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Bare Metal Stents
Albeit the technology of stenting has gone from strength to strength, it can not be viewed without the due mention of Bare Metal Strength (BMS). BMS with their tubular, lattice structure can be assembled from a range of materials, including nitinol, gold, stainless steel, and cobalt chromium. “The new BMS which are available with cobalt chromium with thinner struts have further reduced the risk of restenosis,” explains Dr Haresh Mehta, Interventional Cardiologist, PD Hinduja Hospital. Palmaz-Schatz Baloon, the first stent approved by the US FDA was introduced by Johnson and Johnson in 1994. In the past decade, over 25 companies have used various materials and designs in the construction of these BMS.
Today, the cost of stainless steel BMS is between Rs 25,000 to Rs 30,000 and cost of Cobolt Corium BMS is between Rs 35, 000 to Rs 40,000. “Today, around 30 to 35 per cent market stent market is for BMS, be it in India or Europe,” explains Rakesh Dube, Vice President, EuroCor GmbH, South Asia.
Even as millions of people have undergone angioplasty using BMS, restenosis rate was as high as 30 per cent.
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Drug eluting stents
The idea of coating a clinically effective drug on the stent for local drug delivery at the lesion site, led to the first DES, named Cypher from J&J. DES came in early 2000 and hit the Asian market in 2002 and European market in 2003. The first drug which was used was Sirolimus. Subsequently, Everolimus, Tacrolimus, Zotanolimus and Paclitaxel have been used on stents in clinical practice. All these drugs are loaded on a polymer, which is a “carrier” of the drug as the stent. The drug is gradually released on the walls of the coronary artery and prevents inflammation and retards neointimal formation on the stent, thereby reducing restenosis. In simple words, this drug prevents the aggressive growth of the mussel cells which causes restenosis.
There is patient data available on thousands of patients, studied in controlled randomised clinical trials, to confirm the superior patient outcome, after implantation of DES versus BMS. “The major clinical endpoint is the reduction of the Late Lumen Loss (LLL) after stenting, which indicates the neointimal thickness that develops after stenting. DES provides clinically proven lower loss of the arterial lumen. The LLL seems to co-relate with the rate of restenosis. The restenosis rate of DES is between 8-12 per cent, six months after DES implantation,” states Dr Michael Orlowski, CEO , EuroCor GmbH, Germany.
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First Generation DES:The first generation DES devices apply a synthetic polymer coating on the stent. The drug is embedded into the synthetic polymer and is released by diffusion through the polymer within 30 days. Current scientific publication reveals an increased risk of late thrombus formation, even two years after DES implantation. Those late adverse effects may be caused also by the synthetic polymer and not only by the drug. Clinical pathologist, Dr Renu Virmani from USA, consistently report on polymer-induced late adverse effects, like blood clot formation and myocardial infarction. Clearly, any synthetic polymer is not tissue-friendly and induces inflammatory signals to the arterial wall, often resulting in further consequences for the patient. Swiss study found 3.3 more heart attacks and deaths per 100 patients with DES than with the bare-metal ones. The results which are seen with DES Vs BMS showed more MI and death in DES group due to the non-re-endothelialisation with DES even at 33 months. Endothelialisation is a thin layer which is protective in nature and is supposed to grow within the stent in one month after stent implantation. The drug which is eluted from the first generation DES not only inhibits the smooth muscle cell proliferation of the vessel wall, but it non-selectively inhibits the growth of endothelium, sometimes permanently, unlike in BMS and now the more recent second generation stents. Therefore, when the free flowing blood is exposed to underlying naked stent (devoid of endothelium), it has a tendency to form clot.
From the period 2000 to 2005, cardiologists thought that they have conquered restenosis as the figures of restenosis in non-diabetic patients were less than three percent, whereas in diabetic patients it was less than 10 per cent. However, DES came under the scanner after speakers at the World Congress of Cardiology (WCC), Barcelona last year suggested that DES carries a higher risk of potentially fatal blood clots than BMS. A March 2006 presentation of the results of the Basel Stent Kosten Effektivitäts Trial — Late Thrombotic Events (BASKET-LATE) suggested that between 7 and 18 months after implantation, the rates of nonfatal MI, death from cardiac causes, and angiographically documented stent thrombosis were higher with DES than with BMS. When the fear of late stent thrombosis being higher in DES was discussed in Barcelona, USFDA came up with a warning to be more vigilant and expressed a concern over its usage. “It is proven that if compared with BMS, efficiency wise DES give significantly long-term results and is good to curb restenosis. But the dilemma that the patient will suffer a late stent thrombosis is always at the back of the mind,” says Dr Mehta.
In the opinion of some interventionists, first generation DES have withstood the time and are far more efficacious than the BMS and the newly evolved second generation polymer-less or with biodegradable polymer coated DES. The answer to this is right selection of cases for the use of DES (diabetics, long length lesions and small calibre vessels). One can still use BMS in 40-60 per cent (with almost comparable results) of cases, which do not fall in the above subset. Therefore, the concern is not of increase in MI or death due to late thrombosis, but it of over-use of DES. “Of late, in my clinical practice, on many occasions when I wanted to use BMS for low-risk patients for restenosis, patients have demanded DES due to the hype surrounding it,” states Dr Kumar. According to Dr Anand Rao, Interventional Cardiologist, Holy Family Heart Institute, Mumbai, the ratio of recurrence of late stent thrombosis in Indian patients is not as high as in USA. “The reason could be that our patients are on the antiplatelet drugs for a longer period. The antiplatelet drug also comes at a very cheap price. Secondly, we also do not have hundred per cent follow-up of the patients coming to us, some of whom live in far away villages,” explains Dr Rao.
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Second Generation DES: Driven by the suspicion that the polymer could be the culprit for the late stent thrombosis, continuous research were conducted to maximise the safety aspect of DES. Thus, came DES with bio-degradable polymer, popularly known as second generation DES. Some companies like J&J and Eurocor now have come out with polymer-free DES as well. What the polymer does in the polymer-based DES, is now taken care by the newer designs of craters and wells created in the second generation stents, which holds and slowly releases the drug in the blood vessel. When the stent with the biodegradable polymer is implanted in the artery, the drug does its work in the first two months and then the biodegradable polymer dissolves in the next 120-180 days. So, what remains is only the stent. “The long-term studies about the effect of polymer in DES are still awaited. Moreover, some cases have occurred showing the hypersensitivity reaction of the biodegradable polymer,” explains Dr Kumar. The First In Man’s Study (FIMS) has been undertaken by Aberts on 30 patients to establish the safety of this stent.
Taxcor from Eurocor has a bio-degradable polymer, while J&J has also introduced second generation Conor stent with biodegradable polymer properties. The EuroSTAR study with Conor’s CoStar stent and Jupiter study with Janus stent (see box) have shown that there is no late stent thrombosis in the second generation as compared to first generation DES.
Cypher developed by Cordis, a Johnson & Johnson company, in year 2002 is coated with Rapamycin (Sirolimus), which is an immunosuppressant agent and also acts anti-inflammatory. Such drug is usually used for blockage of organ transplant rejection. The key function against restenosis is the cytostatic effect on smooth muscle cell division. The substance prevents migration and proliferation of SMC´ s into the arterial lumen at the lesion site. The second DES which was developed successfully is Taxus, a Paclitaxel-eluting coronary stent, made by Boston Scientific, USA. Paclitaxel was also evaluated as being antiproliferative, thus preventing SMC proliferation, causing intimal hyperplasia at the lesion site, which was stented.
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Whats new!
EuroCor GmbH, Germany is on a verge of introducing DIOR - a new Paclitaxel-eluting coronary balloon dilatation catheter. This technique promises to reduce restenosis significantly by providing patient treatment opportunities, mainly for two medical indications. – For the successful treatment of coronary in-stent restenosis and for provisional stenting. A patient potential of up to 30 per cent of the total patient number treated by a coronary stent, may be helped by DIOR. It will also eliminate the stent-into stent treatment approach which was typical for the treatment of the in-stent restenosis. The cardiologist usually re-opens the in-stent restenosis by a conventional balloon dilatation catheter and places another stent into the previously stented artery lesion site. Such treatment may stiffen the lesion site by too much metal implantation and lead to further partially heavy patient restenosis problems. DIOR (Dilatation of Restenosis) catheter technology, the in-stent restenosis is dilated and due to the simultaneous Paclitaxel-elution to the retreated coronary lesion, the patient is treated without using a second stent , much more successfully. The clinical efficacy of DIOR seems to promise a significant drop of the incidence of the re-occurance of any restenosis. Most importantly, the patient who is treated by this catheter remains always accessible for further treatments, if the first attempt by DIOR would still make necessary another DIOR treatment. In contrary, a patient who received a second stent into the fist stent, is much less accessible for any further re-intervention. His further treatment options are significantly reduced his risk of life threatening complications increases. Coronary stents are needed for the treatment of coronary artery dissections after balloon angioplasty and they are needed to prevent any recoil of the treated arterial wall. – However, this technology will replace the stent for the stent-into stent treatment of the coronary in-stent restenosis. The big patient number having bifurcated lesions, also may save one stent. Small diameter coronary arteries (< 2.5mm) may be treated exclusively, without any stent. The long-term patient outcome after treatment with DIOR may be compared with drug-eluting coronary stent patient results. A “first in man” clinical study revealed excellent and promising results on using a Paclitaxel-eluting balloon catheter. (New England Journal of Medicine, Nov. 2006). Further clinical trials are needed for more patient data. DIOR is in registration process for availability in India. Availability in India is expected by the month of May, 2007.
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What to Look in Stents?
Parameters that are considered before selecting a stents:
- Should be flexible and less inflammatory in nature
- Balloon platform should be good
- The edges of the stents should be good
- Clinical trials record should be well maintained and accurate
- Cost is the last parameter in terms of importance for a cardiologist
Reasons Giving Rise to Late Stent Thrombosis
- Polymer and Polymer related cause
- Drugs preventing endothelium formation
- Discontinuation of antiplatelet drugs –Asprin and Clopidogrel
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EuroSTAR study
A total of 176 lesions were treated in 145 patients using the CoStar stent formulated to release a therapeutic dose of 10mcg of paclitaxel per 17mm stent over approximately 30 days (based on in vitro measurements). At 24-month follow-up, the target lesion revascularization rate was 3.6 percent, compared to 2.8 percent at 12-month follow-up, and the cumulative major adverse cardiac event rate was 10.4 percent, compared to 8.3 percent at 12-month follow-up. There were no reported cases of stent thrombosis between the cessation of anti-platelet therapy at six months and 24-month follow-up.A low-dose, long-release formulation of paclitaxel from a bioresorbable polymer proved to be efficacious over the long-term. The rate of adverse clinical events from six months to 24 months was very low in this population of patients with chronic ischemic heart disease.
In contrast to conventional surface-coated stents, Conor's stents have been specifically designed for vascular drug delivery. Conor's CoStar stent incorporates hundreds of small holes, each acting as a reservoir into which drug-polymer compositions can be loaded. In addition, the CoStar stent uses bioresorbable polymers that are absorbed by the body after the drug is released, leaving no permanent residual polymers at the target site.
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Jupiter Study
JUPITER II is an international multi-center, double blind, randomised clinical trial designed to evaluate the safety and efficacy of JANUS Tacrolimus-eluting Carbostent in the treatment of coronary lesions in "direct stenting" procedures as compared to TECNIC Carbostent. A total of 332 patients were enrolled in 16 European centers and randomised to either JANUS (166 patients) or TECNIC (166 patients). Enrolment was completed on December 20, 2004 and performed with direct stenting in 86.1 per cent of procedures for Tecnic group and in 75.9 per cent of procedures for JANUS group. The complete six-month clinical data (160 patients in Tecnic group and 157 patients in JANUS group ) clearly highlight strong clinical efficacy and safety. The study reported stent related MACE of 10.6 per cent (17 TLR out of 160 patients) for the control Tecnic group and a more favourable rate of 6.4 per cent (9 TLR and 1 AMI out of 157 patients) for JANUS group. The six-month clinical efficacy of JANUS stent is expressed by a reduction of 46% of TLR in respect to Tecnic stent (TLR of 5.7% with JANUS versus 10.6% with Tecnic).
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