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Developments In Stent Technology

Stents have revolutionised the procedure of coronary angioplasty. Sonal Shukla reviews the developments in stent technology over the years.

Dr Anand Rao of Holy Family Hospital, Mumbai explains the efficacy of stents

The use of angioplasty to open clogged arteries has taken off since the mid-1990s, increasing from about 4,30,000 procedures in 1995 to nearly 1.3 million in 2004.

The recent 'Clinical Outcomes Utilising Revascularisation and Aggressive Drug Evaluation' (Courage) Study presented at the American College of Cardiology's annual meeting in New Orleans, USA found that angioplasty works no better than medication in preventing heart attacks or death.

The new study, published in The New England Journal of Medicine, suggests that patients with partially obstructed arteries can put off angioplasty or skip surgery altogether. Half of the 2,300 patients studied, underwent angioplasty and took heart drugs, and were told to make lifestyle changes, such as exercising, losing weight, and giving up smoking. The other half received only lifestyle counselling and medication, including drugs to lower cholesterol, relax blood vessels, slow the heart rate, and prevent blood clots. Both groups fared equally well after an average of four and a half years, according to the study.

The study was conducted on patients with chronic stable angina. However, in Indian practice, interventional cardiologists claim that patients with this subset constitute only 10 per cent of the total number of interventions performed. Around 60 to 70 per cent patients have unstable angina and the rest present with acute myocardial infarction (MI). For the large group of patients who require angioplasty, it is important to understand the evolution of stents.

According to analysts, the Indian market uses 80,000 stents annually and is likely to grow at 15 per cent over the next two-three years. Lifestyle-related diseases like diabetes and stress would be the key growth drivers. With only 20 per cent of patients coming for regular health check-ups, a huge market remains still untapped.

Preventing Complications

"The biggest problem with balloon angioplasty and coronary stenting is restenosis" - Dr Uday Khanolkar Interventional Cardiologist, Apollo Victor Hospital, Goa

Initially, stents were needed to prevent acute complications after Plain Old Balloon Angioplasty (POBA) e.g. acute occlusion of the coronary artery, and to maintain the lumen of the dilated segment of the coronary artery. However, follow-ups showed that patients who had received a stent faced reduced chances of restenosis compared with those who did not.

"The biggest problem with balloon angioplasty and coronary stenting is restenosis. After the coronary intervention, the patient might need to come back for re-intervention within six months. With the usage of stents, restenosis rate was reduced to approximately 12-25 per cent as compared to 50-65 per cent without it," states Dr Uday Khanolkar, Interventional Cardiologist, Apollo Victor Hospital, Goa. Hence, intensive research in stents took over.

Regular use of stents has also simplified angioplasty as it reduced immediate complications. Simultaneously, anti-clotting (antiplatelet) drugs were developed which reduced the early thrombosis of the stent.

"Once the stents started showing long-term results, more refinement began in stent technology with sleeker and malleable stents (which could pass through even difficult anatomies and torturous vessels)," explains Dr AV Ganesh Kumar, Chief Interventional Cardiologist, Dr LH Hiranandani Hospital, Mumbai. Moreover, people started using stents in almost all balloon angioplasties as the results were better.

With the revolution in stent technology, stents today have moved from Bare Metal Stents (BMS) to Drug Eluting Stents (DES). Today, the world of medicine is all gung ho about imminent biodegradable stents.

Bare Metal Stents

"The new BMS available with cobalt chromium with thinner struts have further reduced the risk of restenosis" - Dr Haresh Mehta Interventional Cardiologist PD Hinduja Hospital, Mumbai

While stenting technology has gone from strength to strength, mention has to be made of BMS. They, with their tubular, lattice structure can be assembled from a range of materials, including nitinol, gold, stainless steel and cobalt chromium. "The new BMS available with cobalt chromium with thinner struts have further reduced the risk of restenosis," explains Dr Haresh Mehta, Interventional Cardiologist, PD Hinduja Hospital, Mumbai. Palmaz-Schatz stent, the first stent approved by the USFDA was introduced by Johnson and Johnson (J&J) in 1994. In the past decade, over 25 companies have used various materials and designs in the construction of BMS.

Today, the cost of a stainless steel BMS is between Rs 25,000 and Rs 30,000 and the cost of cobalt chromium BMS is between Rs 35, 000 and Rs 40,000. "Today, in India and Europe, around 30 to 40 per cent of stent market is for BMS," 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.

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 from J&J in early 2000, named Cypher. DES hit the Asian and European markets in 2002 and the US market in 2003. The first drug used was sirolimus. Subsequently, everolimus, tacrolimus, zotanolimus and paclitaxel have been used on stents in clinical practice. These drugs are loaded on a polymer, which is a ‘carrier’ of the drug in 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. Simply put, this drug inhibits aggressive growth of the smooth muscle proliferation to prevent restenosis.

Patient data for thousands of patients, studied in controlled randomised clinical trials, confirms the superior patient outcome after implantation of DES vs 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 correlate 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.

Nanyang Technical University’s future biodegradable stent

A bare metal stent

First Generation: 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 publications reveal an increased risk of late thrombus formation, even two years after DES implantation. Those late adverse effects may be caused not only by the synthetic polymer but also by the drug. Clinical Pathologist, Dr Renu Virmani and her co-workers from the USA consistently publish report on polymer-induced late adverse effects, like blood clot formation and MI. Clearly, any synthetic polymer is not tissue-friendly and sends inflammatory signals to the arterial wall, often resulting in serious consequences for the patient.

A Swiss study found 3.3 more heart attacks and deaths per 100 patients with DES than with the BMS. Results showed more MI and death in DES group due to the non-re-endothelialisation even after 33 months. Endothelium is a thin protective layer which is supposed to grow within the stent in one month after 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 clot.

Clotting Concerns: Between 2000 and 2005, cardiologists thought that they conquered restenosis as the figures of restenosis in non-diabetic patients were less than three per cent, 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. US FDA came up with a warning to be more vigilant and expressed a concern over DES usage. It is proven that compared to BMS, efficiency wise DES gives 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 interventional cardiologists, first generation DES have withstood the test of time and are far more efficacious than BMS and the newly evolved second generation polymerless or biodegradable polymer-coated DES. The answer lies in right selection of cases for the use of DES (diabetics, long length lesions and small calibre vessels). One can still use BMS (with almost comparable results) in 40-60 per cent 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 of overuse 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 Ganesh Kumar. According to Dr Anand Rao, Interventional Cardiologist, Holy Family Heart Institute, Mumbai, the occurrence of late stent thrombosis in Indian patients may not be as high as in the US. "The reason could be that our patients are on antiplatelet drugs for a longer period. The antiplatelet drug also comes at a very cheap price. However, we also do not have 100 per cent follow-up of the patients coming to us, especially who live in far away villages,” says Dr Rao.

Second Generation: Driven by the suspicion that polymer could be the culprit for late stent thrombosis, continuous research was conducted to maximise the safety aspect of DES, leading to second generation DES with biodegradable polymer or polymerless stents. Some companies like J&J and EuroCor now have come out with polymer-free DES as well. The polymer's function in polymer-based DES is now taken over by the newer designs of craters and wells in the second generation stents, which hold and slowly release the drug in the blood vessel. When the stent with 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. "Long-term studies about the effect of polymer in DES are still awaited. Moreover, some cases have shown hypersensitivity reaction even to biodegradable polymers," informs Dr Ganesh Kumar.

The EuroSTAR study with Conor's CoStar stent and Jupiter study with Janus stent have shown that there is no late stent thrombosis in second generation as compared to first generation DES.

The problem of late stent thrombosis of first generation DES has been addressed by the now second generation polymer less DES, as shown by 18 to 24 months of follow-up studies of second generation DES. However, there is a catch here. In a complex subset of cases like diabetes with smaller vessels and long length of the disease, efficacy of the second generation DES cannot be compared with that of first generation ones. “For this subset, one needs more data with the second generation stents and at this point of evidence, I would still advocate the first generation stents for these complex cases,” explains Dr Ganesh Kumar. On the other hand, for instance, in a 75-year-old patient who cannot take clopidogrel for a longer period due to pending non cardiac surgery or GI intolerance to dual antiplatelets, BMS or second generation polymer less DES should be preferred over the first generation DES. This is because clopidogrel can be stopped in both the stents after two to three months, which is not the case with first generation polymer based DES.

A flip side of the DES is that there may be a late thrombosis of the stent more than 30 days to six months after stenting. However, this incidence is less than one per cent ( 0.16 per cent) per year. "Such a miniscule incidence of complication is at present being unduly highlighted. Interventional cardiologists all over the world would like to reduce even this miniscule complication to near zero percent. If DES is strictly used for appropriate indication without including the ‘off label’ indication and if Clopidogrel is used for more than one year, even this miniscule complication may be avoided," informs Dr Khanolkar.

"Fifty per cent of all coronary artery disease patients in this country are suffering from diabetes and our genetic background shows we have long blockages in small arteries. This makes DES an indispensable choice," said Dr Brian Pinto, Director, Cathlab and Head of Cardiology, Holy Family Hospital, Mumbai at the Interventional Cardiology Summit-2007, in Goa. Experts at this conference also pointed out that the benefits of having to avoid repeat stenting or bypass surgery far outweigh the 0.2 per cent increased risk of in-stent thrombosis in DES treatment.

A magnisium alloy stent

A biodegradable stent

Bioactive Stents

"Long-term studies about the effect of polymer in DES are still awaited" - Dr AV Ganesh Kumar Chief Interventional Cardiologist Dr LH Hiranandani Hospital Mumbai

Bioactive stents are not DES, but are metal stents coated with bioactive materials like titanium nitrous oxide which are presently in commercial use. Doctors have been using these stents parallel to DES. Data has shown that these bioactive stents have less restenosis than BMS (but slightly more than DES) and also are much safer on stent thrombosis issue. Nitrous oxide may help as a vessel regulator by keeping the vessels open with less reaction. "Companies manufacturing this stent claim it to be a bioactive stent. Although the results have shown that they perform better than BMS, efficiency wise they are not as good as DES. Therefore, they should not be labelled as DES," says Dr Ganesh Kumar.

Future Prospects

Future technology in stents will include biodegradable stents and better drugs. The dawn of biodegradable stents has taken stent technology a step further with its capacity to get dissolved after a certain period in the body (in 30 days to six months). Biodegradable stents are at primary stages of research, with some ‘first in man’ implants done in lower limbs (below knee). The stent is still not out in the market and has evoked mixed reactions about its effectiveness from cardiologists. These stents have mainly two types of platforms: absorbable metal alloy (like magnesium alloy) and bioabsorable polymers. Initial studies in both have shown hopes. In biodegradable stents, the stent will be degraded with biological tissues after a certain period of time and thus, no residual stent material will be left in the wall of the coronary arteries. This will be possible when some inert polymer materials are used in the manufacturing of the stent. "Active drug coated biodegradable stents have a great future and I believe it will be possible to have them for routine use. However, it is difficult to comment if they will be able to prevent restenosis in bifurcation lesions," says Dr Prof Asok Kumar Kar, Department of Cardiology, BM Birla Heart Research Centre and Peerless Hospital, Kolkata.

However, bifurcation stenosis is one area where biodegradable stents can be used more favourably, feels Dr Rao. "At this moment, clinical trials for biodegradable stents are scarce and thus it is difficult to come to a conclusion until more large multi-centre trials are conducted in a large number of patients," he adds.

"Biodegradable stents are a very good concept, as after a certain period of time, the stent material is completely removed from the vascular system. This is likely to reduce late complications of metallic stents which remain in the vasculature for ever," opines Dr Subash Chandra, Consultant Cardiologist, Wockhardt Hospital, Bangalore. According to him, the most likely candidate for this technology is a metal ie magnesium-based metallic stent where the magnesium alloy gets absorbed in 90-120 days. Also, there is a polymer-based bioabsorbable stent which is more difficult to implant. These stents are likely to be better in all clinical situations including bifurcations.

The Future is Biodegradable

Dr Mathew Samuel Kalarickal, Director, Interventional Cardiology and Cardiac Catheterisation Laboratories, Apollo Hospitals, Chennai, says, "The future of stent would be bioabsorbable stents with medication. Trials are already ongoing on patients in different parts of the world and the results are encouraging. Once the stent is dissolved completely, none of the deficiencies of the present stents like sub acute thrombosis or in stent restenosis will be there. If this stent is workable, it would virtually replace bypass surgery completely."

However, cardiologists voice concerns about this future stent technology. "The whole stent will not vanish in one go. The thinner parts of it will get absorbed before the thicker ones. And a time may come during the natural process of bioabsorption when the linear cylindrical tube of the stent may have only a few struts hanging here and there," says Dr Ganesh Kumar. There also is a possibility that those hanging struts would hit and damage the vessel.

Innovation for the Ideal

The research in stenting technology has been more or less an outcome of the consistent innovation in their constitution and designing. Currently, stents with resevoir technology (canals/holes in stent strut) are available commercially, which either have no polymer or have biodegradable polymer. Further, research is done on microporous (even smaller holes/canals) technology and nanoporous technology for drug elution. Stents with larger cells have increased the possibility of free flow of blood in the bifurcated vessel adjacent to the main vessel with the stent. "The larger cells of the stent will help not to compromise the flow of the blood to the bifurcated vessel, which will reduce the chances of blockage in this artery," explains Dr Rao. The new generation DES and BMS are now available in the market with this design of larger cells.

Moreover, the newer stents are sleeker, with less thick struts which has increased their trackability inside the artery. These stents also show signs of getting endothelialised early in comparison to stents with thicker struts, further reducing the chance of late thrombosis. "Today, research in stents has been captivated by the comparison between different types of DES, and also between the newer kinds of drug combinations to be coated on stents to find a solution to the problem of late stent thrombosis," explains Dr Praveen Chandra, Senior Consultant and Director, Cardiac Cath Lab and Acute MI Services at Max Devki Devi Heart and Vascular Institute, New Delhi. In the opinion of Dr Subash Chandra, the ideal stent would be completely inert, not activate the clotting system and will disappear after a given period (four-six months).

Says Dr Kar: "There cannot be an ideal stent in the near future. Stenting is not based on sound biological principles. It is a mechanistic therapy for a diffused biological abnormality and it should be tackled by proper pharmacological therapy rather than putting metallic stents. Otherwise, the ideal stents should be biodegradable with 100 per cent restenosis prevention and zero incidence of stent thrombosis, which can be deployed anywhere in the vascular tree in an effective manner by any interventional cardiologist with minimal training."

In the near future, the technology that is being talked about is that only BMS will be put in the artery, whereas the balloon will carry the drug. This will reduce the restenosis rate as well as the complications of DES. "The new drug delivery mechanism of the balloon, which inflates the narrow artery itself carrying a drug, which will be delivered to the endothelium will either delay or reduce restenosis," states Dr Ravi Kasliwal, Director, Cardiology, Escorts Heart Institute and Research Centre, New Delhi. Nanyang Technical University in Singapore has developed a self expandable, biodegradable stent with multiple drug delivery capability. However, these stents are still in primary stages of development and long-term data with large multi-centric randomised trials are needed to establish their safety and efficacy.

The Right Selection

The selection of stents by a cardiologist depends on the clinical data available on their long-term safety and efficacy. "We in India not only select the stent based on the financial criteria but also look for what is best for the patient. For acute heart attack, with a higher risk of thrombosis, we hugely prefer BMS," explains Dr Pankaj Bohra, Consultant Interventional Cardiologist, Soni Hospital, Jaipur. In India, while selecting the stent for the patient, the socio economic angle also cannot be overlooked with BMS available for one third the price of DES.

The presence of Certificate of Excellence (CE) on the stent is another criterion considered by the cardiologists to verify the authenticity and safety of the stent. "For the cardiologist, it makes sense to differentiate the application from DES to BMS or cobalt chromium stents, according to the diameter of the coronary artery to be treated. Artery diameter larger than 3.25 mm may be treated by non-coated coronary stents (BMS) only. DES may be preferred for arteries with a diameter smaller than 3.25 mm," explains Dr Orlowski.

There are diabetic patients who require such favourable stent implant quality. However, according to Dr Orlowski, BMS will not fade out. “There are new cobalt chromium stent systems with super-thin stent struts which reduce the total metal implant volume. The long-term patient outcomes with these new cobalt chromium stents have been favourable,” he adds.

Many cardiologists believe that stents are being overused all over the world, which should be discouraged. Many patients can be treated by proper medical therapy rather than by putting multiple stents. "A patient of acute MI without any post-infarction angina does not need any stenting just to support the much maligned open artery hypothesis," says Dr Kar. According to Dr Rao, more than the insertion of any particular stent, it is the compliance with medication and patient follow-ups that hold the key in the Indian scenario.

sonal.shukla@expressindia.com