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Managing Cholesterol With PCSK9 Inhibitors and Overcoming Operational Challenges in Practice


Panelists discuss what PCSK9 inhibitors are, the evidence to support them, and challenges with operationalizing them in practice.

Recent trials have cemented evidence that PCSK9 inhibitors reduce cardiovascular events and fewer prescriptions are being rejected by health plans, according to panelists at a session hosted by The American Journal of Managed Care® and Pharmacy Times Continuing Education at the Academy of Managed Care Pharmacy (AMCP)’s Managed Care and Specialty Pharmacy Annual Meeting.

Ty J. Gluckman, MD, FACC, FAHA, medical director, Center for Cardiovascular Analytics, Research, and Data Science, Providence Heart Institute, led a discussion on what PCSK9 inhibitors are, the evidence to support them, and challenges with operationalizing them in practice with panelists Seth S. Martin, MD, MHS, FACC, FAHA, FASPC, associate professor of medicine, Johns Hopkins University School of Medicine; Joseph J. Saseen, PharmD, professor and vice chair, University of Colorado Anschutz Medical Campus; and Sheila L. Stadler, PharmD, BCPS-AQ Cardiology, CLS, clinical pharmacy specialist, Kaiser Permanente Colorado, and clinical assistant professor, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences.

In 2013, when the first blood cholesterol guidelines came out, the message was that evidence supported statin-based therapy, explained Saseen. However, by 2018 there had been 4 major landmark trials that built off prior knowledge and only 1 of those trials was about statins, the other 3 were about non—statin-based therapies, which gave evidence about where to place non-statin drugs, like PCSK9 inhibitors and ezetimibe in the treatment of patients with cardiovascular risk.

The new guidelines still have the 4 statin benefit groups that are target populations for interventions and they’re now bucketed into primary prevention and secondary prevention. In primary prevention, the overall theory is that lower is better of low-density lipoprotein (LDL) cholesterol. Three of the statin benefit groups fall under primary prevention:

  • Patients with very high cholesterol values of 190 mg/dL and greater. High-intensity statin therapy is recommended.
  • Patients with diabetes.
  • Patients without diabetes who have higher cardiovascular risk.

Patients in this primary prevention group are eligible for not only statin therapy, but also ezetimibe after they have maximized statin therapy.

The high-risk populations with known atherosclerotic cardiovascular disease (ASCVD) are in the secondary prevention group. With this group, patients start with high-intensity statin therapy and if they don’t meet the goal, then that is the indication to go beyond statin therapy. When a patient goes beyond statins, the first option is ezetimibe and there is also clinical information that PCSK9 inhibitors can be used in 2 of the groups: patients with cholesterol of at least 190 mg/dL and those with clinical ASCVD.

Another high-risk condition for cardiovascular events is familial hypercholesterolemia (FH), which is an inherited disorder of very high levels of cholesterol. These patients have elevated levels even at a young age. There are 3 key genes: APOB, LDLR, and PCSK9. There are also 2 types of FH: heterozygous, where the gene is inherited from 1 parent, and homozygous, where genes are inherited from both parents. Homozygous is the more severe type with levels of cholesterol that can get as high as 900 mg/dL or 1000 mg/dL, said Stadler.

Heterzygous FH is pretty common and affects 1 in 250 patients. Once clinicians identify a patient meeting the criteria, it is important to make the patient aware of their FH not only so they know their own risk but also to inform their family members.

“…If we can identify and treat people [with FH] can it reduce overall, not just the morbidity for them, but also costs for the health system, too,” Stadler said.

Treatment for all patients starts with statins, and providers should maximize statin use when it is recommended, Saseen said. Some patients are not on statins yet or they aren’t on them at the right dose. What is the right dose? With perfect adherence on high-intensity statins should result in at least a 50% reduction in LDL cholesterol.

Adherence to statins can be particularly difficult. Real or perceived side effects to statins are the biggest challenge, such as muscle pain, cognitive issues, and elevated liver enzymes, Stadler said.

“If you’re having that shared decision making [conversation] upfront, and talking about it, those are some of the things that rise to the top of patient concerns with side effects, even before starting the medication,” she said.

Clinicians should be aware of these patient concerns and discuss the benefits of statin therapy, as well as what the real incidence of those risks are and whether or not they are reversible, she added.

Martin highlighted the ACC Statin Intolerance App from the American College of Cardiology, which is detailed and includes questions to get a sense of how likely it is that statin intolerance is the cause of the patient’s symptoms. One of the questions is about the timing of when the symptoms started in relation to the statin therapy starting.

“Often if patients are going to have statin-associated muscle symptoms, it happens pretty early on,” he said. “It happens right away or within a week—it happens pretty quickly. And then if they stop [taking statins], [the symptom] goes away.”

Many practices ask these sorts of questions at a surface level, Martin said. It might be as simple as asking if the patient is having any problems and automatically making the decision to stop treatment with statins. In addition, there are a lot of options with statin intensity, so if a patient is having issues with 1 statin, they are likely to tolerate another statin.

Moving beyond statins to look at PCSK9 inhibitors, Martin and Saseen outlined the results from the FOURIER trial of evolocumab and the ODYSSEY Outcomes trial of alirocumab. Both trials took place with patients with ASCVD, although ODYSSEY Outcomes had sicker patients who were closer to their cardiovascular events.

The primary end point in FOURIER was a combined cardiovascular end point that included cardiovascular death, heart attack, stroke, hospitalization for unstable angina or coronary revascularization. There was a 15% relative risk reduction in that end point. In ODYSSEY Outcomes the primary end point was similar to FOURIER but not exactly the same, and it included things like death from coronary heart disease, nonfatal heart attack, and nonfatal stroke. The relative risk reduction was also 15% in ODYSSEY Outcomes.

In FOURIER, the number needed to treat was about 50, Martin said, and Saseen added that it was comparable in the ODYSSEY Outcomes trial.

In FOURIER, there was no reduction in death, although Martin pointed out that the trial was not powered for death and the trial was too short to really see a big benefit there. Similarly, in ODYSSEY Outcomes, the trial was not powered to study just mortality, and the trial ran for a similar length of time.

Pulling apart the data makes it possible to see which patients have “the biggest bang for your buck,” Saseen said, if you stratify patients based on their baseline LDL cholesterol.

“It was clear that patients with higher baseline LDL values at entry, despite their acute coronary syndrome, did seem to have the more robust reductions,” Saseen.

Reports of side effects of both alirocumab and evolocumab were fairly high in both groups, Stadler said, but the side effects were similar between the active drug and the placebo in the trials. Injection site reactions do come up, she said. What she found interesting was that we are now driving LDL cholesterol levels down “lower than we’ve ever seen.” A concern that pops up is if there might be any neurocognitive effects, but there has been no signal of these types of issues, which she said was reassuring.

Martin and Saseen both said that PCSK9 inhibitors are fairly clean treatments because getting rid of PCSK9 isn’t a problem and the drugs don’t really interact with other drugs.

With the evidence of success and the safety of PCSK9 inhibitors outlined, the panel moved on to economic issues and access considerations. When they were first approved, there were challenges with getting patients access to these medications because of the high cost of them.

They came onto the market at $14,000 a year, but that price has come down. First, Sanofi and Regeneron made a deal with Express Scripts for alirocumab to be the preferred PCSK9, which brought down the out-of-pocket costs for Express Scripts’ patients. Then, in October 2018, Amgen reduced the wholesale acquisition cost of evolocumab to $5850. Finally, in February 2019, Sanofi and Regeneron matched the price.

With the price coming down, access seems to have eased. Initially, most requests for PCSK9 inhibitors were rejected. Saseen noted there were rejection rates of about 50% and some reports of reject rates as high as 80%. Some practices were persistent, but other were discouraged and stopped trying to get these prescriptions approved, he said.

In the beginning, Martin’s practice submitted the prescription for prior authorization and expected a rejection, so they had a response ready to go. “We accepted that it would take a lot of effort,” he said. But now, the situation is getting better.

“I would say, if you are in a practice where you tried [to get a PCSK9 prescription approved], and you got frustrated and quit…the waters are better, and now is the time to go after it again,” Martin said.

Newer research is now showing some practices have 90% of requests getting approved, Stadler said. It is important that physicians have clear and comprehensive documentation that show the patient’s diagnosis, if they have clinical ASCVD, any cardiovascular events or recurring events, if they have FH, and the biggest piece is the medication history. Stadler recommends showing what the patient is currently on and what their past adherence rate has been, because this shows that their LDL cholesterol is still at a certain level despite being adherent on recommended therapy.

“So, if you can set up that very clear story on what’s going on, and why the medication is appropriate, I think you have a much higher chance of success of getting it approved,” Stadler said.

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