1 / 36

Gregg W. Stone, MD PROSPECT Investigators

The PROSPECT Trial. P roviding R egional O bservations to S tudy P redictors of E vents in the C oronary T ree. A Natural History Study of Atherosclerosis Using Multimodality Intracoronary Imaging to Prospectively Identify Vulnerable Plaque. Gregg W. Stone, MD

ronny
Télécharger la présentation

Gregg W. Stone, MD PROSPECT Investigators

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. The PROSPECTTrial 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 PROSPECTTrial • Gregg W. Stone • Scientific Advisory Board, Abbott Vascular Devices and Boston Scientific • Consultant to InfraReDx

  3. The PROSPECTTrial 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

  4. PROVE-IT TIMI-224,162 Randomized Pts with ACS 26.3% Pravastatin 40 mg/d 22.4% 16% RR P = 0.005 Atorvastatin 80 mg/d Death, MI, UA requiring hosp, revasc >30d, or stroke (%) How many events were attributable to: 1) Restenosis, stent thrombosis, etc. vs. 2) Significant disease left behind, vs. 3) VP with rapid lesion progression? ACS median 7d PCI 69% Cannon CP et al. NEJM 2004;350:1495-1504

  5. The PROSPECTTrial Background • We therefore performed a prospective, multicenter natural history study using 3 vessel multimodality intracoronary imaging to quantify the clinical event rate due to atherosclerotic progression and to identify those lesions which place pts at risk for unexpected adverse cardiovascular events

  6. The PROSPECTTrial 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 • Biomarkers • Hs CRP • IL-6 • sCD40L • MPO • TNFα • MMP9 • Lp-PLA2 • others PCI of culprit lesion(s) Successful and uncomplicated Formally enrolled PI: Gregg W. Stone Sponsor: Abbott Vascular; Partner: Volcano

  7. Culprit artery, followed by non-culprit arteries Angiography (QCA of entire coronary tree) IVUS Virtual histology Palpography (n=~350) Proximal 6-8 cm of each coronary artery Meds rec Aspirin Plavix 1yr Statin Repeat biomarkers @ 30 days, 6 months MSCT Substudy N=50-100 Repeat imaging in pts with events The PROSPECTTrial 3-vessel imaging post PCI F/U: 1 mo, 6 mo, 1 yr, 2 yr, ±3-5 yrs

  8. PROSPECT: Primary Endpoint • MACE attributable to rapid angiographic progression of a non-culpritlesion* • Cardiac death • Cardiac arrest • Myocardial infarction • Unstable angina • - Requiring revascularization • - Requiring rehospitalization • Increasing angina • - Requiring revascularization • - Requiring rehospitalization Most severe Hierarchical Least severe MACE during FU were adjudicated by the CEC as attributable to culprit lesions (those treated during or before the index hospitalization) or non culprit lesions (untreated areas of the coronary tree) based on angiography (+ECGs, etc.) at the time of the event; events occurring in pts without angiographic follow-up were considered indeterminate in origin. Rapid lesion progression = ↑ in QCA DS by >20% from baseline to FU.

  9. Performed on every coronary artery (main vessel and branch) visually ≥1.5 mm in diameter Detailed qualitative and quantitative parameters recorded for every 1.5 mm length segment Distance from ostia and at major branch points were registered and corrected for foreshortening after IVUS co-registration Lesions with DS ≥30% by visual assessment identified Output available as lesions, CASS segments, and vessels, by every mm, or any other parameter PROSPECT: MethodologyAngiographic Core Lab Analysis

  10. Gray-scale IVUS volumetric and cross-sectional analysis performed Each IVUS/VH frame co-registered to corresponding QCA location using fiduciary branch points IVUS lesions (≥3 consecutive frames with cross sectional plaque burden >40%) were characterized IVUS-VH analysis performed using the latest classification tree (pcVH 2.1) Plaque characterized as fibrotic, fibrofatty, necrotic core or dense calcium, and reported as absolute and relative area/volumes PROSPECT: MethodologyIVUS/VH Core Lab Analysis

  11. PROSPECT: MethodologyVirtual 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-thincap fibroatheroma (VH-TCFA) (presumedhighrisk)

  12. PROSPECT 82910-012: 52 yo♂ 2/13/06: NSTEMI, PCI of MLAD 2/6/07 (51 weeks later): NSTEMI attributed to LCX Index 2/13/06 Event 2/6/07 QCA PLCX DS 28.6% QCA PLCX DS 71.3%

  13. PROSPECT 82910-012: Index 2/13/06 Baseline PLCX QCA: RVD 2.82 mm, DS 28.6%, length 6.8 mm IVUS: MLA 5.3 mm2 VH: ThCFA 1 * Lesion prox *OM 1. ThCFA 5.3 mm2 38

  14. PROSPECT: Event Categories CEC adjudicated MACE during follow-up • Culprit lesion (stent) related - Stent thrombosis - Restenosis - New side branch lesion • Non culprit lesion related - With rapid lesion progression (by QCA) (classic “vulnerable plaque”) - Without rapid lesion progression • Indeterminate

  15. PROSPECT:Organization • PI: Gregg W. Stone; Co-PI: Patrick W. SerruysEuropean Co-PI: Bernard de Bruyne • Data management: Abbott Vascular; Zhen Zhang (lead statistician) • Clinical events committee: CRF, Roxana Mehran (Chair), George Dangas • Core laboratories • QCA: CRF, Alexandra Lansky (Director), Ecaterina Cristea • IVUS, Virtual Histology: CRF, Akiko Maehara (Director), Gary S. Mintz • Palpography: Cardialysis, Marie-AngèleMorel • MSCT: Thoraxcenter, Pim de Feyter (Director) • Biomarkers: CRLMedinet • DSMB: Steve Steinhubl (Chair) • Sponsor and Partner: Abbott Vascular and Volcano Corp. • Abbott Vascular Program Leads: Barry Templin and Wai-Fung Cheong

  16. PROSPECT:Enrollment 700 pts enrolled between Oct. 2004 and June 2006 and followed for at least 3 years Top 10 enrollers

  17. PROSPECT: Baseline Features N = 697* *3 patients who were never consented were de-registered

  18. PROSPECT: Baseline Features N = 697

  19. PROSPECT: Imaging Summary Length of coronary arteries analyzed (core lab)

  20. PROSPECT: Imaging Summary Virtual histology (N=2689 lesions in 615 pts) - Mean plaque composition-

  21. PROSPECT: MACE All Culprit lesion (CL) related Non culprit lesion (NCL) related Indeterminate 25 20.4% 20 15 12.9% MACE (%) 10 11.6% 5 2.7% 0 0 1 2 3 Time in Years Number at risk

  22. PROSPECT: MACE All Culprit lesion (CL) related Non culprit lesion (NCL) related Indeterminate 25 20.4% 20 18.1% 13.2% 15 12.9% MACE (%) 11.4% 7.9% 10 11.6% 9.4% 5 6.4% 2.7% 1.9% 0.9% 0 0 1 2 3 Time in Years Number at risk

  23. PROSPECT: MACE 3-year follow-up, non hierarchical Rates are 3-yr Kaplan-Meier estimates (n of events)

  24. PROSPECT: MACE Sensitivity analysis*: 3-year FU, non hierarchical Rates are 3-yr Kaplan-Meier estimates (n of events) *Assuming all indeterminate events are non culprit related

  25. PROSPECT: NCLMACE 11.6% Non-culprit lesion (NCL) related, all - Without rapid lesion progression (RLP) - With rapid lesion progression (RLP) 12 10 8 6.7% MACE (%) 6 6.4% 4 2 0 0 1 2 3 Time in Years Number at risk

  26. PROSPECT: NCLMACE 11.6% Non-culprit lesion (NCL) related, all - Without rapid lesion progression (RLP) - With rapid lesion progression (RLP) 12 9.4% 10 8 6.4% 6.7% 5.5% MACE (%) 6 6.4% 4.1% 4.9% 4 Median time to event No RLP: 223 [85, 663] days RLP: 401 [229, 666] days 2 2.9% 0 0 1 2 3 Time in Years Number at risk

  27. 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)

  28. 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 VariableKM Rate (n)HR [95% CI]HR [95% CI]P Insulin DM (n=21) 41.4% (6) 4.07 [1.75, 9.46] 0.001 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] 0.006 No prior PCI (n=613) 10.8% (61) ≥1 visible angio lsn* (n=582) 13.7% (73) 4.72 [1.49, 14.98] 0.008 No visible angio lsn (n=107) 3.2% (3) 0 1 5 10 15 *Visually assessed DS >30% Univariate, unadjusted. * 8 patients with indeterminate events were excluded.

  29. 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) VariableRate (n)HR [95% CI]HR [95% CI]P MLA < median 5.9 mm2 (n=1336) 3.4% (45) 7.53 [3.21, 17.65] <0.0001 MLA ≥ median 5.9 mm2(n=1337) 0.4% (6) MLA ≤ 4.0 mm2 (n=496) 5.4% (27) 5.01 [2.89, 8.68] <0.0001 MLA > 4.0 mm2(n=2177) 1.1% (24) PBMLA ≥ median 0.55 (n=1337) 3.3% (44) 6.37 [2.87, 14.15] <0.0001 PBMLA < median 0.55 (n=1336) 0.5% (7) PBMLA ≥ 0.70 (n=242) 9.1% (22) 7.94 [4.56, 13.81] <0.0001 PBMLA < 0.70 (n=2431) 1.2% (29) EEMMLA ≥ med 14.3 mm2 (n=1337) 1.4% (19) 0.60 [0.34, 1.06] 0.08 EEMMLA < med 14.3 mm2 (n=1336) 2.4% (32) Lsn length < med 11.6 mm (n=1336) 0.7% (10) 4.01 [2.01, 8.02] <0.0001 Lsn length ≥ med 11.6 mm (n=1337) 3.1% (41) 0 1 5 10 15 MLA = minimal luminal area; PBMLA = plaque burden at the MLA; EEMMLA = external elastic membrane at the MLA. Data represent univariate associations, unadjusted.

  30. 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 VariableRate (n)HR [95% CI]HR [95% CI]P VH-TCFA (n=590) 4.4% (26) 3.84 [2.22, 6.65] <0.0001 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] 0.001 Not PIT (n=1691) 2.7% (45) Fibrotic (n=67) 0% (0) - 0.99 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) 0 1 5 10 15 TCFA = thin cap fibroatheroma; ThCFA = thick cap fibroatheroma; PIT = pathologic intimal thickening. Univariate, unadjusted.

  31. PROSPECT: Multivariable Correlates of Non Culprit Lesion Related Events Independent predictors of lesion level events by logistic regression analysis VariableOR [95% CI]P value PBMLA≥70% 4.99 [2.54, 9.79] <0.0001 VH-TCFA 3.00 [1.68, 5.37]0.0002 MLA ≤4.0 mm22.77 [1.32, 5.81]0.007 Lesion length ≥11.6 mm 1.97 [0.94, 4.16] 0.07 EEMMLA <14.3 mm21.30 [0.62, 2.75] 0.49 Variables entered into the model: Minimal luminal area (MLA); plaque burden at the MLA (PBMLA); external elastic membrane at the MLA (EEMMLA) <median; lesion length ≥ median (mm); VH-TCFA.

  32. PROSPECT: Correlates of Non Culprit Lesion Related Events Lesion HR 3.8 (2.2, 6.6) 5.0 (2.9, 8.7) 7.9 (4.6, 13.8) 6.4 (3.4, 12.2) 6.7 (3.4, 13.0) 10.8 (5.5, 21.0) 10.8 (4.3, 27.2) P value <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 Prevalence* 51.2% 49.1% 30.7% 17.4% 15.4% 11.0% 4.6% *Likelihood of one or more such lesions being present per patient. PB = plaque burden at the MLA

  33. PROSPECT: VH-TCFA and Non Culprit Lesion Related Events Lesion HR 3.84 (2.22, 6.65) 6.41 (3.35, 12.24) 10.77 (5.53, 21.00) 10.81 (4.30, 27.22) P value <0.0001 <0.0001 <0.0001 <0.0001 Prevalence* 51.2% 17.4% 11.0% 4.6% *Likelihood of one or more such lesions being present per patient. PB = plaque burden at the MLA

  34. PROSPECT: PIT and Non Culprit Lesion Related Events Lesion HR 0.24 (0.10, 0.56) 1.15 (0.36 3.70) 1.36 (0.19, 9.86) 2.85 (0.39, 20.67) P value 0.001 0.81 0.76 0.30 Prevalence* 68.6% 17.2% 5.7% 2.6% *Likelihood of one or more such lesions being present per patient. PB = plaque burden at the MLA

  35. 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

  36. 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 angiographic 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

More Related