PROSPECT and the Gumpian Theory of Atherosclerosis
With the recent publication in the NEJM of the long awaited PROSPECT trial,[1] I have been literally “Pondering across the pond” about the implications of this landmark trial. Should we just give up on the vulnerable plaque hypothesis? Steve Nissen has been saying this for a few years now and he is a smart chap.
On release of the initial final results at TCT, Edo Kaluski (a prominent cardiologist in Newark) summarized the data to me as follows (I have highlighted the most important points) and must credit him with this excellent synopsis.
In PROSPECT, 697 subjects were studied [STEMI (30.3%) and acute coronary syndrome without ST elevation (NSTEMI 69.7%)]. After PCI of culprit and other significant lesions (PCI of single vessel 72% double vessel 28%) all patients had a 3 vessel virtual histology intravascular ultrasound (VH-IVUS) of 6-8 cm of the proximal portion of the 3 major vessels. 2091 coronaries (42.8% of these with previous PCI) with a total length of 118.6 meters, which harbored 2689 lesions that were analyzed. Major adverse clinical events (MACE) were determined as culprit lesion or non-culprit related. The investigators characterized each lesion as fibrotic, fibro-calcific, pathological intimal thickening (PIT), thick cap fibroatheroma (ThCFA) and thin cap fibroatheroma (TCFA was defined as atheroma with confluent necrotic core abutting the lumen, on at least 1.5 mm longitudinal length). Culprit lesion-related MACE were defined stent thrombosis, restenosis or new side branch lesions. Non-culprit MACE were determine as with rapid progression (>20% worsening stenosis) or without rapid progression. Of the 2689 lesions analyzed: plaque subtype was characterized as PIT (35.9%), ThCFA (37.8%) and TCFA (22.1%). Only 28.4% of pts have ≥ 1 VH-TCFA (Mean 0.42 ± 0.78 VH-TCFAs per patient; range 0–5 per patient).
In a median follow up of 3.4 [IQR 1.9, 3.9] years, a total of 20.4% of patients experienced events with more than half of these within the first year. More than half of these events (12.9%) and most of the severe events were “culprit lesion related.” While 11.6% of the events (driven by unstable angina 3.3%, worsening angina 8.5% and MI 1%) were non-culprit events, only 55% of these (6.4% event rate) were associated with rapid progressive lesions. 2.7% of the events were rendered indeterminate of which 1.8% were cardiac death. Besides the infrequency and the benign nature of the non-culprit related events the investigators attempted to assess the value of clinical and IVUS-VH based predictors on the likelihood of events.
The 3 predictors for patient events emerged as increased plaque burden >70%, minimal lumen diameter < 4 mm and TCFA. However the presence of these predictors did not suggest the location of a vulnerable plaque but the presence of a vulnerable patient.
From the final paper in the NEJM, I would like to add these significant points to the debate:
1. Prospect makes bold statements about coronary plaque composition in non-culprit lesions despite imaging less than half of these lesions. (51/106).
2. The statistical suggestion that IVUS-derived thin cap fibroatheroma (TCFA) is a marker of future lesion progression is hard to believe when an identical number were non-TCFA related. (25/26)
3. The outcome of this analysis could therefore be influenced greatly by the missing 55 results.
4. Utilizing contemporary data from fractional flow reserve (FFR) studies,[2,3] could have provided a better methodology to image residual plaque. This would have involved treatment of the culprit lesion only, followed by FFR and IVUS-VH assessment of the other lesions. This may have increased the yield of future non-culprit events, while simultaneously decreasing the proportion of culprit events. It is possible that in PROSPECT a lot of plaques were erroneously treated (from angiographic assessment alone) resulting in conclusions that are now not applicable to everyday interventional cardiology.
I am nearing the final analysis of our ACS IVUS-VH study called V-HEART – Virtual-Histology Evaluation of ACS Requiring Treatment. This is a smaller observational study that may shed a little more light on this controversial technology.
So, in conclusion for early 2011, should we adopt the Edo’s “Gumpian theory of atherosclerosis??”: "Atherosclerosis is like a box of chocolates……...You never know what you are going to get!?! What do you think about all of this?? I would be very interested in your thoughts.
My hope still remains that one day through invasive and non-invasive techniques we can provide a coronary “lesion guide” that will allow us to leave hard stable lesions alone and focus on the soft centers!
Best wishes and good luck for 2011.
Dr Scott Murray is a Specialist Registrar in Cardiology and a Clinical Research Fellow at Liverpool Heart and Chest Hospital, United Kingdom.
References
1. Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011; 364:226–235.
2. Pijls NH, Fearon WF, Tonino PA, et al. FAME Study Investigators.Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study. J Am Coll Cardiol 2010;56(3):177–184.
3. Ntalianis A, Sels JW, Davidavicius G, et al. Fractional flow reserve for the assessment of non-culprit coronary artery stenoses in patients with acute myocardial infarction. JACC Cardiovasc Interv 2010;3(12):1274–1281.
