WASHINGTON, DC — (Updated with commentary) In addition to significantly lowering levels of LDL-C, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab (Repatha, Amgen) decreased major CV-events risk, according to results from the long-anticipated outcomes trial Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER)[1].

The study, which included more than 27,000 participants with atherosclerotic CVD and already receiving statins, showed that patients who received injections of evolocumab at doses of 140 mg every other week or 420 mg monthly had a 15% reduced risk for the composite of MI, stroke, CV death, coronary revascularization, and unstable angina hospitalization at 22 months compared with those receiving matching placebo (P<0.001).

For a key secondary end point—MI, stroke, or CV death—the study showed a 20% risk reduction for the evolocumab group (P<0.001).

When researchers parsed out the primary composite end point's individual components, the evolocumab-treated patients also had significantly lower risks for MI (P<0.001), stroke (P=0.01), and coronary revascularization (P<0.001). But there were no significant between-group differences for cardiovascular death or death from any cause.

Dr Marc_Sabatine

Still, the treatment "on a background of statin therapy" decreased LDL-C to a mean of 30 mg/dL while decreasing serious outcomes, write the investigators, led by Dr Marc S Sabatine (Brigham and Women's Hospital and Harvard Medical School, Boston, MA). Sabatine presented the results here at the American College of Cardiology (ACC) 2017 Scientific Sessions today, with simultaneous publication in theNew England Journal of Medicine.

When asked for comment, ACC president Dr Richard Chazal (Heart and Vascular Institute for Lee Health System, Fort Myers, FL), told heartwire from Medscape that this large trial has given a huge amount of data "that support the LDL-lowering hypothesis."

But is all this enough to offset the high costs for medications in the PCSK9 class? "I don't know yet," admitted Chazal. "This is an issue that continues to be clinically relevant, and it's a conversation point that all of us have had at this meeting and in practice."

Waiting for a Deep Dive

The US Food and Drug Administration approved evolocumab in 2015, but it did so without results from any trial evaluating hard outcomes. Even before that, there's been a steady clamor from the field for outcome studies for any of the PCSK9 inhibitors.

As reported by heartwire , FOURIER's positive top-line results were released last month. But there's been high anticipation for a deeper dive into the findings.

"These are long-awaited data," said Chazal.

At 1242 sites in 49 countries, the investigators enrolled 27,564 patients (75% men; mean age 63 years) who had baseline LDL-C levels of at least 70 mg/dL (mean 92 mg/dL). All were randomized to receive subcutaneous injections of evolocumab (n=13,784) or matching placebo (n=13,780). Mean follow-up was 2.2 years.

Between baseline and 48 weeks, the "least-squares mean percentage reduction" in LDL-C was 59% for those receiving evolocumab compared with those receiving placebo (P<0.001). In addition, while 87% of the treatment group had a reduction to < 70 mg/dL, 42% had a reduced level of < 25 mg/dL.

"Pushing the Levels"

In the evolocumab group, 9.8% experienced the primary composite end point vs 11.3% of the placebo group (hazard ratio [HR] 0.85, 95% CI 0.79–0.92). Risk reduction increased progressively for the treatment group, from 12% in the first year to 19% at later time points.

The key secondary end point occurred in 5.9% and 7.4% of the groups, respectively (HR 0.8, 95% CI 0.73–0.88). And risk reduction rose for evolocumab from 16% to 25% over time.

These composite findings were also significant for all LDL-C subgroups, including those with the highest baseline level of 126 mg/dL and those with the lowest level of just 74 mg/dL. Interestingly, the latter group's final reduced LDL was 22 mg/dL.

Dr Richard Chazal

"They really pushed it, with [LDL] levels that almost approached those of newborns," added Chazal. "These were really, really low levels."

For individual outcomes, "evolocumab had no observed effect on cardiovascular mortality, and hence P values for other outcomes should be considered exploratory," write the investigators. Still, the HRs were 0.73, 0.78, and 0.79 for MI, coronary revascularization, and stroke, respectively.

"I would remind you that over the past decade, none of the trials of intensive LDL lowering, when compared with patients on moderate-intensity-statin therapy, showed significant reduction in CV mortality—which is thankfully now less common after an acute MI and acute stroke than it had been in the past," Sabatine told attendees during his late-breaking clinical-trials session.

In addition, "as has been well documented in the statin trials, it takes time for LDL cholesterol lowering to translate into a clinical benefit. And we saw the same exact phenomenon in FOURIER," said Sabatine. The risk reduction for fatal or nonfatal MI or stroke was 19% at 1 year and rose to 33% by the end of 3 years.

When safety was evaluated, the only difference in treatment-related adverse events came from injection-site reactions, which occurred at low rates in both groups but a little more in those receiving evolocumab (2.1% vs 1.6%). Also, laboratory results showed that 0.3% developing binding antibodies, while no patient developed neutralizing antibodies.

"These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL-cholesterol levels below current targets," write the investigators. But they add that the relatively short follow-up time was a limitation.

Sabatine reported that an open-label extension trial is being planned for 6000 FOURIER participants to assess long-term safety issues.

"Prohibitively High" Costs

In an accompanying editorial[2], Dr Robert PF Dullaart (University Medical Center Groningen, the Netherlands) called FOURIER a "landmark trial" but echoed concern about the short treatment duration.

"The efficacy, with regard to atherosclerotic cardiovascular disease, of PCSK9-inhibition treatment that is started shortly after an acute event still needs to be determined, as does the efficacy . . . in other categories of high-risk patients," writes Dullaart.

Still, he notes that the FOURIER findings are likely to be added to international guidelines, which will direct clinicians "in the use of this new and expensive class of drugs."

"It's amazing how much time it often takes to try to get clearance for insurance coverage because the cost is so prohibitively high currently," added ACC president Chazal. In 2016, the reported annual cost for evolocumab was $14,100 and was $14,600 for fellow PCSK9 inhibitor alirocumab (Praluent, Sanofi/Regeneron).

Although it's hard to know what insurance companies will decide, "there's no doubt that the ongoing evidence that continues to support the use of agents like this is really starting to add to the pressure to figure out a way to get them paid for," he said.

After Sabatine's presentation, official discussant Dr Pamela B Morris (Medical University of South Carolina, Charleston) said she was "very struck" by the high event rate in the study population, even when LDL-C levels were down to 30 mg/dL. "I think what that says to all of us here in this room is: although LDL cholesterol is etiologic and incredibly important, there are multiple other risk factors. Given the 4.2% event rate per year, we can't take our foot off the gas."

Dr Valentin Fuster

"I am impressed with the way you carried out this study. I am less impressed about the absolute results," said editor-in-chief of the Journal of the American College of Cardiology Dr Valentin Fuster. Still, "I'm most impressed with the curves that were diverging over time. It seems to me that the future is brighter than the present."

Dr Sidney Smith (Universityof North Carolina School of Medicine, Chapel Hill) noted that from a guideline standpoint, he's interested in which is more important: "Is it the percent reduction that is associated with the benefit, or is the range in which LDL is reduced? We labored with that in the 2013 guidelines."

"Based on other analyses that we have done, it appears that the benefit is more closely related to the absolute reduction than the percent reduction. And I think that makes good sense," answered Sabatine. "If this were smoking, we wouldn't want to just reduce it by 50%. We'd want patients to reduce it as low as they could.

"All of the data continue to suggest that LDL is such a powerful risk factor for atherosclerosis, it can be safely reduced to very low levels and the benefit continues to improve," he added.

Blowing Up Guidelines?

Approached for comment about the trial overall, Dr Steven E Nissen (Cleveland Clinic, OH) said that the results were "a big deal," yet about what he expected.

"Like a lot of people who do clinical trials, I think the hard end points of cardiovascular death and stroke and MI are the more important, even though they were listed as secondary," Nissen told heartwire ."What we care about are the irrevocable events," he said, adding that he was impressed with the 20% reduction in the composite key secondary outcome.

He also noted that this was a relatively short-term trial, "so this event reduction was seen relatively quickly, which I think is important. We also saw benefit with incremental LDL reduction, all the way down into the 20s and 30s. And frankly, that blows up the ACC/AHA prevention guidelines."

"In 2013, the guidelines were based on dosing of therapeutics and not based so much on level of LDL. But there's a lot of new science, including this trial, that's been published since then. And there are deliberations going on right now about updates," reported Chazal.

Dr Steven Nissen

"If these drugs were inexpensive, I think they would be used by almost everybody. But because they are expensive, most clinicians are going to be selective. We're going to take the higher-risk patients and treat them," said Nissen.

More discussion on the medication's high cost continued at an afternoon press conference. "This is very expensive, and we can't say everybody will take it now. Instead, we need to be very cautious, and we have to be sure that we identify the right people for treatment," said Fuster.

The risk reduction at 2 years translated to a number needed to treat (NNT) of 74 to prevent a CV death, MI, or stroke. At 3 years, the NNT was about 50, reported Sabatine.

When asked if these NNTs are cost-effective for treating a wider patient population, Sabatine said that a cost analysis is definitely needed.

Is Lower Actually Better?

When asked whether she had any concerns over patients being treated to very low levels of LDL-C for a long time, panelist Dr Roxanne Mehran (Mount Sinai, New York City) told heartwire , "With any kind of treatment that is prolonged and lifelong, you want to make sure that there are no safety issues."

However, "I'm not so concerned about that," said Mehran. "They showed tremendously that the lower the LDL is, the better the clinical outcomes." Could there possibly be a J-curve after a certain level or time period? "I haven't seen it, but I'm always open to watching the data as they come in," she answered.

"I think, overall, that in certain patient populations we're going to have a very good case for these drugs," said Mehran. "The absolute reduction was small for the overall group, but I wonder if it could be a lot larger for certain patients who really are at risk. Hopefully they'll show that analysis at some point."

The study was funded by Amgen. Sabatine reports grants from Abbott Laboratories, Critical Diagnostics, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Roche Diagnostics, Takeda, Gilead, Poxel, Novartis, Janssen Research Development, and Genzyme; grants and personal fees from Amgen, AstraZeneca, Intarcia, Merck, and MedImmune; and personal fees from CVS Caremark, Alnylam, Ionis, Cubist, Esperion, the Medicines Company, MyoKardia, and Zeus Scientific. Disclosures for the coauthors are listed in the paper. Dullaart reported a relevant relationship with Eli Lilly, which measured PCSK9 concentrations for free in about 450 samples. Chazal has reported no relevant financial relationships. Although not involved with FOURIER, Nissen has been involved with other trials that have assessed evolocumab. Mehran reports research grants from Abbott Vascular Research, AstraZeneca, AUM Cardiovascular, Bayer Healthcare Pharmaceuticals, Beth Israel Deaconess Medical Center, Bristol-Myers Squibb, CSL Behring, Medtronic, Novartis Pharmaceuticals, OrbusNeich, the Medicines Company, and Watermark Research Partners; and consultant fees/honoraria from AstraZeneca, Boston Scientific, Cardiovascular Systems, Medscape, Merck, Shaghai BraccoSine Pharmaceutical, and the Medicines Company. Morris, Smith, and Fuster have no relevant financial relationships.

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