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Evolocumab effective regardless of PAD, MI status
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ANAHEIM, Calif. — In two new analyses of the FOURIER trial, treatment with the PCSK9 inhibitor evolocumab reduced CV events in various populations, including those with peripheral artery disease and MI.
Researchers said the analyses demonstrate that evolocumab (Repatha, Amgen) may be appropriate for patients with very high risk.
“We wanted to understand how the drug works and what the effects are in various populations,” Ransi M. Somaratne, MD, MBA, FACC, executive medical director, global clinical development, cardiovascular and metabolic therapies for Amgen, told Cardiology Today. “The FOURIER study included patients at high risk of cardiovascular events, but there are populations inside that population that could be at higher risk. This is an opportunity to better understand how the drug works in these higher-risk patient populations. These analyses have shown us that there are groups of patients who could benefit in particular from aggressive or additional LDL reduction.”
PAD analysis
Marc P. Bonaca, MD, MPH, and colleagues analyzed the treatment effect of evolocumab in 13.2% of the overall FOURIER population with PAD vs. the rest of the participants.
“We know that patients with lower-extremity peripheral artery disease are at heightened risk for major adverse cardiovascular events as well as major adverse limb events,” Bonaca, investigator for the TIMI Study Group, associate physician in cardiovascular medicine at Brigham and Women’s Hospital and assistant professor at Harvard Medical School, said during a presentation. “We know that statins reduce cardiovascular risk in patients with PAD and also the need for peripheral revascularization. In addition, observational studies show a relationship between statin use and lower rates of amputation. But questions remain: For patients with PAD on statin therapy, does further reducing LDL reduce cardiovascular risk? And does lowering LDL further reduce the risk of major adverse limb events?”
For the primary outcome of CV death, MI, stroke, hospital admission for unstable angina, or coronary revascularization, patients assigned evolocumab had reduced risk vs. those assigned placebo regardless of whether they had PAD (HR = 0.79; 95% CI, 0.66-0.94) or no PAD (HR = 0.86; 95% CI, 0.8-0.93; P for interaction = .4), Bonaca said.
There was also no difference in treatment effect for the key secondary outcome of CV death, MI or stroke, which favored the evolocumab group in those with PAD (HR = 0.73; 95% CI, 0.59-0.91) and those without PAD (HR = 0.81; 95% CI, 0.73-0.9; P for interaction = .41), he said.
Absolute risk reductions from evolocumab treatment were higher in the PAD group because of their higher-risk status (primary endpoint, 3.5% vs. 1.4%; key secondary endpoint, 3.5% vs. 1.6%), he said.
Over 2.5 years, the number needed to treat to prevent a primary outcome event was 29 in patients with PAD and 72 in patients without PAD, according to the researchers.
Compared with placebo, evolocumab treatment lowered risk for major adverse limb events (HR = 0.58; 95% CI, 0.38-0.58). This was observed in patients with PAD (HR = 0.63; 95% CI, 0.39-1.03) and those without PAD (HR = 0.37; 95% CI, 0.16-0.88), Bonaca said.
The lower the LDL achieved down to < 10 mg/dL, the less likely a patient was to experience a major adverse limb event (P = .026 for beta coefficient), he said.
For all outcomes, patients with PAD who did not have a history of MI or stroke benefited from being assigned evolocumab, Bonaca said.
“LDL reduction to very low levels should be considered in patients with PAD, regardless of history of MI or stroke, to reduce the risk of MACE and [major adverse limb events],” he said.
MI analysis
In a second analysis, researchers analyzed 22,351 patients from FOURIER with prior MI, stratifying them as follows: recent MI within 2 years or beyond 2 years before baseline; those with one or more than one prior MI, and those with single-vessel disease or multivessel disease.
“We postulated that patients at higher CV risk may derive greater benefit from PCSK9 inhibition,” Marc S. Sabatine, MD, MPH, chairman of the TIMI Study Group and the Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine at Brigham and Women’s Hospital, said during a presentation. “Therefore, within the broad subgroup of patients with prior MI in FOURIER, we investigated who was at higher CV risk and whether they derived greater benefit from PSCK9 inhibition.”
Sabatine and colleagues analyzed the outcome of CV death, MI or stroke based on assignment to evolocumab or placebo in patients with or without one of the high-risk features: MI less than 2 years before baseline, more than one prior MI and multivessel disease.
Overall, those with MI had reduced risk for the outcome of interest if assigned evolocumab (HR = 0.82; 95% CI, 0.74-0.91).
Among those assigned placebo, the outcome of interest occurred more often in those with more recent MI vs. those more distant MI (HR = 1.19; 95% CI, 1.04-1.37), in those with more than one MI vs. those with one MI (HR = 2.04; 95% CI, 1.78-2.35) and in those with multivessel disease vs. those with single-vessel disease (HR = 1.47; 95% CI, 1.27-1.7), Sabatine said. These remained significant after multivariable adjustment.
Assignment to evolocumab benefited both those with more recent MI (HR = 0.76; 95% CI, 0.64-0.89) and those with more distant MI (HR = 0.87; 95% CI, 0.76-0.99), although the relative risk reduction was twice as large and absolute risk reduction nearly three times as large (2.9% vs. 1%) in those with MI less than 2 years prior, he said.
The treatment effect of evolocumab was similar in those with one MI (HR = 0.79; 95% CI, 0.67-0.94; absolute risk reduction, 2.6%) and in those with more than one MI (HR = 0.84; 95% CI, 0.74-0.96; absolute risk reduction, 1.7%), Sabatine said.
Those with multivessel disease derived greater benefit from evolocumab (HR = 0.7; 95% CI, 0.58-0.84; absolute risk reduction, 3.4%) than those without it (HR = 0.89; 95% CI, 0.79-1; absolute risk reduction, 1.3%), according to the researchers.
Among all patients with at least one high-risk MI feature, evolocumab conferred a 19% relative risk reduction between baseline and 1 year (HR = 0.81; 95% CI, 0.68-0.95) and a 27% relative risk reduction between 1 and 3 years (HR = 0.73; 95% CI, 0.62-0.86), Sabatine said. Extrapolating those data produce a number needed to treat of approximately 20 to prevent one event in 5 years, he noted.
“These patients [with high-risk features] experience substantial relative reductions and absolute risk reductions with intensive LDL lowering with the PCSK9 inhibitor evolocumab,” Sabatine said. “These readily ascertainable clinical features offer one approach to tailoring therapy for our patients.” – by Erik Swain
References:
Bonaca MP, et al.
Sabatine MS, et al. LBS.02 – Late-Breaking Science in Prevention. Both presented at: American Heart Association Scientific Sessions; Nov. 11-15, 2017; Anaheim, California.
Bonaca MP, et al. Circulation. 2017;doi:10.1161/CIRCULATIONAHA.117.032235.
Disclosure: The study was funded by Amgen. Bonaca reports he receives consultant fees from Aralez, AstraZeneca, Bayer, Merck and Roche Diagnostics. Sabatine reports be receives consultant fees from Alnylam, Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, Esperion, Intarcia, Ionis, Janssen Research and Development, The Medicines Company, MedImmune, Merck, MyoKardia and Novartis. Somaratne is an employee and shareholder of Amgen.
Perspective
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Sripal Bangalore, MD, MHA, FACC, FAHA, FSCAI
These are very important analyses. In recent months, there have been a number of cost-effectiveness analyses showing that full-price PCSK9 inhibitors at $14,000 per year, even at the discounted price at $10,000 per year, will only be cost-effective if they are used to treat the highest-risk patients, ie, patients in the range of 8% to 10% annual risk for CVD. That is a 2.5-times higher risk than seen in the overall FOURIER cohort.
The analysis of prior MI implies that if you treat the highest-risk group of patients, you are maximizing the benefit; the number needed to treat is much lower than in the overall FOURIER cohort.
I was even more intrigued by the PAD analysis. The researchers showed that if you have PAD, the benefit of evolocumab is much larger and the number needed to treat is much lower. But what intrigues me most is that even in patients with PAD and no CAD, there is a benefit, which is not just CV protection, but also protection from limb-related events. That’s very compelling.
That being said, the higher-risk groups in FOURIER only translate to around 5% to 6% annual risk for CVD. It still does not meet 8% to 10% annual rate we need for the medication to be cost-efficient. This is a topic that needs to be discussed and debated.
Perspective
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Martha Gulati, MD, MS, FACC, FAHA, FASPC
We have a lot of questions about who should be getting PCSK9 inhibitors. Obviously we want to use them and advocate for them, but ideally I would like to see them come down in cost. Until they do, we have to consider in whom are we getting the greatest bang for the buck. In terms of saving lives, we should use them in the highest-risk groups.
One analysis looked at who had had an MI: their specific characteristics such as how recent was the MI, how many MIs a patient had and whether there was multivessel disease. In all of those groups, the researchers found greater benefit from use of evolocumab vs. placebo. Sixty-three percent of the population had at least one high-risk feature. Since FOURIER was positive overall, it was not surprising that it was also positive in those with high-risk features, since they made up so much of the population. What’s important is that there was a 2% absolute risk reduction for 2 years, and the number needed to treat for 5 years to prevent one event was 20. Those numbers are powerful and enhance what we know about FOURIER and the impact of this drug in addition to optimal medical therapy.
However, a very compelling argument is needed to use a very expensive drug. I was hoping for a cost-effectiveness analysis, but we did not see it. We should be working with these companies to make these drugs more affordable to justify their use until someone convinces me that the cost is worth it. That has been the most difficult aspect of these medications. We can write prescriptions for them, but when they get denied, it makes it look like we’re withholding something from a patient. More often, it’s the commercial payers, not Medicare, that are pushing back. We have more work to do to convince insurers that using this drug is effective and will save lives.
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