Percutaneous transluminal coronary
angioplasty (PTCA) has revolutionized the management of coronary artery disease (CAD). This involves the introduction of a fine balloon tipped catheter across the narrowed segment of the coronary artery. Inflation of the balloon compressing the atherosclerotic plaque leads to increase in the cross sectional area of the narrowed artery. However the major limitation of the PTCA was restenosis which used to occur in 30-40% of the patients at around 6 months after PTCA.
Intra Coronary Stents
Introduction of intracoronary stents in 1986 marked the beginning of the new “stent era” in interventional cardiology. Stents are metallic scaffoldings which are mounted on a deflated balloon and postioned across the narrow segment of the coronary artery either after initial dilatation with a plain balloon or directly without predilation. Stents brought down the restenosis rate to approximately 22-32%. However the restenosis following balloon angioplasty was replaced by another new disease “instent restenosis”. This problem was seen more often in diabetics, patients with small vessel and long segments of disease.
The reason for the instent restenosis is exaggerated healing response caused by neointimal proliferation. The initial inflammatory phase is characterized by platelet growth factor and smooth muscle cell activation. The subsequent granulation phase is marked by smooth muscle cell and fibroblast migration. In the final remodeling phase maturation of the neo-intima, synthesis of proteoglycans and collagen occurs.
Drug Eluting Stents
Drug eluting stents (DES) combines the technique of mechanical scaffoldings with that of local pharmacological drug delivery. The antiproliferative drugs can be delivered directly from the surface of the stent into the vessel wall. The most predictable method of delivering the drug is by using a polymer coating which releases the drug slowly over a period of 2 to 3 weeks.
A number of pharmacological agents have been used but the best results have been achieved by sirolimus and paclitaxel. A number of new agents are being evaluated in clinical trials and these are “Everolimus” and “Picerolimus”.
These agents have effects which are anti-inflammatory and reduce the proliferation of cells to minimize the healing process to very low levels.
Clinical Trials to Evaluate Efficacy and Safety
The sirolimus eluting stents Cypher (Johnson and Johnson) has been evaluated in a number of studies. RAVEL (European Study n=238 patients), SIRIUS (US Study n=1055). Both these studies recruited relatively low risk cases and showed a very significant lowering of restenosis rate as compared to the bare metal stent of the same design. This resulted in more than 93% event free survival at no additional risks.
These results were duplicated in other studies like E-SIRIUS, C-SIRIUS. In general the restenosis rates have been reduced by 60-70% in these studies as compared to bare metal stents. Several small studies done in diabetic patients with small vessels and completely occluded vessels show very encouraging results of lowering restenosis rates akin to the lower risk patients.
The polymer based paclitaxel eluting stent TAXUS (Boston Scientific Co.) likewise has been evaluated in a very systematic fashion in TAXUS-I, II, IV, V and VI. These studies done in patients with various levels of complexities have reported very consistent benefits in reducing restenosis and improving event free survival like the Cypher studies. No significant safety issues have been reported in any of these studies as compared to the bare metal stents of the same design.
A large multicenter study comparing Cypher with Taxus (REALITY) has shown no significant difference in their performance upto 1 year of follow up. There are some small studies which have shown superiority of sirolimus eluting Cypher stent over Paclitaxel eluting Taxus stent. The consensus however is that both of these stents are equivalent in clinical results although the neo-intimal hyperplasia reduction is more with Cypher giving it a theoretical benefit in very high risk lesions like small vessels and very long lesions.
Diabetic patients, especially those requiring insulin, however seem to have a trend of doing better with Taxus as per the data of several studies and registries.
Real World Scenario
There was a real concern that the randomized trials discussed in the earlier section may not be applicable to patients seen in every day practice (Real World Cases).
A large body of data collected in several registries (RESEARCH, WISDOM, BASKET, T-SEARCH, E-CYPHER) have confirmed the safety and efficacy of drug eluting stents (Cypher and Taxus). The data suggests near equivalence of both Cypher and Taxus as far as event free survival concerned. Patients after DES implantation need dual antiplatelet therapy for atleast 6 months as per the standard recommendation. The general feeling emerging in the recent times is to continue aspirin and clopidogrel for at least for one year and in high risk patients indefinitely.
Newer Indication of D.e.s.
Acute Myocardial Infarction (Ami)
Recent data from randomized studies have shown that DES are safe in patient undergoing primary PCI for acute MI (TYPHOON study for Cypher & PASSION study for Taxus). TYPHOON study also confirmed that Cypher is superior to bare metal stent for improving event free survival at one year by reducing restenosis.
Instent Restenosis (ISR)
SISR Study (for Cypher) and Taxus V (ISR) for Taxus have confirmed the utility of D.E.S. in the management of ISR. Both studies have shown that DES is superior to vascular brachytherapy. The best treatment for patients presenting with instent restenosis is performing a repeat angioplasty and deploying a drug eluting stent within the restenosed stent.
Left Main Coronary Disease
Stenosis of the ostium and body of the left main coronary artery disease is very amenable to angioplasty using a drug eluting stent with nearly 0% restenosis rate. The lesions at bifurcation of the left main however are more complex and have 10-12% chance of getting a problem during follow up. Improvement in stent design and techniques of deployment should overcome these problems in future. A dedicated study “COMBAT” has been initiated to compare coronary artery bypass surgery with PCI in LMCA disease using D.E.S. SYNTAX study is also evaluating this group of patients vis-a-vis CABG.
Safety Issue and Concerns
One of the issues which has come to light during long term follow up of patients with D.E.S. is the occurrence of late stent thrombosis (LAST) in a small percentage of patients 0.7-1.3%. This phenomenon which can be catastrophic usually occurs after clopidogrel stoppage. The causes of LAST are not clearly understood but are possibly related to lack of healing and delayed hypersensitivity to the polymer. There are some subgroups, which are more prone for late stent thrombosis. These groups are : patients with renal failure, diabetes, small vessels, long lesions and post brachytherapy failure.
Very long term dual antiplatelet therapy is therefore recommended in all these subgroups. It is hoped that the second generation of drug eluting stents may see a solution for this problem.
Future of DES
Newer designs specially made for drug delivery using laser cut holes or wells, use of bioresorbable polymer, newer pharma-cological agents, surface modification of the stent to obviate the need of polymer are some directions in which work is being done. Several of these concepts are being evaluated in dedicated clinical trials. Development of bio-engineered stents to attract progenitor endothelial cells to accelerate normal healing process is another concept, which is under investigation. Absorbable metal stents and biodegradable stents, which will get completely absorbed and disappear from the vessel is another attractive concept being verified.
Drug eluting stents are here to stay and will eventually replace the bare metal stents. The cost issues and safety issues will have a good solution in the near future.
HOMOCYSTEINE LOWERING WITH FOLIC ACID AND B VITAMINS IN HIGH-RISK CHRONIC VASCULAR DISEASE
In epidemiologic studies, the plasma total homocysteine level has been found to be a risk factor for cardiovascular disease. In the HOPE-2 trial of high-risk patients, treatment with folic acid, vitamin B12, and vitamin B6 reduced plasma total homocysteine levels. However, treatment with B vitamins was not associated with a reduction in cardiovascular risk.
N Engl J Med, 2006; 1567, 1629, 1658.