For Most Patients, Maximize Oral Lipid Therapy and Skip PCSK9s

Debra L Beck

August 14, 2017

BOSTON, MA — A clear majority of patients can achieve target cholesterol levels with just statins and ezetimibe and do not need to take proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, a new report suggests[1].

Simulation of optimal lipid-lowering treatment in a large sample showed that 86% of patients could be treated to the <70 mg/dL LDL target using just statin intensification (uptitration from atorvastatin 20 mg to 80 mg) and add-on ezetimibe, as needed. After maxing out oral therapies, 14% would require a PCSK9 to get to target.

The researchers also tested other treatment goals and found a similarly low need for PCSK9 inhibitors given optimized oral therapy, although in some of their tested scenarios, the need for PCSK9 inhibitors rose to >30% of patients with atherosclerotic cardiovascular disease (ASCVD).

"Our goal was to better define the need for PCSK9 inhibitors—in part because they are expensive—looking at it according to different guidance and different health systems," said lead author Dr Christopher P Cannon (Brigham and Women's Hospital, Boston, MA) in an interview with theheart.org | Medscape Cardiology.

"What we found was that a lot of people aren't taking the drugs they should be taking," he said. "If we use these lower-cost therapies properly, then only a modest percentage actually need the PCSK9 inhibitor."

The investigators, which included employees from the study's funders, Sanofi and Regeneron Pharmaceuticals, published their findings August 2, 2017 in JAMA Cardiology.

Simulation Cohort

For this analysis, they used the MarketScan Research database to identify a contemporary and representative US cohort of patients with ASCVD (termed the database cohort).

The MarketScan database is a large administrative database of medical and pharmacy claims administered by Truven Health Analytics, a healthcare data and analytics company that is part of IBM's Watson Health unit.

From the 105,269 patients (57.2% male; mean age 65.1 years) with ASCVD identified, 53.2% were receiving statins at baseline and only 25.5% had achieved LDL-cholesterol levels of <70 mg/dL.

ASCVD was defined as a recent acute coronary syndrome, other coronary heart disease, ischemic cerebrovascular disease, or peripheral arterial disease.

"Even though it's fairly well known that people are undertreated, it always blows my mind to see that half of people with a prior MI or stroke aren't taking a statin," Cannon said.

Their base-case simulation assumed treatment was intensified to achieve an LDL cholesterol of <70 mg/dL, first by maximizing statin dosing and then by adding ezetimibe and the PCSK9 inhibitor alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals), as needed.

From this "real" database cohort, a study population of one million patients called the simulation cohort was generated by randomly sampling with replacement (bootstrapping method). The goal was to develop a cohort that matched the proportions of patients across the US with regard to how many have coronary, cerebrovascular, or peripheral arterial disease, making it more representative of the entire US population.

Bootstrapping is a way of estimating statistical parameters, allowing the sampled population to represent a good approximation of the population distribution.

For this study, the large, bootstrap-sampled cohort allowed for multiple replications per individual and the simulation of varied effects of maximal treatment intensification, the researchers say.

"The model is very sophisticated in that it incorporates variability. Each person doesn't achieve the exact same 24% reduction of LDL with ezetimibe, so this method accommodates the distribution of responses," Cannon noted.

In the simulation cohort, before treatment intensification, 51.5% of patients were using statin monotherapy and 1.7% statins plus ezetimibe. Again, only 25.2% achieved an LDL cholesterol level of <70 mg/dL.

All patients not receiving a statin were assigned atorvastatin 20 mg and their subsequent LDL-C was estimated. If further treatment was needed, (ie, they were above the goal) uptitration to atorvastatin 80 mg was done, followed by add-on ezetimibe therapy and then add-on alirocumab (75 mg, uptitrated to 150 mg, if needed).

With just maximum statin monotherapy, 67.3% of patients could be expected to achieve the target LDL level; 18.7% required add-on ezetimibe; and 14% required add-on alirocumab.

Of the 14% of patients who required a PCSK9 inhibition, 12% could reach goal with the lower alirocumab dose, and only 2% required uptitration to the higher dose of alirocumab. After this final step, only 0.7% of the original cohort failed to achieve an LDL cholesterol <70 mg/dL.

Dr Sidney C Smith (University of North Carolina, Chapel Hill) authored an editorial accompanying the study[2].

"The article by Cannon and coauthors, albeit subject to limitations of its simulation design, correctly emphasizes that there is a major opportunity to improve LDL-C treatment results in the ASCVD population using oral-only lipid-lowering therapy and that if stronger efforts are put forward to correctly using these recommended medications, the role for PCSK9 inhibitors in this population could be in the order of 15%," Smith told theheart.org Medscape Cardiology in an email.

While their paper assumed perfect adherence to treatment and no statin intolerance, Cannon's group presented a poster in March at the ACC 2017 meeting that performed similar analyses accounting for full or partial statin intolerance in a proportion of patients. The findings are set to be published soon.

"Assuming full statin intolerance in 5% of patients—meaning you couldn't even take a low-dose statin—and partial intolerance in 10%, we found that we'd only increase the proportion of patients requiring ezetimibe by 0.9% and a PCSK9 inhibitor by 2.5%," Cannon said. "So, it goes from 14% to 16.5% of patients needing a PCSK9 inhibitor."

A Monte Carlo Simulation Study

To be clear, no patients were actually treated to derive these findings. The researchers used a Monte Carlo simulation model applied to a large cohort to determine how many patients with ASCVD would require additional therapy to be considered fully treated.

Monte Carlo simulation is a computerized mathematical technique that allows researchers to build models that perform risk analysis by accommodating a range of possible results for any factor that has inherent uncertainty, like response to treatment.

Besides the base-case analysis, additional analyses were done representing a large range of alternate assumptions: treating to an LDL that is 50% lower than baseline LDL, treating to an LDL goal of <100 mg/dL, and stopping ezetimibe before starting the PCSK9 inhibitor, among others.

They also ran a simulation that increased the threshold for intensification to alirocumab to an LDL cholesterol goal of <80 mg/dL, which would answer, said Cannon, those asking how to manage a patient who achieves a "just-miss" LDL cholesterol of, say, 72 mg/dL on statins plus ezetimibe.

"There is evidence directly from FOURIER to say you will get benefit, which is great, but many clinicians would just sit tight for a patient with an LDL of 72, so we ran the scenario where we only start the PCSK9 at LDL over 80 mg/dL," Cannon explained.

"Of course, the twist here is that FOURIER took the average person down to 30 mg/dL, so 70 is so two generations of trials ago," he said.

They also tested an LDL <55 mg/dL scenario, which increased the need for PCSK9 inhibitors to 31.3%.

ODYSSEY OUTCOMES Still to Come

Smith said that it's important to note that results of the phase 3 ODYSSEY OUTCOMES trial with alirocumab have not yet been presented "and will have an important impact on understanding the true potential role of PCSK9 inhibitors for patients with ASCVD."

Although alirocumab was the PCSK9 inhibitor used in the base-case simulation, the key results also apply to evolocumab (Repatha, Amgen), said the authors.

The findings of the present study are in line with a recent US Department of Veterans Affairs letter published in May that showed without any change in their current lipid therapy, 24.5% of veterans with ASCVD would be eligible for evolocumab treatment using the FOURIER inclusion and exclusion criteria[3]. This would come at an annual cost of $2.08 billion.

However, if high-dose statin and ezetimibe were used, 60% of these would achieve an LDL-C <70 mg/dL, leaving approximately 10% needing a PCSK9 inhibitor. Uptitration of statin therapy and use of ezetimibe would reduce this by about 60% to $838 million.

Cannon noted that this analysis used the list price for evolocumab, which is about double what is actually paid for the drug, so the actual cost would be much lower than the $838 million. His study did not include information on the cost of using a PCSK9 inhibitor to get more patients with ASCVD to goal cholesterol levels.

"We have not heard the end of the discussion about the balance between cost and outcomes for new lipid-lowering therapies," Smith said. "To my way of thinking, a strong focus on better implementation of established therapy with intensive statin treatment must be part of that discussion."

This study was funded by Sanofi and Regeneron Pharmaceuticals. Cannon reported receiving research grants and consulting fees from several pharmaceutical companies, including Sanofi and Regeneron. Disclosures for the coauthors are listed in the paper.

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