乌鸦传媒

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WASHINGTON -- Patients with atherosclerosis who had LDL cholesterol levels average 92 mg/dL or higher lowered their LDL by a mean of 59% by adding the PCSK9 inhibitor evolocumab (Repatha) and that reduction reduced their risk of heart attack, stroke and revascularization.

At 2.2 years, the number needed to treat (NNT) to prevent one of those events was 74, a finding that University of Wisconsin cardiologist James Stein, MD, said was "Not a home run, but still an extra base hit."

The Cleveland Clinic's Steve Nissen, MD, called it "a triple."

"As a practicing cardiologist who sees a lot of patients with severe dyslipidemia and/or statin intolerance, I am very excited by these data because I need all the tools I can get to reduce CVD risk, especially for patients with severe dyslipidemia or who can't tolerate statins, " Stein wrote in an email. He said the NNT was "comparable to that seen in other landmark studies like TNT and JUPITER. Indeed, it does for treatment of lipids in coronary artery disease today what TNT did over a decade ago -- it shows us that lower is better and safe in the mid-term."

Those earlier trials were with statins, drugs that even when they were on-patent were much less expensive than evolocumab, which has an estimated annual cost of $15,000 per patient.

The results are not surprising because Amgen, which developed evolocumab and paid for the trial, announced the topline results last month.

That move added to the drum beat of interest leading up to ACC.17 and when Marc Sabatine, MD, of the TIMI Study Group and Brigham and Women's Hospital, finally took the podium to report the findings from the 27,564-patient study, the audience was ready for a grand slam.

And, in fact, the results were good enough for "for all of [third-party payers'] eligible patients who have a heart attack or stroke." Moreover, the company said it would "continue to offer innovative contracts that provide reasonable budget predictability to help address budget impact concerns raised by payers."

FOURIER, as the study is called, was hands-down the most anticipated event on the schedule for the meeting, and as such it was the highlight of the meeting's opening late-breaking clinical trials session.

Yet the question remains: Is it enough to drive uptake of the drug, which was highly touted even in its earliest clinical trials but slow out of the box? Can the findings turn this PCSK9 drug into the blockbuster that many had been predicting since Amgen won FDA marketing approval for it in August 2015?

2% Absolute Benefit

Journal of the American College of Cardiology editor Valentin Fuster, MD, PhD, noted that the trial was positive but he cautioned that relative risk reductions -- 15% for the primary endpoint and 20% for the key secondary endpoint -- while encouraging, should not be the focus of attention. "The absolute benefit was just 2% ... and this is a very expensive drug." Fuster was a co-moderator of the late-breaking trials session.

Steven Ellis, MD, a Cleveland Clinic interventional cardiologist, said he was surprised by how small the absolute difference was. Ellis questioned whether a 1.5%-2.0% absolute difference would be sufficient to influence evolocumab use.

Just moments after the FOURIER findings were reported, the Institute for Clinical and Economic Review (ICER), announced that it would release an updated report on the clinical effectiveness and value of PCSK9 inhibitors in May. An initial ICER review of PCSK9s concluded that "evidence was not sufficient to show that the drugs provided a net health benefit for patients with cardiovascular disease who cannot take statins, or who take statins but have not reached a suitable cholesterol level."

That update will "incorporate the newly released data, including updated economic analyses and value-based price benchmarks."

In FOURIER, mean patient age was 63 and 75% were men. All patients had atherosclerotic cardiovascular disease -- 81% had a history of myocardial infarction, 19% stroke, 13% symptomatic peripheral arterial disease.

At baseline 69% of the patients were on high intensity statin therapy, 30% on moderate intensity statin therapy and 5% were taking ezetimibe.

On average, patients receiving evolocumab reduced LDL by 56 mg/dL and achieved average LDL of 30 mg/dL but some patients "had LDL levels as low as 20 or 25," Sabatine said. Moreover, "the reduction was rock solid ... we seen similar results out to 4 years," he added.

Because it "takes a long time to make unhealthy arteries healthy," Sabatine said it was reasonable to expect that the NNT to prevent one event at 5 years could be in 20-25 range, and the discussant panel assembled for the presentation agreed with that estimate.

Why No Mortality Benefit?

The lack of a benefit for cardiovascular death was a sticking point for some discussants, but Sabatine noted that none of the previous LDL reduction trials demonstrated a mortality benefit and said one reason may be the flip side of advances in cardiovascular treatment.

He pointed out that the study that put statins on the map -- the Scandinavian Simvastin Survival Study (4S) -- was reported in 1994 when the mortality rate after MI or stroke was about 25%. "Today that case rate is about 5%," Sabatine said, which makes it more challenging to demonstrate a reduction in deaths.

Fuster said he was encouraged that "the event lines appear to diverge with time. They are going in the right direction," so he theorized that the 2% absolute benefit might grow to 4% by 4 years and by that time there might also be a measurable mortality benefit. "The future looks brighter than the present," he added.

At baseline, the average LDL was 92 mg/d, but after 48 weeks the median was just 30 mg/d (P<0.001). Patients were randomized to receive 140-mg evolocumab by injection every 2 weeks or a single injection of 420 mg/month or to sham injections.

Even more impressive were the clinical results: Evolocumab reduced the risk of cardiovascular death, stroke, heart attack, hospitalization for unstable angina, or coronary revascularization by compared to placebo, which worked out to a difference of 219 patients, a risk reduction of 15% (P<0.001), but the absolute risk reduction compared to placebo was 1.5% (9.8% of evolocumab patients reached the endpoint vs 11.3% of controls).

A similar benefit was seen for a composite of cardiovascular death, stroke, or myocardial infarction as a secondary endpoint: 816 evolocumab patients achieved the composite endpoint versus 1,013 in the placebo arm (HR 0.80, 95% CI 0.73-0.88, P<0.001).

But the evolocumab benefit was driven by a reduction in heart attacks, revascularization, and stroke, with no difference in mortality, or hospitalization for unstable angina, or worsening heart failure. For that reason, Sabatine said the P values for outcomes should be considered "exploratory."

Stein noted that "these are the lowest lipid levels that have been achieved in a randomized controlled trial, I'm not surprised that it's not a perfect predictive relationship. I also won't be surprised if the investigators present it and say that it is. That devil will be in the details."

Next Hurdle: Insurance Coverage

ACC scientific program chair , called the trials results game changing but, turning to those devilish details, he added, "The question is, is it going to be actually able to change practice. We have to see how patients respond, how practitioners respond, how insurers respond.... A significant portion of this is going to be how it's going to be accepted by insurance."

And with a list price of $14,400 per patient per year, that question for third-party payers will be significant.

During a press conference following the late-breaking presentations, 乌鸦传媒 asked about rumored difficulties in getting third-party payers to cover PCSK9 treatments.

ACC President Richard A. Chazal, MD, medical director of the Heart and Vascular Institute for Lee Memorial Health System in Fort Myers, Fla., called the process "a war of attrition."

"You can't expect a cardiologist who is working 12 hours to spend another 3 hours on the phone to get approval for these drugs," said Roxana Mehran, MD, of Mount Sinai Medical Center in New York. Mehran, who chairs the ACC's Interventional Leadership Council, agreed that it's important to identify the patients who will most benefit from PCSK9 therapy but it is also important to remove the barriers so "when the physician makes a decision to prescribe the drug, the patient can get it."

Asked to cite specific difficulties, Fuster said he had 13 patients that he wanted to put on PCSK9 therapy; "only three were approved." He added that it is easier to get approval for a patient with familial hypercholesterolemia "with an LDL of 190 than it is to get approval for 150 or 160. That is just the way it is."