The PROSPECT Trial. A Natural History Study of Atherosclerosis Using Multimodality Intracoronary Imaging to Prospectively Identify Vulnerable Plaque

Transcription

1 The PROSPECT Trial Providing Regional Observations to Study Predictors of Events in the Coronary Tree A Natural History Study of Atherosclerosis Using Multimodality Intracoronary Imaging to Prospectively Identify Vulnerable Plaque Gregg W. Stone, MD PROSPECT Investigators

2 The PROSPECT Trial Background Most cases of sudden cardiac death and MI are believed to arise from plaque rupture with subsequent thrombotic coronary occlusion of angiographically mild lesions ( vulnerable ( plaques ), the prospective detection of which has not been achieved The event rate attributable to progression of vulnerable plaque has never been prospectively assessed

3 Death, MI, UA requiring hosp, revasc >30d, or stroke (%) ACS median 7d PCI 69% PROVE-IT TIMI-22 4,162 Randomized Pts with ACS 16% RR P = Pravastatin 40 mg/d Months of Follow-up Atorvastatin 80 mg/d Cannon CP et al. NEJM 2004;350: % 22.4% How many events were attributable to: 1) Restenosis, stent thrombosis, etc. vs. 2) Significant disease left behind, vs. 3) VP with rapid lesion progression?

4 The PROSPECT Trial 700 pts with ACS UA (with ECGΔ) or NSTEMI or STEMI >24º undergoing PCI of 1 or 2 major coronary arteries at up to 40 sites in the U.S. and Europe Metabolic S. Waist circum Fast lipids Fast glu HgbA1C Fast insulin Creatinine PCI of culprit lesion(s) Successful and uncomplicated Formally enrolled PI: Gregg W. Stone Sponsor: Abbott Vascular; Partner: Volcano Biomarkers Hs CRP IL-6 scd40l MPO TNFα MMP9 Lp-PLA2 others

5 PROSPECT: Methodology Virtual histology lesion classification Lesions are classified into 5 main types 1. Fibrotic 2. Fibrocalcific 3. Pathological intimal thickening (PIT) 4. Thick cap fibroatheroma (ThCFA) 5. VH-thin cap fibroatheroma (VH-TCFA) (presumed high risk)

6 PROSPECT: Imaging Summary Virtual histology (N=2689 lesions in 615 pts) - Mean plaque composition- 21.1% Dense calcium Fibrofatty 13.0% 6.5% Fibrotic Necrotic core 59.4% Plaque subtype N=2689 Fibrotic 2.5% Fibrocalcific 1.1% PIT 35.9% Fibroatheroma 59.9% - Thick cap 37.8% - VH-TCFA 22.1% - Single, - Ca 5.4% - Single, + Ca 0.5% - Multiple, - Ca 9.8% - Multiple, + Ca 6.4% Unclassified 0.7%

7 PROSPECT: Imaging Summary Per patient incidence of VH-TCFAs 100% N lesions/patient: % Patients 75% 50% 25% 48.8% 51.2% of pts have 1 1 VH-TCFA 0.97 ±1.30 VH-TCFAs per pt (range 0 7 per pt) Total of 594 VH-TCFA lesions in 615 pts 27.3% 12.0% 6.2% 5.7% 0%

8 PROSPECT: MACE All Culprit lesion (CL) related Non culprit lesion (NCL) related Indeterminate 18.1% 20.4% MACE (%) % 7.9% 11.4% 9.4% 12.9% 11.6% % 0.9% 1.9% 2.7% Time in Years Number at risk ALL CL related NCL related Indeterminate

9 PROSPECT: NCL MACE 12 Non-culprit lesion (NCL) related, all 11.6% - Without rapid lesion progression (RLP) - With rapid lesion progression (RLP) % MACE (%) % 4.1% 5.5% 4.9% 6.7% 6.4% % Median time to event No RLP: 223 [85, 663] days RLP: 401 [229, 666] days Time in Years Number at risk NCL related, all without RLP with RLP

10 PROSPECT: Correlates of Non Culprit Related Events Baseline variables examined (n=152) Demographic, history and PE (n=19) Labs (n=7; including CrCl, lipids, hgba1c, CRP) Angio non core lab (n=1; visible lesions >30% DS) QCA measures (n=12) IVUS area and volumetric measures (n=22) Virtual histology measures (n=74) Treatment related (n=1; # vessels stented) Medications in-hosp. and at discharge (n=16)

11 PROSPECT: Correlates of Non Culprit Lesion Related Events Patient level events at median 3.4 yrs (76 events in 689 pts*) Baseline Demographic and Angiographic Variables Variable KM Rate (n) HR [95% CI] HR [95% CI] P Insulin DM (n=21) 41.4% (6) 4.07 [1.75, 9.46] Non insulin DM (n=96) 16.3% (14) 1.55 [0.86, 2.79] 0.14 Non diabetic (n=569) 10.7% (56) Hypertension (n=314) 14.7% (42) 1.64 [1.03, 2.60] 0.04 No hypertension (n=369) 9.1% (31) Prior PCI (n=75) 23.1% (15) 2.20 [1.25, 3.86] No prior PCI (n=613) 10.8% (61) 1 1 visible angio lsn* (n=582) 13.7% (73) 4.72 [1.49, 14.98] No visible angio lsn (n=107) 3.2% (3) *Visually assessed DS >30% Univariate, unadjusted. * 8 patients with indeterminate events were w excluded.

12 PROSPECT: Correlates of Non Culprit Lesion Related Events Lesion level events (51 events from 2673 lesions in 609 pts at median 3.4 yrs) IVUS Characteristics (area data) Variable Rate (n) HR [95% CI] HR [95% CI] P MLA < median 5.9 mm 2 (n=1336) 3.4% (45) 7.53 [3.21, 17.65] < MLA median 5.9 mm 2 (n=1337) 0.4% (6) MLA 4.0 mm 2 (n=496) 5.4% (27) 5.01 [2.89, 8.68] < MLA > 4.0 mm 2 (n=2177) 1.1% (24) PB MLA PB MLA PB MLA median 0.55 (n=1337) 3.3% (44) 6.37 [2.87, 14.15] < PB MLA < median 0.55 (n=1336) 0.5% (7) PB MLA PB MLA PB MLA 0.70 (n=242) 9.1% (22) 7.94 [4.56, 13.81] < PB MLA < 0.70 (n=2431) 1.2% (29) EEM MLA EEM MLA EEM MLA med 14.3 mm 2 (n=1337) 1.4% (19) 0.60 [0.34, 1.06] 0.08 EEM MLA < med 14.3 mm 2 (n=1336) 2.4% (32) Lsn length < med 11.6 mm (n=1336) 0.7% (10) 4.01 [2.01, 8.02] < Lsn length med 11.6 mm (n=1337) 3.1% (41) MLA = minimal luminal area; PB MLA = plaque burden at the MLA; EEM MLA = external elastic membrane at the MLA. Data represent univariate associations, unadjusted. Note: All NC MACE events occurred at IVUS lesions.

13 Variable PROSPECT: Correlates of Non Culprit Lesion Related Events Lesion level events (51 events from 2655 lesions in 609 pts at median 3.4 yrs) Virtual Histology Plaque Type Rate (n) HR [95% CI] HR [95% CI] VH-TCFA (n=590) 4.4% (26) 3.84 [2.22, 6.65] < Not VH-TCFA (n=2065) 1.2% (25) ThCFA (n=1005) 1.8% (18) 0.89 [0.50, 1.58] 0.69 Not ThCFA (n=1650) 2.0% (33) PIT (n=964) 0.6% (6) 0.23 [0.10, 0.53] Not PIT (n=1691) 2.7% (45) Fibrotic (n=67) 0% (0) Not Fibrotic (n=2588) 2.0% (51) Fibrocalcific (n=29) 3.4% (1) 1.75 [0.24, 12.63] 0.58 Not fibrocalcific (n=2626) 1.9% (50) TCFA = thin cap fibroatheroma; ThCFA = thick cap fibroatheroma; PIT = pathologic intimal thickening. Univariate, unadjusted. P

14 PROSPECT: Multivariable Correlates of Non Culprit Lesion Related Events Independent predictors of lesion level events by logistic regression analysis Variable OR [95% CI] P value PB MLA 70% 4.99 [2.54, 9.79] < VH-TCFA 3.00 [1.68, 5.37] MLA 4.0 mm [1.32, 5.81] Lesion length 11.6 mm 1.97 [0.94, 4.16] 0.07 EEM MLA <14.3 mm [0.62, 2.75] 0.49 Variables entered into the model: Minimal luminal area (MLA); plaque burden at the MLA (PB MLA ); external elastic membrane at the MLA (EEM MLA ) <median; lesion length median (mm); VH-TCFA.

15 PROSPECT: VH-TCFA and Non Culprit Lesion Related Events Lesion HR 3.84 (2.22, 6.65) 6.41 (3.35, 12.24) (5.53, 21.00) (4.30, 27.22) P value < < < < Prevalence* 51.2% 17.4% 11.0% 4.6% *Likelihood of one or more such lesions being present per patient. t. PB = plaque burden at the MLA

16 PROSPECT: PIT and Non Culprit Lesion Related Events Lesion HR 0.24 (0.10, 0.56) 1.15 ( ) 1.36 (0.19, 9.86) 2.85 (0.39, 20.67) P value Prevalence* 68.6% 17.2% 5.7% 2.6% *Likelihood of one or more such lesions being present per patient. t. PB = plaque burden at the MLA

17 PROSPECT: Conclusions From this trial, the first prospective, natural history study of atherosclerosis using multimodality imaging to characterize the coronary tree, we can conclude that: Approximately 20% of pts with ACS successfully treated with stents and contemporary medical Rx develop MACE within 3 years, with adverse events equally attributable to recurrence at originally treated culprit lesions (treatment failure) and to previously untreated non culprit coronary segments Approximately 12% of pts develop MACE from non culprit lesions during 3 years of follow-up Patients treated with contemporary medical therapy who develop non culprit lesion events present most commonly with progressive or unstable angina, and rarely with cardiac death, cardiac arrest or MI

18 PROSPECT: Conclusions While plaques which are responsible for unanticipated future MACE are frequently angiographically mild, most untreated plaques which become symptomatic have a large plaque burden and a small lumen area (which are detectable by IVUS but not by angiography) Only about half of new events due to non culprit lesions exemplify the classic notion of vulnerable plaque (rapid lesion progression of mild angiographically lesions), while half are attributable to unrecognized and untreated severe disease with minimal change over time The prospective identification of non culprit lesions prone to develop MACE within 3 years can be enhanced by characterization of underlying plaque morphology with virtual histology, with VH-TCFAs representing the highest risk lesion type The combination of large plaque burden (IVUS) and a large necrotic core without a visible cap (VH-TCFA) identifies lesions which are at especially high risk for future adverse cardiovascular events