Vascular Restoration Therapy: the fourth revolution in interventional cardiology and the ultimate “Rosy” prophecy

The invention of balloon angioplasty as a treatment of obstructive coronary disease by Andreas Gruntzig in 1977 was a huge leap forward in technology, and undoubtedly will always remain the first revolution in interventional cardiology. However, this technique was plagued by multiple problems including the risk of acute occlusion of the vessel due to extensive dissection requiring emergency bypass surgery 1 . While late luminal enlargement and vascular remodelling could occur, more often constrictive vascular remodelling was the case instead, with consequent restenosis. The advent of bare metal stenting and the landmark BENESTENT trial have established bare metal stenting as the second revolution in interventional cardiology 2 . This technology provided a solution to acute vessel occlusion by sealing the dissection flaps and preventing recoil. The rate of subacute occlusion was reduced to 1.5%, making emergency by-pass surgery a rare occurrence, truly a thing of the past. Restenosis rates were further reduced from 32% to 22% at seven months, but this was still high, and neointimal hyperplasia still occurred, necessitating repeat revascularisation. Since the vessel was now caged with metal, late luminal enlargement and advantageous vascular remodelling no longer occurred. Another problem, namely that of late stent thrombosis, was also first described 3 . To solve the issue of in-stent restenosis - after the failure of brachytherapy - drug eluting stents were introduced. Indeed, the followup of the first 45 patients implanted with the sirolimus eluting Bx velocity stent (Cordis, Johnson & Johnson, Warren, NJ, USA) had negligible neointimal hyperplasia. This was confirmed in the RAVEL study 4,5 . Drug eluting stents were thus dubbed the third revolution in interventional cardiology. Both large scale randomised trials and allcomer registries showed excellent results in terms of the need for repeat revascularisation. This technology brought closer the results of percutaneous coronary intervention to that of coronary bypass graft surgery. Serruys’ “rosy” prophecy came true 6 , however, it soon turned out that, as in all true “roses”, this one also has its thorns. The thorn of the first generation of drug eluting stents was an increased risk of late stent thrombosis. Registries of all comers treated with drug eluting stents showed late stent thrombosis rates of 0.53% per year, with a continued increase to 3% over four years 7,8 . In patients with complex multivessel disease (ARTS II), the rate of combined definite, probable and possible stent thrombosis was as high as 9.4% at five years, accounting for 32% of MACE events 9 . In addition, the pathology showed uncovered struts and inflammatory reaction in post-mortem specimens. Vasomotion testing showed abnormal vasoconstriction response to acetylcholine distal to the stent, suggesting that the structure and function of the endothelium remained abnormal 10 . All