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?