The Vulnerable Plaque “Hype”othesis Steven E. Nissen MD Disclosure Clinical Trials: AstraZeneca, Amgen, Cerenis, Eli Lilly, Novartis, Takeda, Resverlogix, Orexigen, and Pfizer. Companies are directed to pay any honoraria, speaking or consulting fees directly to charity so that neither income nor a tax deduction is received.

Plaque Rupture: Sudden Cardiac Death

Vulnerable Plaque: Hype vs. Reality A PubMed search for “vulnerable plaque” or “high-risk” plaque yields >2,000 references over the past 20 years. Many techniques to “detect” vulnerable plaques have come and gone with initially promising “findings” followed by a sobering reality check. Thermography, spectroscopy, palpography, virtual histology, OCT, NIR and many more. A large number of startup companies with “breakthrough” approaches have come and gone, leaving investors with empty pockets, but no progress.

What Went Wrong? The exact characteristics of “vulnerable” plaque remain uncertain. The evidence for the importance of “thin cap fibroatheromas” is flimsy at best. Vulnerability is diffuse and global, not local. Even if we knew what to look for, we would have to scan every branch of every vessel, a virtual impossibility. Evidence suggests that atheromatous lesions are everywhere and ruptured plaques ubiquitous. Even if we could identify such lesions, current treatment modalities are unlikely to decrease adverse outcomes.

Death or MI by Type of Coronary Syndrome 16 12 Death or Nonfatal MI (%) USA/non-Q-wave MI (FRISC II) 8 Stable angina (SAPAT) Primary prevention (WOSCOPS) 4 2 4 6 8 10 12 Slide 4 The difference in outcomes between patients with stable angina and unstable angina/non-Q-wave MI is illustrated in 12-month follow-up data from the FRagmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II) trial and the Swedish Angina Pectoris Aspirin Trial (SAPAT). The cumulative incidence of death or nonfatal MI among the population with unstable coronary disease in FRISC II increased sharply to approximately 8% within one month, gradually levelling off to around 15% by 12 months’ follow-up [2]. By contrast, the cumulative incidence of death or nonfatal MI among patients with stable angina in SAPAT remained low throughout the same follow-up period [3]. After 12 months’ follow-up in SAPAT, the combined number of patients in the aspirin and sotalol treatment group with a primary endpoint was only 16 out of 1009 patients (1.6%). This suggests a difference in the relative risk of this combined event, between these two study populations at 12 months. For further comparison, in a primary prevention population with hypercholesterolemia but without CHD – the West of Scotland Coronary Prevention Study (WOSCOPS) – the event rate over the first year was exceedingly low [4]. This slide shows the trend lines for FRISC II, SAPAT and WOSCOPS. References 2. Wallentin L et al. Lancet 2000;356:9–16. 3. Juul-Moller S et al. Lancet 1992;340:1421–1425. 4. Shepherd J et al. N Engl J Med 1995;333:1301–1307. Months of follow-up Wallentin L et al. Lancet 2000;356:9–16. Juul-Moller S et al. Lancet 1992;340:1421–1425. Shepherd J et al. N Engl J Med 1995;333:1301–1307.

ACS: The Tip of the Atherothrombotic “Iceberg” Acute Plaque Rupture (UA/ NSTEMI/ STEMI/TIA/stroke) Clinical Subclinical Presence of Multiple Coronary Plaques Persistent Hyperreactive Platelets Vascular Inflammation Bhatt DL. Journal of Invasive Cardiology. 2003; Vol. 15: Suppl B, 3B-10B. Not Approved

The “Vulnerable” Patient The entire concept of “vulnerable plaque” is an overly simplistic characterization of an exceedingly complicated phenomenon. In patients with acute plaque rupture, there is widespread inflammation, white blood cell activation, increased thrombogenicity, and oxidative stress. These increase biomarkers demonstrate that systemic factors are more important than local anatomy in determining who will have a acute event.

Vulnerable plaques are everywhere Vulnerable plaques are everywhere. With the appearance of the first luminal irregularity, more than 80% of the epicardial coronary bed is atherosclerotic

Ultrasound Measurement of Atheroma Volume Motorized Pullback: Cross-sections Selected at 1 mm Intervals 1 mm spacing Cross-section 48 Cross-section 26 Cross-section 10

Multiple Ruptured Plaques in ACS Patients 80% of patients have 1 ruptured plaque Patients (%) Number of ruptured plaques in addition to culprit lesion Rioufol G et al. Circulation. 2002;106:804-808.

AMI Trial: IVUS in Segment Proximal to Stent

Prevalence: Ulceration Proximal to Culprit Lesion 20% 19% MI All Angina Unstable Angina Stable Angina 15% 10% p=0.014 7% 5% 4% 0% 0% MI All Angina Unstable Angina Stable Angina

Inflammatory and oxidative factors (systemic processes) drive transition of the extensive plaque burden to the threshold of rupture and thrombosis

CRP and Multiple Plaques in ACS Patients Patients with Multiple Plaques ≥2 (p < 0.001) Percent of Patients CRP Tertile (mg/L) M.N. Zairis et al. Atherosclerosis. 2002;164. 355-359.

CD40L in ACS: 6 Month Risk of Death/MI Variable HR (95% CI) p Age > 65 yr 1.36 (0.91-1.82) 0.34 Diabetes mellitus 1.22 (0.83-1.49) 0.61 ST-segment  1.04 (0.76-1.54) 0.74 Troponin T >0.1 µg/l 2.94 (1.75-7.26) <0.001 C-reactive protein >10.0 mg/l 2.03 (1.11-3.59) 0.02 Soluble CD40 ligand >5.0 µg/l 2.71 (1.51-5.35) 0.001 Heeschen, et al, NEJM, 348:1104 -11, 2003

Courage: Long-Term Survival Free from Myocardial Infarction Event Free Survival (%)

Summary Atherosclerosis is a systemic disease with widespread inflammation and multiple ruptured plaques, not one or two. Platelets, white cells and other systemic factors play an critical role in determining “patient vulnerability.” No imaging technique has shown the ability to reliably predict behavior of individual plaques. Imaging to guide local treatment would require interrogation of all three major epicardial vessels, a practical impossibility. No studies have demonstrated improved outcomes following stenting of “vulnerable plaques.”

Prognostic Value of MPO in Chest Pain Adverse Cardiac Events in Troponin Negative Patients 6 months (n=462) 30 days (n=462) 1.00 Unadjusted Myeloperoxidase Q2 Q2 Adjusted 0.75 0.75 Troponin T Q3 Q3 Sensitivity 0.50 0.50 CRP 0.25 0.25 Q4 Q4 CK-MB 0.00 0.00 2 2 4 4 6 6 8 8 10 10 0.00 0.25 0.25 0.50 0.50 0.75 0.75 1.00 1.00 Odds Ratio 1-Specificity Brennan et al., NEJM 349:1595-604, 2003