Experts deliberate LDL cholesterol goals, statin adherence post-ACS

With the intensity of lipid-lowering therapy in high-risk patients after an ACS an ongoing clinical conundrum, two experts took center stage at the annual American College of Cardiology Scientific Session and reviewed the considerations in context of the IMPROVE-IT trial.

Robert P. Giugliano, MD, SM, FACC, FAHA, and Brendan M. Everett, MD, MPH — both of Brigham and Women’s Hospital and Harvard Medical School in Boston — took their stances, advocating respectively for a decrease in LDL to below 50 mg/dL and for statin adherence without a micro-focus on the numbers.

Lower is better

Robert P. Giugliano

“When we’re treating our high-risk patients with recent ACS or familial hypercholesterolemia, lower is even better,” Giugliano said. “We have lines of evidence from following patients long-term in clinical trials and from looking at the natural history of different populations of humans and animals with various levels of cholesterol.”

He noted that compared to the average cholesterol in animals in the wild or hunter-gatherer societies, people in the United States and many Western cultures actually have two to three times the LDL level necessary for normal functioning.

“In parsing out the data from the IMPROVE-IT trial and also the PCSK9 trials, it looks like one can achieve very low LDL cholesterol levels these days starting with a statin therapy and then adding in ezetimibe — or, if the response is not sufficient, a PCSK9 inhibitor,” Giugliano said. “The evidence to date is that this can be done with relatively very good safety.”

Brendan Everett

He argued that in addition to achieving lower LDL levels — on average 53 in the IMPROVE-IT trial — adding ezetimibe (Zetia, Merck) to statin therapy improves clinical outcomes and emphasized the field is eagerly awaiting data from phase 3 clinical trials of PCSK9 inhibitors to provide more information in that regard.

“I think the numbers do matter. I don’t know whether 40 mg/dL is better than 50 mg/dL, or 30 mg/dL is better than 40 mg/dL, because studies where we target specific cholesterol levels haven’t really been done,” Giugliano said. “But the data so far suggest lower is even better, and that’s what I would recommend for your patients.”

Statins work remarkably well — if patients take them

Statins seem to work quickly in diminishing the risk for recurrent CV events, with reductions seen within 30 days of the event in the PROVE IT-TIMI 22 trial, Everett said. By contrast, those differences took a much longer time to appear in the IMPROVE-IT trial, he noted.

“Getting patients on a high-intensity statin, and helping the patients to adhere to that regimen, ought to be the foremost goal after an ACS,” Everett said.

He highlighted data from the MI FREEE trial, which demonstrated nearly 50% of patients were not taking a statin after experiencing an MI, despite the statin being provided free-of-charge.

“If our focus is on reducing patients’ risk for CV events, how about actually working with them so they can take their statin regularly?” Everett said. “Getting this number to 90% or 100%, rather than 50% would make a huge impact on outcomes.”

He emphasized the importance of taking a broad view of patients rather than focusing so exclusively on an LDL threshold, of communicating to them the prevention benefits of statins and other medications and encouraging them to take their medications as prescribed.

“There is likely more ground to be made up in terms of improving outcomes by working hard with our patients to make sure they can adhere to these recommended therapies than there is by lowering their LDL cholesterol from 65 to 45,” Everett said.

Although it is clear from post-hoc analyses — including of both PROVE IT and IMPROVE-IT — that patients who achieve lower LDL levels do better than those who achieve higher LDL levels on these therapies, he underscored that those analyses are non-randomized, and that residual confounding was likely to explain some of the observed differences. Patients who achieved the lowest LDL thresholds in IMPROVE-IT had additional prognostic signs that might account for their better outcome.

“Investigators do their best, but ultimately it’s very hard to account for all that confounding,” Everett said. “The people who achieve these very low LDLs are less likely to be smokers, to have had a prior MI and to have hypertension. Maybe they are the people who are going to actually take their medication, or they’re younger or they started off with lower LDLs to begin with.”

He also expressed optimism that PCSK9 inhibitors would improve outcomes, but noted that the formal CV endpoint trials are ongoing and it would prove challenging to be as effective as statins in the immediate post-MI period.

“In the background is the development and approval of PCSK9 inhibitors, which I think everybody is optimistic will show event reduction but have not done so yet,” he said. “I worry these newer and sexier agents are available and that patients will just be started on those rather than the tried-and-true ones that have been so successful and had so much demonstrable benefit.” – by Allegra Tiver

Disclosures: Giugliano reports financial relationships with Amgen, Bristol-Myers Squibb, Daiichi Sankyo and Merck. Everett reports financial relationships with Abbot Diagnostics, Novartis and Roche Diagnostics.