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Interventional techniques have evolved from the evaluation of balloon angioplasty versus surgery, balloon angioplasty versus medical therapies, stenting versus surgery, stenting versus medical therapy, and now the era of drug-eluting stents.

The EAST study, sponsored by the NIH and conducted at Emory University, showed after 8 years no significant difference in survival for multivessel patients treated with either balloon angioplasty versus surgery. EAST showed a trend in diabetic patients for angioplasty to do less well than surgery, whereas patients without diabetes had nearly the same outcomes with both approaches. The BARI results showed a definite advantage for surgery over balloon angioplasty in the diabetic population—presenting a challenge to interventional cardiology, which has struggled with the concept that diabetic patients did not do as well with balloon angioplasty.

A number of trials concluded that mortality was about equal for diabetic and non-diabetic patients, including EAST, BARI, RITA, CABRI, GABI, and 2 stenting trials. However, the need for repeat revascularization favored the surgical approach and the diabetic patient was problematic for angioplasty whereas surgery seemed to do better. A meta-analysis suggests that at about 5-8 years surgery performs better than angioplasty for multivessel patients. Confirmation comes from a recent registry in New York state, in which there were 8.6 excess deaths per 100 persons with angioplasty compared to surgery at 4 years. These discouraging figures illuminate an area for improvement for interventional cardiology to compete against the best vascular surgery in multivessel disease.

For stenting, no significant difference in risk has been seen, but the follow-up is short. No difference in overall survival compared to surgery was seen in the South American ERACI II trial, the ARTS trial, or the SOS trial. Comparing stenting to medical therapy, there is little data. The RITA-2 trial with 7-year follow-up showed no difference in mortality and infarction between the groups (about 1/3 of patients had balloon angioplasty with stenting).

Re-intervention has shown dramatic progress. In patients with multivessel disease, great improvement in re-intervention rates is shown in a comparison of the DYNAMIC registry (data collected on consecutive patients from 16 centers) and the BARI trial. Other registries confirm this improvement. Survival has also improved, using the BARI surgery data as the gold standard.

In acute myocardial infarction (AMI), primary angioplasty has been shown superior to thrombolytic therapy in patients suitable for primary angioplasty that is immediately available. Primary angioplasty saves about 3 of 100 patients compared to thrombolytic therapy. Thrombolytic therapy showed a dramatic reduction in overall mortality prior to the development of primary angioplasty, and the two approaches can be used together.

The DANAMI and PRAGUE trials have shown that certain patients can be successfully treated, even if they must be transferred to another institution. Patients with ST elevation can be transferred with primary angioplasty if transfer can be completed within 3 hours, with superior outcomes to thrombolytic therapy alone.

In facilitated primary angioplasty for AMI, patients first undergo thrombolysis, followed by angioplasty if unsuccessful. Most trials comparing angioplasty and thrombolysis evaluated the period of 3-6 hours post-AMI, where little benefit is seen with thrombolysis. However, thrombolytic trials show this therapy can have dramatic impact if given in the first couple of hours post-MI. Therefore, systems should be developed to apply either primary angioplasty within the first 2 hours or apply thrombolytic therapy followed by angioplasty to take advantage of this potential. Results from clinical trials, including ASSETT and FORE, will further developments in this area.

 Drug-eluting stents (DES) will have limited impact in ST elevation MI. DES, compared to a regular stent, will not prevent death, infarct size or cost, but will reduce the need for re-intervention in the index artery. The RESEARCH registry provides the best snapshot of DES in AMI, which investigated the impact of sirolimus-eluting stents by comparing outcomes from DES and from stenting 1 year prior to the availability of DES. Survival was the same with DES and the bare metal stent. However, a difference was seen favoring DES for the incidence of death, MI, or target vessel revascularization (TVR), driven by TVR. But, the difference may not be from the DES alone. Medical therapies may have contributed to the difference. Patients who received bare metal stents received clopidogrel and aspirin therapy, for 1 month in one group and 6 months in another; this therapy reduces late events, as shown by the CREDO trial. Late thrombosis has been a problem with DES, but is not thought to be a serious problem.

Brachytherapy enabled the treatment of in-stent restenosis, a dramatic breakthrough that probably led to the era of DES, because it was the first demonstration of the efficacy of interrupting the cell cycle at the time of stent placement. Too much neointimal proliferation, beyond the small amount to cover the stent wires, can result in recurrent ischemia. The drugs used in DES induce cell-cycle arrest in the late G1 phase, decrease TGF-beta, elevate p53 levels, inhibit microtubular assembly, and inhibit CDK/cyclin complexes.

In the SIRIUS trial, restenosis was reduced by about 9% in the entire segment. A rather high restenosis rate in the treatment arm was seen. The most reduced clinical event was re-intervention. No change was seen for death and MI with DES in the SIRIUS trial. In the TAXUS trial, in-stent restenosis was reduced in the entire segment with paclitaxel. The TAXUS results are similar to those in SIRIUS. A series of follow-up studies in Europe and Canada showed very good reductions in restenosis and events.

Late loss and binary restenosis are not adequate surrogates for broad clinical results with a DES. The follow-up angiogram, comprising part of the clinical endpoint, performed in SIRIUS and RAVEL influenced the results. In RAVEL, the follow-up angiogram at 6 months showed a great deal of activity, 50% of which was in asymptomatic patients with in-stent restenosis undergoing re-dilatation. In SIRIUS, a difference in MACE-free survival was seen, but this difference widened dramatically based on the 9-month follow-up angiogram.

The 6-month re-intervention rate was 2.7% after using DES exclusively, but was 7.1% for the year preceding the use DES—translating to only 4.4 of 100 patients avoiding a repeat intervention. Survival was not different.

Regarding the long-term safety of DES, another 5-10 years is needed to answer remaining questions. Although restenosis is not a fatal event, thrombotic complications can be fatal. No overall difference in survival was found over 6 years in an Emory University study of 3000 patients, comparing those with and without restenosis. In contrast, late thrombosis could conceivably be caused by anything, such as malapposition of stents.  Hypersensitivity reactions to the polymer have been reported, although this is thought to be a very rare event.

There is certainly a place for non-drug eluting stents. New stents are coming that may be even better than the current bare metal stents. Some very low profile stents tested in registries have TVR rates that are exceedingly low, in the range seen with DES, although the lesions are probably mild.

The local delivery of agents to block inflammatory and immune responses and antimitotic agents without stent coating is one of the rich research opportunities in the area of restenosis. Recent papers from Germany describe antimitotics delivered on the balloon when placing a bare metal stent in the animal model and showed a marked reduction in restenosis. Systemic therapies may address the treated lesion, and perhaps also the vulnerable plaques outside that lesion. For example, systemic agents that can be given to the macrophage to interfere with the restenosis process.

Clinical events are heavily determined by disease progression in untreated segments. A fascinating study of 2nd generation trials showed that at 5 years only 20% of events were related to restenosis, while 38% of events were related to disease progression, not restenosis. At 5 years, only 8% of patients had only restenosis as their only clinical outcome. Clearly, about a 40% event rate will remain, even if restenosis is eliminated using new advances.

DES are an important breakthrough. Their greatest impact will be in long lesions, small vessels, perhaps bifurcations and other aspects for which treatment is not well understood. In Japan, the arrival of DES will be accompanied by many research opportunities. These include comparisons between current practice and DES and between clinical outcomes with bare metal stents and with DES, and the development and improvement of methods for using DES. Other topics that need research are many of the technical aspects of stent use, chronic total occlusion, left main disease, and bifurcation lesions, which have a 20-30% restenosis rate with DES.

Interventional cardiology has a bright future. There are technical advances that will be crucial, including improved therapies for bifurcations and for chronic total occlusion. Bioabsorbable stents are being developed. Developments in angiogenesis and myogenesis may enable the interventional cardiologist to perform revascularization in patients who cannot otherwise be treated. The future of coronary artery and venous bypass is unclear. Detection of vulnerable plaque has been suggested as a major field for interventional cardiology; perhaps magnetic resonance or other imaging modalities may be performed non-invasively to detect vulnerable plaque. Prophylactic intervention is unclear, but perhaps in partnership with prevention to try to influence plaque stability and regress plaques.

Trials that are underway will give more insight on the value of interventional cardiology compared to medical therapy. The BARI 2D trial of revascularization is comparing either surgery or angioplasty to medical therapy in diabetic patients. COURAGE is a stenting versus medical therapy trial. The FREEDOM trial sponsored by the NIH will compare DES to surgery in multivessel diabetic patients.

Interventional cardiology will have a bright future if it works to advance not only the technology but also become an active participant in the ongoing medical care, which has the greatest potential to extend life. The application of medical therapies, such as the use of statins, ACE inhibitors, beta -blockers, is not the prerogative of one discipline, but should applied to all patients. The best new technology in interventional cardiology is always secondary to prevention.