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HomeA FocusEvolocumab with statins slashes cholesterol, reduces major CV events

Evolocumab with statins slashes cholesterol, reduces major CV events

Digital illustration of Human heart
Digital illustration of Human heart

Added to statins, the drug evolocumab decreased major cardiovascular (CV) events by cutting bad cholesterol to unprecedented levels, found the FOURIER trial on 27,000 patients. The British Heart Foundation said the findings were ‘a significant advance’.

The international team says the drug could provide added benefit to patients already taking statins by further reducing the levels of low-density lipoprotein (LDL) cholesterol in their blood.

“This is one of the most important trials of cholesterol-lowering since the first statin trial, published 20 years ago,” said Professor Peter Sever, from the National Heart and Lung Institute at Imperial, who led the UK arm of the trial involving 1,500 patients across 75 centres. “Our results suggest this new, extremely potent class of drug can cut cholesterol dramatically, which could provide great benefit for a lot of people at risk of heart disease and stroke.”

In the study, researchers looked at the protective effect of evolocumab on patients in 49 countries, with a history of atherosclerotic vascular disease, who were already taking statins to reduce their cholesterol.

Patients on the trial, who continued to take statins, were chosen to randomly receive either injections of evolocumab – 140mg twice a month, or 420mg once a month – or placebo injections. Almost 14,000 patients were recruited to the treatment arm of the study, receiving the drug over a 48-week period. The primary endpoint of the study was measured as a composite of a number of related conditions such as heart attack or stroke, or death from CVD.

At the end of the treatment period, researchers found that on average, patients taking evolocumab plus statins were able to reduce their LDL cholesterol levels by an average of 59%, from 92mg/dL to 30mg/dL, compared to those taking placebo plus statins.

The group which had received evolocumab experienced fewer primary endpoint events, compared to the placebo arm of the study, with 1,344 (9.8%) compared to 1,563 (11.3%) respectively.

Overall, this equated to a 15% reduction in the risk of serious cardiovascular events for patients taking the drug with statins. The benefits were seen across all sub-types of patients, even in those who started with low levels of cholesterol.

According to the researchers, the findings demonstrate the protective effect of the drug through lowering LDL cholesterol levels, with no significant difference in the occurrence of side effects between the treatment and placebo arms of the study.

“The idea is that the lower you can get your cholesterol, the better. There are a lot of people already on optimal doses of statins who have levels of cholesterol that could be lowered further,” explained Sever. “The question is, if you can lower them further, do you confer additional benefit. The findings show they produce almost the exact predicted benefit from extrapolating from all the other studies – as the cholesterol level goes down, you get increasing protection.” “What this trial shows is that if you achieve these really low levels of cholesterol, you get the additional benefit, and you get that without any apparent adverse effects.”

Evolocumab is a human monoclonal antibody that works by blocking a protein that reduces the liver’s ability to remove LDL cholesterol from the blood, called PCSK9.
The treatment was approved for use in the US in 2016 as an addition to statin therapy and lifestyle changes aimed at lowering LDL cholesterol in some adults with cardiovascular disease.

In the UK, the National Institute for Health and Care Excellence (NICE) has considered the drug for select cases only, such as patients with familial hypercholesterolaemia, a genetic condition that results in high cholesterol levels and which increases the risk of developing coronary heart disease.

Dr Marc Sabatine, from Brigham and Women’s Hospital in Massachusetts and lead researcher on the study, presented the findings at the American College of Cardiology’s (ACC) 66th Annual Scientific Session in Washington. Sabatine said: “These data show that lowering LDL cholesterol beyond current treatment targets confers significant benefits for our patients with cardiovascular disease who are at a high risk of cardiovascular events.

“Given these findings, patients with cardiovascular disease should review their LDL cholesterol with their physicians and discuss whether it should be lowered beyond what they have achieved with diet, lifestyle modifications and statin therapy.”

The research was funded by Amgen Inc, which manufactures evolocumab and licenses the drug under the brand name Repatha.

Abstract
Background: Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain.
Methods: We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years.
Results: At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%).
Conclusions: In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets.

Authors
Marc S Sabatine, Robert P Giugliano, Anthony C. Keech, Narimon Honarpour, Stephen D Wiviott, Sabina A Murphy, Julia F Kuder, Huei Wang, Thomas Liu, Scott M Wasserman, Peter S Sever, Terje R Pedersen

 

Another cardiology meeting, another big prevention trial – and questions abound. Harlan Krumholz, a cardiologist and the Harold H Hines Jr professor of medicine at Yale School of Medicine, writes that people at risk for cardiovascular disease will be wondering about the implications for them. So are the doctors.

Krumholz writes: “For the past couple of years, experts in prevention have debated the merits of two new drugs, evolocumab and alirocumab (known as Repatha and Praluent), that were approved by the US Food and Drug Administration in 2015 for the treatment of high cholesterol.

“These drugs, which emerged from some very clever basic science, were distinctive in that they simulated a favorable genetic variation and produced remarkable reductions in the levels of bad cholesterol.

“The drugs, which are taken by injection rather than by pills, starting raising the question of whether we should be reducing bad cholesterol levels to a range we have rarely been able to achieve previously. Some experts believed that doing so might virtually eliminate cardiovascular disease.

“These drugs engendered a lot of excitement. However, the problem was that they were approved before any major clinical trials had tested their effect on people's risk of disease. The approval was largely based on the ability of these drugs to reduce bad cholesterol, but that does not always translate into a benefit for people. In fact, there is a famous case where a drug, torceptrapib, reduced the bad cholesterol levels by 25% and, surprisingly, the death rate actually increased.

“So the companies producing these drugs pursued studies to test whether the medications improve outcomes – not just lab tests. In these studies, people are given either the drug or a placebo and then monitored over time to see how they affect health.

“The first study evaluated Amgen's evolocumab. The manufacturer-sponsored study, called FOURIER, enrolled about 27,000 people with cardiovascular disease and who were already well treated with statin therapy. The people had an LDL level of about 90 mg/dl when they entered the study and those receiving evolocumab, reduced their LDL levels to around 30 mg/dl. That's right, 30 mg/dl.

“What they found was that evolocumab, over about two years of study, reduced the risk of cardiovascular events, including heart attacks and stroke, by about 15%. For about every 66 people treated, one person avoided one of these events. There was no reduction, however, in the risk of death. No obvious safety concerns emerged from the study.”

So, writes Krumholz, what are people to do now? He says three things worth knowing are first, that the trial represents good, tangible evidence that the drug can reduce risk.

“Many of us have been clamoring for the community to withhold judgment on these drugs until clinical trials are completed. Validating this approach, at the same meeting, a Pfizer trial of a similar drug was ended early after showing some development of antidrug antibodies.

“Clearly, the company did the right thing by testing evolocumab to see whether it would improve outcomes, and the findings were supportive. I am glad to have another tool to offer patients to reduce their risk. In this case, the benefit was shown in people with heart disease whose cholesterol was already well controlled on statin therapy. It is remarkable to be able to lower cholesterol even more and get some benefit.

“Second, the hope that cardiovascular disease would be eliminated by these drugs is dimmed. Although the study is positive, the size of the benefit is less than what many would have predicted based on the change in LDL. Getting people down to an LDL of around 30 mg/dl is extraordinary, but many people in the treatment group still had heart attacks or strokes. Some might have thought that the drug would cut the risk of cardiovascular events in half or even more. It did not.

“Cardiovascular disease is more complicated than just one risk factor. The people in this study had established disease, and it may be that reducing LDL, even to very low levels, cannot turn back time. At least in this study, it did not.

“In the end the drug appears to be an effective agent, but not one that makes history by its dramatic effect on risk. The size of the benefit is about the same as is achieved with statins. That reduction in risk is meaningful – but no new records on risk reduction were set.

“Third, this study raises the issue of pricing and value. The drug has been priced at about $14,000/year – in part on the promise of a dramatic reduction in risk that was anticipated because of its marked effect on lowering cholesterol. Now that we can see what the drug can achieve, a natural question is: What is this amount of risk reduction, on top of statins, worth?

“Also, until now access to these drugs has, for some people, been difficult. In part, this go-slow approach was based on the uncertainty about benefit. It is likely that these issues of pricing and payment will occupy the business of medicine for some time. The issue is critically important because millions and millions of people may be contemplating the use of these medications.”

Krumholz writes that in the end, Amgen should be congratulated for getting the drug to market and conducting a study focusing on what the drug can do for people.

He writes: “The findings were not a home run – but perhaps a solid double. There remain questions about whether the risk reduction would be similar in other populations and whether the injectable approach provides better outcomes because there is no need for people to remember to take pills. And there will be a continuing need to monitor the experience people have with the drug. We do not yet know the long-term effects.

“People, particularly those with high risk or who cannot tolerate statins (even though those people were not in the study), might want to take this news as a good opportunity to have a discussion with their doctor about plans to stay healthy. What can you do with your lifestyle approach? And what medications might supplement your approach? The trial has made that discussion a bit more nuanced.

“In any case, for today, there is reason for everyone to be happy. Patients and doctors have a new drug with evidence of benefit. Insurance companies and other payors can be glad that the benefit gives them an opening to discuss what that size benefit should mean in terms of pricing. And cardiologists can celebrate that they have a new option, but not one that yet makes them obsolete. We do all hope that one day cardiovascular disease will be relegated to the history books. It will just not be today.”

[link url="http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_17-3-2017-11-55-33"]Imperial College London[/link]
[link url="http://www.nejm.org/doi/full/10.1056/NEJMoa1615664"]New England Journal of Medicine abstract[/link]
[link url="http://www.npr.org/sections/health-shots/2017/03/17/520516314/pricey-new-cholesterol-drugs-effect-on-heart-disease-is-more-modest-than-hoped"]NPR report[/link]

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