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IVUS offers insight into causes, treatments for coronary atherosclerosis
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BOSTON — Since its development in the early 1990s, IVUS has revealed a unique coronary picture never seen on an angiogram — one that shows arterial plaque can be present in patients with little to no evidence of carotid stenosis.
That insight, according to Steven E. Nissen, MD, MACC, chairman of the department of cardiovascular medicine at Cleveland Clinic’s Heart & Vascular Institute, continues to have profound implications for CAD and how it is treated.
A series of IVUS trials over the last 13 years have helped establish which therapies ultimately slow the progression of coronary atherosclerosis or even regress the disease, including several trials that have pushed the boundaries of lower LDL targets. Data being presented from two new IVUS trials later this year may offer more answers and even lower LDL targets, Nissen, a member of the Cardiology Today Editorial Board, said.
“When we were looking at coronary angiograms, and we thought we understood the disease,” Nissen said during a presentation at the 11th annual Cardiometabolic Health Congress. “We were looking at truly the tip of the iceberg.”
Instead, what clinicians were seeing on angiogram was “a tiny fraction” of a patient’s disease burden, Nissen said. He cited patients who underwent both balloon angioplasty and IVUS who showed no significant luminal narrowing on angiogram, yet, “as you move through the artery, virtually every slice is just chock full of atherosclerotic plaque.
“You learn that coronary disease is not an intraluminal disease,” Nissen said. “It’s an extraluminal disease. It occurs outside the lumen and about 95% to 97% of all the atheroma in the artery does not appear as an angiographic narrowing.”
The discovery explained another phenomenon, Nissen said. In about two-thirds of men and half of women, the first manifestation of CAD is sudden death or acute MI. If CAD were a disease of progressive luminal narrowing, he said, most patients would have angina before they had an infarction.
“In fact, most of these people don’t have enough stenosis to have angina,” Nissen said. “They just drop dead or have an MI.
“When we come together at a meeting like this to talk about how to treat this disease, it’s important to understand that IVUS has taught us that the burden of this disease is unbelievably huge by the time we see patients with symptoms,” Nissen said.
New LDL targets
There was a time when research suggested that LDL targets should not be lower than 125 mg/dL, Nissen said; however, IVUS data has helped changed the conversation.
In the REVERSAL trial, Nissen and colleagues showed that patients with a mean baseline LDL of 150.2 mg/dL randomly assigned to intensive lipid-lowering therapy (80 mg atorvastatin) saw a greater reduction in LDL at 18 months (mean LDL, 79 mg/dL) vs. patients assigned to moderate lipid-lowering therapy (40 mg pravastatin; mean LDL, 110 mg/dL). IVUS performed at baseline and again at 18 months revealed patients treated with atorvastatin had no change in their atheroma burden, whereas patients treated with pravastatin showed progression of coronary atherosclerosis.
“What we said at the time is, if you can get LDL down to about 80 mg/dL, you can halt the progression of coronary atherosclerosis,” Nissen said. “About 6 months later, the PROVE-IT trial began to shift the argument toward lower LDL [levels].”
Data from several IVUS trials that followed suggest that reducing LDL levels to levels as low as 60 mg/dL results in less progression and more regression of disease, Nissen said, though debate remains regarding what LDL level should be targeted.
“To date, all of the data that we have suggest that reducing LDL to lower and lower levels produces less and less progression of disease and more regression of disease, but the question remains, how low do you go?” Nissen told Endocrine Today. “And right now, we have very good data down to about 60 mg/dL. My own personal view is that it makes sense to treat patients to as low an LDL as can be achieved safely within that range.”
“We’re able to get to levels we could never get to before with combination therapy,” Nissen said in an interview. “And someone has to study it to answer the question about whether it is actually going to produce incremental benefit.”
IVUS data has also revealed what therapies may not work, Nissen said. IVUS data from the trial for the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib (Pfizer) showed that, despite raising HDL by a mean of 61% and decreasing LDL by a mean of 20%, patients assigned the drug in combination with atorvastatin experienced no reduction in coronary atherosclerosis vs. those assigned atorvastatin monotherapy. The trial was halted after an increase was observed in adverse CV events, including death from all causes.
“It’s a mechanism that just has not worked out successfully,” Nissen said. “But at least we know, and now we can move on to other targets.”
New studies, lower targets
At the upcoming American Heart Association Scientific Sessions, Nissen and colleagues will present data from two more IVUS studies, including results from the GLAGOV trial. The double blind, randomized, placebo-controlled study in approximately 1,000 patients analyzed whether ultrahigh-intensity LDL lowering with the PCSK9 inhibitor evolocumab (Repatha, Amgen) will result in a significantly greater change from baseline in coronary atheroma volume vs. placebo in patients receiving maximally tolerated statin therapy.
The intent of the trial, Nissen said, is to treat patients who receive combination therapy to much lower LDL levels than researchers have previously been able to study.
“There are really two principal scientific questions that are going to be addressed,” Nissen told Endocrine Today. “One is, do PCSK9 inhibitors actually slow the progression or reduce the regression of coronary atherosclerosis? We know that statins do, but we haven’t been able to show regression with any other therapy, other than statins, in the 15 or more years that we’ve been doing these trials.
“The secondary question is, what’s the shape of the curve when you go down to LDL levels below about 50 to 60 mg/dL?” he said. “Is it linear? Is it J-shaped? Is there no further benefit below a fixed level of LDL? That isn’t known either. You’ll see the answer in about 5 weeks.” – by Regina Schaffer
Reference:
Nissen SE. Intravascular Ultrasound Insights into the Regression and Progression of Coronary Atherosclerosis. Presented at: Cardiometabolic Health Congress; Oct. 5-8, 2016; Boston.
Disclosure: Nissen reports that his institution receives funding to perform clinical trials from Abbvie, Amgen, AstraZeneca, Cerenis, Esperion, Eli Lilly, Novartis, Novo Nordisk, Orexigen, Pfizer, Takeda and The Medicines Company. He receives no compensation for his participation.