FOURIER: Aim PCSK9 Inhibitors at Highest of High-CV-Risk Patients?

November 21, 2017

ANAHEIM, CA — Patients with any of several markers of especially increased CV risk within the secondary-prevention vascular-disease population, a group already considered high risk, have the most to gain from adding expensive proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors to statin therapy, suggests a pair of subanalyses based on the FOURIER trial[1,2].

Those markers include very recent MI, multiple prior MIs, and multivessel (MV) CAD in one of the new reports[1], and peripheral artery disease (PAD)[2] in a separate analysis, both of which were presented here at the American Heart Association (AHA) 2017 Scientific Sessions.

Dr Mark Sabatine

"Clinically, there's heterogeneity among secondary-prevention patients," Dr Marc S Sabatine (Brigham and Women's Hospital, Boston, MA), who presented the former report on the three risk markers, told | Medscape Cardiology.

"With these three simple, readily identifiable features, you identify patients who are at higher baseline risk, and their relative risk reduction is also higher" when given PCSK9 inhibitors on top of statins, he said in an interview. They "offer one approach to tailoring therapy for our patients."

As previously reported, FOURIER randomized more than 27,000 patients with clinical atherosclerotic cardiovascular disease, including a history of MI, ischemic stroke, or symptomatic PAD, to receive evolocumab (Repatha, Amgen) or placebo on top of statin therapy.

The add-on drug was associated with LDC-cholesterol reductions to a mean of 30 mg/dL and, compared with the control group, a 15% decline in risk for a clinical composite end point at 22 months (P<0.001).

The advent of PCSK9 inhibitors has in a way put increased demands on traditional CAD risk stratification based on clinical features. Traditionally, the levels of risk start with a presence of CV disease, followed by "CV-disease plus" when comorbid conditions like diabetes are added, said Dr Jennifer Robinson (University of Iowa, Iowa City), who isn't connected with the FOURIER analyses.

"And now we're talking about 'CV-disease plus-plus,' " she said in an interview, referring to, for example, CV disease plus diabetes but also PAD, multiple prior MIs, very recent MI, or multivessel disease. "That's where these drugs are going to benefit."

"One of the Most Malignant Phenotypes"

In the other FOURIER analysis, the risk of major adverse cardiovascular events (MACE) in patients with PAD but no history of MI or stroke "was higher than in patients with MI or stroke but without PAD," Dr Marc P Bonaca (Brigham and Women's Hospital, Boston MA) said when interviewed.

The addition of PAD to risk-assessment tools for patients with vascular disease "enhances risk tremendously. It's a marker of one of the most malignant atherothrombotic phenotypes, and it should be a marker for more intensive treatment," Bonaca said. He presented the PAD analysis at the AHA sessions and is lead author on its simultaneous publication in Circulation.

The reports from Sabatine and Bonaca are in part a response to ongoing questions about the value of PCSK9 inhibitors like evolocumab, despite their almost unprecedented efficacy as LDC-cholesterol–lowering agents.

"At the end of the day, not all of our patients with CV disease can have these expensive medications," Dr Lynne T Braun (Rush University, Chicago IL) pointed out as assigned discussant following presentations of the two FOURIER reports.

"So I commend these subgroup analyses, because they will help clinicians to really target the use of PCSK9 inhibitors to the patients who will benefit the most."

Robinson agreed that third-party payers might be more likely to cover the drugs and clinicians more likely to prescribe them, if they are aimed at the extra–high-risk subgroups, for whom the number needed to treat (NNT) to prevent clinical events is more favorable for cost-effectiveness.

The high-price challenge that comes with PCSK9-inhibitor therapy is exacerbated "by the perverse reimbursement system in the United States," she said.

Sabatine personally thinks all secondary-prevention patients should be getting LDL-C down to the levels possible with the PCSK9 inhibitors, he said. "And if they cost a penny a day, you would treat everyone."

That not being the case, the subgroup analyses "gives you a way to say that until there's easier, wider availability of the drugs and less resistance by payers to start the drug, then here are patients who enjoy the greatest benefit. Hopefully we can all agree on that and make it easier for physicians to prescribe it for those patients."

Three Highest-Risk Subgroups

About 81% of the FOURIER population, 22,351 patients, had history of MI as their study-qualifying clinical atherosclerotic disease.

Of those, 63% had their MI within the past 2 years, had experienced at least 2 prior MIs, or had "residual multivessel disease," Sabatine reported, leaving 37% in this prespecified analysis without any of those three features.

Of the three "high-risk subgroups" in an analysis solely of the post-MI patients in the placebo group, the risk of CV death, MI, or stroke was highest in patients with multiple prior MIs.

Hazard Ratio (HR) for CV Death, MI, or Stroke by High-Risk Feature in FOURIER
End points *HR (95% CI)
Qualifying MI <2 years ago (vs >2 y) 1.36 (1.18–1.57)
>2 prior MIs (vs 1 prior MI) 1.90 (1.65–2.19)
Residual multivessel CAD (vs no multivessel disease) 1.34 (1.16–1.55)
*P<0.001 for all three features in multivariate analysis adjusting for those features plus demographics, weight, history of stroke or PAD, hypertension, diabetes, smoking status, eGFR, high-intensity statin use, and baseline LDL-C.

Also, of the three high-risk subgroups, those with MV disease showed the steepest reduction in risk for CV death, MI, or stroke from treatment with evolocumab. The 3-year risk reduction was 6% on active therapy for those without one of the high-risk features but 22% for those with at least one of them.

Hazard Ratio (HR) for CV Death, MI, or Stroke for Evolocumab vs Placebo by High-Risk Feature in FOURIER
Presence of high-risk feature HR (95% CI) P
<2 y from most recent MI 0.76 (0.64–0.89) <0.001
> 2 y from most recent MI 0.87 (0.76–0.99) 0.04
> 2 prior MIs 0.79 (0.67–0.94) 0.006
1 prior MI 0.84 (0.74–0.96) 0.008
Multivessel CAD 0.70 (0.58–0.84) <0.001
No multivessel CAD 0.89 (0.79–1.00) 0.055

Pure PAD: An Elusive Risk Predictor

Of the more than 27,000 patients in FOURIER, 3642 (13.2%) had PAD, of whom 1505 had no prior history of MI or stroke. "The biggest take-home message" from the analysis, said Bonaca, is that in the latter group of "pure" PAD patients, there was a 6.3% reduction in absolute risk of a primary end point combining MACE with major adverse limb events (MALE) in patients taking evolocumab vs placebo over 2.5 years, for a "very favorable" NNT of 16 to prevent such events.

The NNT for MACE or MALE in the broader subgroup of all patients with PAD at 2.5 years was 25.

The hazard ratio (HR) for MALE for evolocumab vs placebo over all FOURIER patients was 0.58 (95% CI 0.38–0.88; P=0.0093); and for the composite of MACE and MALE was 0.79 (95% CI 0.72–0.87; P<0.001).

Clinical Outcomes Hazard Ratio [(95% CI), P] for Evolocumab vs Placebo in FOURIER by PAD Status
End points Known PAD n=3642 Without known PAD n=23,922 PAD, no prior MI/stroke n=1505
Primary* 0.79 (0.66–0.94) 0.0098 0.86 (0.80-0.93) <0.001 0.67 (0.47–0.96) 0.0283
MACE 0.73 (0.59–0.91) 0.0040 0.81 (0.73-0.90) <0.001 0.57 (0.38–0.88) 0.0095
MALE 0.63 (0.39–1.03) 0.063 0.37 (0.16–0.88) 0.0197 0.43 (0.19–0.99) 0.042
MACE or MALE   0.73 (0.60–0.88) 0.0014 0.80 (0.72-0.89) <0.001 0.52 (0.35–0.76) 0.0006
*Primary end point=CV death, MI, stroke, hospital admission for unstable angina, or coronary revascularization
MACE=Major adverse cardiac events (MI, stroke, or CV death)
MALE=Major adverse limb events (acute limb ischemia, urgent peripheral revascularization, and major amputation)

Many clinicians may not appreciate that patients with symptomatic PAD but no prior MI or stroke would be at significantly increased risk of MACE, Bonaca observed in an interview. Contributing to the confusion, he said, is that the guidelines are oriented toward high-intensity statins as the way to step up management in patients already on standard statin therapy.

"Because of that, a lot of clinicians think that's enough." But among the 60% of patients in the analysis who were already on high-intensity statins when they entered the study, he said, "there was still a significant reduction in major adverse limb events."

On the other hand, "pure" PAD is probably a misnomer most of the time. Most patients who present with PAD will have systemic atherosclerosis, Dr Neil Stone (Northwestern University, Chicago, IL) told | Medscape Cardiology. But their disease in other vascular systems may go unnoticed until late in the game.

"They have a plethora of risk factors and lots of CAD, but once they have claudication may not present with an MI because they never run fast enough to get angina," he said. That underscores the importance of drug therapy in patients with PAD even in the apparent absence of CV symptoms.

Stone agreed that patients at highest risk for vascular disease, "which includes claudication from atherosclerosis, have the greatest chance of benefit, the greatest absolute risk reduction, from evidence-based proven LDL-lowering therapies."

Sabatine discloses receiving research grants from Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen Research and Development, MedImmune, Merck, Novartis, Pfizer, Poxel, and Takeda; and consulting or serving on an advisory board for CVS Caremark, Intarcia, Janssen Research and Development, MedImmune, Merck, Amgen, Esperion, and Ionis. Disclosures for the coauthors are listed in the abstract. Bonaca reports consulting for Aralez, AstraZeneca, Merck, Bayer, and Roche Diagnostics. Disclosures for the coauthors are listed in the paper. Braun discloses consulting or being on an advisory board for UpToDate. Robinson has disclosed consulting or being on an advisory board for Amgen, Dr Reddy Laboratories, Eli Lilly, Merck, Pfizer, Regeneron, Amarin, AstraZeneca, Esai, Regeneron/Sanofi, Takeda; and receiving research grants from Sanofi. Stone had no relevant financial relationships.

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