857.
