Vulnerable Plaque: The Paradigm That Failed

Is it a hallowed paradigm or a hype-othesis?

The “holy grail” of cardiology is to stop heart attacks before they happen by identifying– quickly, noninvasively, and specifically– those coronary artery lesions that result in heart attacks.

The key theoretical underpinning driving this goal has been the vulnerable plaque hypothesis, which holds that the vast majority of heart attacks don’t stem from big obstructive blockages in the coronary arteries. Instead, the main precipitating event is the rupture of a thin blood clot sitting on top of an intermediate sized lipid-rich lesion.

But the vulnerable plaque hypothesis is in big trouble. After more than 20 years its proponents have little to show for their work. At the CRT2016 meeting the interventional cardiology community expressed broad support for continuing the vulnerable plaque quest, . But Steven Nissen (Cleveland Clinic), a well-known bubble buster, told the interventionalists that the underlying vulnerable plaque hypothesis is really a “hype-othesis,” with no real chance of ever achieving anything close to its stated goals.

And Nissen is not the sole dissenting voice.

The united front backing vulnerable plaque ruptured with the publication of an editorial last summer in European Heart Journal by one of the originators of the vulnerable plaque hypothesis, Peter Libby (Brigham & Women’s Hospital).

Another skeptic is Renu Virmani, MD, who has often assumed the role of informing cardiologists, and especially interventional cardiologists, about truths they would rather not hear. (Most spectacularly she was the first to warn that drug-eluting stents would not be the miraculous cure for restenosis as had been initially hoped.) At CRT2016 she told me that she thinks it’s important to perform basic research to try to elucidate how and where heart attacks take place. But, she said , it’s far too early to perform clinical trials seeking to validate specific technologies.

In his talk at CRT2016 Nissen delivered a scorching attack on the vulnerable plaque hype-othesis.
He recited a litany of imaging techniques that over the years have been touted as being able to identify vulnerable plaque, including, among others, thermography, spectroscopy, palpography, virtual histology, OCT, and NIR. The result: “A large number of startup companies with ‘breakthrough’ approaches have come and gone, leaving investors with empty pockets, but no progress.”

The problem isn’t because of the deficiencies of any one technology, said Nissen. Instead, there’s “something wrong with the whole notion.” The problem is that the “exact characteristics of vulnerable plaque remain uncertain” and that 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,” said Nissen. But the available evidence now suggests that the type of lesions once thought to be highly specific for heart attacks are, in fact, everywhere, and ruptured plaques are ubiquitous.

This is why stenting individual coronary lesions doesn’t improve outcomes, he argued. By contrast, systemic therapies, like statins and antiplatelets, can improve outcomes.

Nissen proposed a simple explanation for why there has been so much attention paid to vulnerable plaque: “there are a lot of people looking for reasons to put a stent in a patient.”

He acknowledged that vulnerable plaque may play a role but, he asked, “where’s the beef? I want to see the evidence that finding a vulnerable plaque and treating it can lead to improved outcomes.”

Defender of the Faith

James Muller, MD, is one of the founders of the vulnerable plaque hypothesis. He started a company, Infraredx, that uses both near-infrared spectroscopy and intravascular ultrasound to identify vulnerable plaque, which he said is the “most advanced device so far.”

Muller disagreed with Nissen that ruptured lipid cores are ubiquitous. The gold standard of histology demonstrates that these lesions are not everywhere.

Two large trials now underway may help settle the matter, said Muller. The 1,500 patient Lipid-Rich Plaque Study (LRP) will test whether the Infraredx device can predict future events and the 900 patient PROSPECT 2 will test the use of a bioresorbable stent in patients with a vulnerable plaque. But it should be noted that the first study is observational and the second study is not powered to evaluate clinical outcomes.

A Requiem for Vulnerable Plaque

“The ‘vulnerable plaque’ concept … may not represent the contemporary challenge, an unmet clinical need, or a fertile field for future research,” wrote Peter Libby and Gerard Pasterkamp last summer in the European Heart Journal. They argued, like Nissen, that vulnerable plaque lesions are far more prevalent than had been thought earlier, and many of the lesions may not lead to a clinical event.

In addition, there has been a dramatic shift in the risk profile and demographics of coronary patients. As a result there are now fewer patients with large STEMI heart attacks and more patients with smaller non-STEMI heart attacks. But STEMI patients are more likely to have typical vulnerable plaque lesions while non-STEMI patients have different lesions. Widespread statin treatment and other preventive measures may well have contributed to this change by stabilizing plaques, resulting in less plaque rupture, the defining feature of the vulnerable plaque hypothesis, and more superficial erosion of plaque.

What are the implications?

Here are a few thoughts about the broad implications for cardiology if the vulnerable plaque hypothesis is indeed lost:

Interventional cardiology will never be able to do the work of preventive cardiology. Unless lesions are actively causing harm or pose an immediate and verifiable danger there is no reason to intervene.

Advanced imaging technology imaging may have reached its peak of usefulness. There’s no magic way to find the truly high risk individuals.

Lifestyle changes, statins, and diabetes and blood pressure control will continue to be the mainstay of preventive therapy. I am sure there will be many who will want to add PCSK9 inhibitors to this list but at their current cost, even if these drugs are shown to improve outcomes, it is unlikely they will be even remotely cost effective. Just like stents, PCSK9 inhibitors should be deployed cautiously, since most patients will not receive benefit.

Here’s another additional thought that often gets lost in the usual conversation about health and medicine. The failure of the vulnerable plaque hypothesis suggests there are broader limitations or shortcomings to the research enterprise and the medical paradigm. We keep trying– and failing– to treat public health problems with individual medicine. That is an expensive recipe for disaster. Isn’t it possible that the billions of dollars in research into the vulnerable plaque hypothesis would have been better spent on research into public health measures to reduce cardiovascular disease?



  1. James Stein says

    I think this is a bit out of context. In the context of finding the VP and treating it locally – sure, that likely is a lost cause. And I wholeheartedly agree, as do most interventionalists that interventions will never do what prevention can do. But the idea that a plaque has a characteristics that make it prone to rupture and that those characteristics are related to risk factors and inflammatory changes – that’s not a hypothesis. It’s proven. Ample data from the same people quoted above support it. So in the very narrow window of the TCT audience, sure it might be on life support. But in patients, multiple animal, pathological, and population based studies already have proven the point. The hypothesis is not in trouble – just our hope to treat it locally when systemic treatments are in order. Lifestyle and medical interventions in individual patients and populations prevent and treat these vulnerable plaques. Indeed, the concept of a vulnerable patient might be more fitting, but in the end, its vulnerable plaques that rupture, and vulnerable vessels that erode, thrombose, or form plaques.

  2. Henry Greenspan says

    A patient perspective–whether or not a stent I received will, in itself, lead to a different longer term outcome is unknowable. But there is no question that the elimination of stable angina that followed the procedure led to my exercising more vigorously, more regularly, with less discomfort, and with less anxiety. The distinction between intervention and prevention is, in this and other ways, more nuanced than it may seem.

    • Larry Husten says

      Excellent point, Henry. In stable angina stents definitely have an important role to play in SOME patients for the relief of symptoms. The problem is that even in this post-COURAGE era many patients still believe that they have received life-saving therapy. I wonder where they got that idea?

  3. Dear Mr. Husten,

    On behalf of SHAPE, I would like to submit the following to your readers:

    First, please take a moment and turn your clock back 12 years and 8 months to see this just published Circulation article:

    From Vulnerable Plaque to Vulnerable Patient: A Call for New Definitions and Risk Assessment Strategies: Part I and II

    Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS, de Korte CL, Aikawa M, Airaksinen KE, Assmann G, Becker CR, Chesebro JH, Farb A, Galis ZS, Jackson C, Jang IK, Koenig W, Lodder RA, March K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A, Boerwinkle E, Ballantyne C, Insull W Jr, Schwartz RS, Vogel R, Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT.
    Circulation. 2003 Oct 14;108(15):1772-8.
    PMID: 14557340

    Then fast forward three years and five SHAPE symposia to see Part III:

    From Vulnerable Plaque to Vulnerable Patient—Part III: Executive Summary of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force Report

    Naghavi M, Falk E, Hecht HS, Jamieson MJ, Kaul S, Berman D, Fayad Z, Budoff MJ, Rumberger J, Naqvi TZ, Shaw LJ, Faergeman O, Cohn J, Bahr R, Koenig W, Demirovic J, Arking D, Herrera VL, Badimon J, Goldstein JA, Rudy Y, Airaksinen J, Schwartz RS, Riley WA, Mendes RA, Douglas P, Shah PK; SHAPE Task Force.
    Am J Cardiol. 2006 Jul 17;98(2A):2H-15H.
    PMID: 16843744

    Despite citation stats showing that these articles have been cited and downloaded over 50,000 times, early detection of the vulnerable patient is yet to be viewed a top priority and adopted by our healthcare policymakers and payers. Of course, we do not yet have an accurate method of identifying the vulnerable patient (asymptomatic high risk individuals who will have an event in the next 12 months). However, out of existing modalities it is now abundantly clear that detection of coronary calcification and carotid or femoral plaque can bring us as close to the detection of the vulnerable patient as we possibly can in today’s clinical medicine. Nonetheless, our payers continue to pay for vulnerable plaque detection (IVUS, OCT, NIRS, etc) to (possibly) prevent a second or third heart attacks (too little too late) but do not pay for vulnerable patient detection to prevent the first heart attack, perhaps because compared to coronary intervention, primary prevention is not “sexy” enough! Despite so much talk about “an ounce of prevention” being better than a pound of cure, it receives pennies versus tens of pounds spent on secondary prevention. And perhaps because our healthcare system is wrongly named healthcare. It does not pay for health care, only for sick care. What a misnomer!

    In short, and in a Monday night quarterbacking remark, the answer to your question is yes, the money spent on identifying “the vulnerable plaque” could have given us more return had we broadened our view and spent it on identifying “the vulnerable patient”.

    However, we should not disregard the hard work of so many outstanding pathologists, cardiologists and other cardiovascular researchers on whose shoulders we are now standing tall to see the emergence of Machine Learning algorithms for identification of the Vulnerable Patient. This is indeed the subject of a fascinating “Brave Idea” from SHAPE supported by the following investigators submitted to Google-AHA-AstraZeneca’s 1 Team 1 Vision initiative for the eradication of heart attacks:

    Juan Badimon (Mount Sinai), Daniel Berman (Cedars-Sinai), Michael Blaha (Johns Hopkins), Mathew Budoff (Habor UCLA), Axel C. P. Diederichsen (Odense University Hospital), Raimund Erbel (University Hospital Essen), Erling Falk (Aarhus University), Sergio Fazio (Oregon University), Harvey Hecht (Mount Sinai), Karl-Heinz Jöckel (University Hospital Essen), Ioannis Kakadiaris (University of Houston), Stanley Kleis (University of Houston), Robert Kloner (HMRI), Harry de Koning (ROBINSCA), Tatiana Kuznetsova (University of Leuven), Daniel Levy (Framingham Heart Study), Jes Lindholt (Odense University), Amir-Abbas Mahabadi (University Hospital Essen), David Maron (Stanford University), Ralph Metcalfe (University of Houston), Susanne Moebus (University Hospital Essen), Martin Mortensen (Aarhus University), Tasneem Z. Naqvi (Mayo Clinic), Khurram Nasir (Baptist Health), Christopher O’Donnell (NIH), Ulla Roggenbuck (University Essen), Paolo Raggi (University of Alberta), James Rudd (University of Cambridge), PK Shah (Cedars-Sinai), Henrik Sillesen (University of Copenhagen), Robert Superko (Institute of Lipids & Genetics), Hiro Tanaka (University of Texas), Herman Taylor (MSM), Nathan Wong (UC Irvine). And Dr. Valentin Fuster who has strongly supported the move from Vulnerable Plaque to Vulnerable Patient.

    I will be happy to share with your readers our Brave Idea in details as soon as we hear from the administrators of One Brave Idea.

    Thank you for promoting discussions on primary prevention.

    Morteza Naghavi, M.D.
    Society for Heart Attack Prevention and Eradication (SHAPE)

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