The verdict is in: PCSK9 inhibition with a monoclonal antibody added to statin therapy reduces cardiovascular events, i.e., myocardial infarction (MI), stroke and coronary revascularization, but not mortality. The presentation of FOURIER with evolocumab at ACC.17 demonstrated that pushing LDL to even lower levels provides benefit. SPIRE-2 with bococizumab also showed a reduction in cardiovascular outcomes. Did they deliver as much as hoped for and are the results sufficient to prod payers to increase approval rates? Cardiologists are already fielding more calls from patients and referring physicians about PCSK9 inhibitors (PCSK9i).

In FOURIER, the 59 percent reduction in LDL, from a baseline LDL of 92 mg/dL to 30 mg/dL, produced a 15 percent reduction in the primary endpoint of MI, stroke, hospitalization for angina, revascularization or cardiovascular death. A 20 percent reduction was gained in the secondary endpoint of cardiovascular death, MI or stroke. MIs were reduced by 27 percent, stroke by 21 percent and coronary revascularization by 22 percent. The mean absolute LDL reduction of 56 mg/dL was sustained.

Many voices were heard during and after the meeting asking if the absolute risk reduction was sufficient to justify the cost of a PCSK9i when there was no signal that it reduced mortality. However, the lack of an effect on mortality may be due to the LDL level at the start of the study and relatively short duration. While some question if there is sufficient added clinical value for the cost, most point out they are optimistic that greater efficacy will be seen with time, because the separation in the curves for LDL was going in the right direction in FOURIER. In the setting of contemporary therapy, it may be difficult to observe the large event reductions in the 30-50 percent range that had been expected.

"The data from FOURIER and SPIRE provide evidence that if we push the envelope and push LDL lower it is safe and provides benefit for our patients." — Donna Polk, MD, MPH, FACC

“The data from FOURIER and SPIRE provide evidence that if we push the envelope and push LDL lower it is safe and provides benefit for our patients,” says Donna M. Polk, MD, MPH, FACC. More treatment options with proven benefit is very valuable, she adds, for patients who qualify, such as those with premature coronary disease who have not achieved sufficient LDL lowering even with maximal statin doses.

Polk notes a PCSK9i is not a panacea to be prescribed for every patient who comes to clinic. Indeed, a study that was just published shows how few patients are on a high-dose statin at six months and two years after an MI – 59 percent and 42 percent had a high level of adherence at both times points in this Medicare population.¹ These data and other reinforce the need to work with patients to be more consistent and adherent with prescribed therapies and to maximize therapies before moving to a new drug.

Prediman K. Shah, MD, MACC, reinforces the need to focus on the fundamentals of optimizing lipid-lowering therapy and lifestyle management. He also points out concerns about the balance between the risk reduction seen in FOURIER and the high cost of the drug, viewing the new PCSK9i as providing a modest, incremental benefit on the background of statins that is dwarfed by the cost. “The number needed to treat of 74 for two years to prevent one heart attack or stroke or cardiovascular death at a cost of about $2 million is a hugely expensive proposition,” he says. It is conceivable that the benefit with the drug will increase with time, and time is also needed to fully understand the safety profile, Shah says, noting that it took more than 20 years to recognize that statins increase the onset of type 2 diabetes in some patients.

"The number needed to treat of 74 for two years to prevent one heart attack or stroke or cardiovascular death at a cost of about $2 million is a hugely expensive proposition." — Prediman K. Shah, MD, FACC

Indeed, the impact of not optimizing therapy has a direct effect on costs. The $2.08 billion annual price tag to the Veterans Administration to treat the 154,823 veterans with ASCVD who meet the FOURIER enrollment criteria is escalated by the substantial under-treatment in the population.² “Half of the patients who qualified for FOURIER in our analysis were not on high-intensity statin therapy,” says Christie M. Ballantyne, MD, FACC. Maximizing therapy would reduce costs substantially. In their model, uptitrating to high-intensity statins reduces the proportion of qualifying patients by 20 percent, adding ezetimibe by 50 percent and combining high-intensity statin and ezetimibe by about 60 percent.

So far, the safety data have been reassuring. In FOURIER, there was no difference between the treatment and placebo group except for injection site reactions that were resolved, and no signal of new-onset diabetes. Cognitive function was not adversely affected by the lower levels of LDL, even down to 25 mg/dL, as shown by EBBINGHAUS, a prospectively planned substudy of FOURIER that was the first scientific exploration of this issue using validated assessment tools, rather than patient or physician reports.

“FOURIER provides new data that achieving even lower LDL numbers bears fruit in reducing events and adds to our knowledge base,” says Alan Brown, MD, FACC. The initial reduction in LDL provided an event reduction very similar with the line of linear reduction in the Cholesterol Treatment Trialists’ Collaboration meta-analysis. Because the curves separate out to infinity with any lipid-lowering drug, Brown notes that the comparison of the FOURIER outcomes with those from trials lasting five years is not appropriate. In FOURIER, the magnitude of the risk reduction increased with time, from 16 percent in the first year to 25 percent in the second year for the secondary endpoint. This fits well with the finding in the GLAGOV trial of atheroma regression and continued benefit with LDL reduction to 20 mg/dL.

"FOURIER provides new data that achieving even lower LDL numbers bears fruit in reducing events and adds to our knowledge base." — Alan Brown, MD, FACC

From a cardiovascular team perspective, the FOURIER results are reassuring that “we’re doing the best for our patients,” when prescribing a PCSK9i for secondary prevention in high-risk patients, and that “we don’t have to fear a low LDL level,” says Margo B. Minissian, PhD, ACNP, AACC.

Data from SPIRE-1 and SPIRE-2 also reinforces the mantra that lower is better and the longer the treatment the greater the benefit. Combined data from these trials with the PCSK9i bococizumab showed that patients who had a reduction in LDL that was greater than the median achieved LDL had a greater reduction in events (25 percent) and that benefit was evident at about 10 months – similar with FOURIER – and accrued with time. In SPIRE-2, there was a 21 percent significant reduction in nonfatal stroke, nonfatal MI, unstable angina requiring revascularization and cardiovascular death.

The development of the humanized PCSK9i bococizumab has been abandoned because of immunogenicity, found in about 15-20 percent of patients, that led to an attenuation in the LDL reduction and cardiovascular outcomes that were similar with placebo. In the six trials in the SPIRE program, the 55.2 percent reduction in LDL at 12 weeks was attenuated to 43 percent at 52 weeks.

The take-home message from these data are loud and clear: the magnitude and duration of lowering LDL reduces the patient’s exposure to its risk and the risk of ASCVD events. In this regard, the percent reduction of LDL from the baseline level is crucial. “The data from these studies open the door again to look at the continuum of lowering LDL and risk,” says Polk. High-dose statins remain the mainstay for LDL reduction, and PCSK9i are an option for very high risk patients with disease progression.

“Following the recommendations in the 2013 ACC/American Heart Association guideline on the treatment of blood cholesterol is a good starting point,” says Brown. Select the right dose of statin based on the patient’s risk, with a goal of achieving at least a 50 percent reduction in LDL in high-risk patients, even for patients starting with a low LDL. If LDL remains high even after a 50 percent reduction, it is reasonable to add non-statin therapy, such as ezetimibe or PCSK9i. This is consistent with the 2016 ACC Expert Consensus Decision Pathway for Non-Statin Therapies for LDL lowering in ASCVD and supported by these new data.

As always, more data are needed, and this will come from the open-label 2-year extension of FOURIER, its subgroup analyses, and the ODDYSSEY OUTCOMES trial with alirocumab, which will have 64 months of follow-up and is expected to be reported in 2018.

"From a cardiovascular team perspective, the FOURIER results are reassuring that we’re doing the best for our patients when prescribing a PCSK9i for secondary prevention in high-risk patients. We don’t have to fear a low LDL level." — Margo B. Minissian, PhD, ACNP, AACC

Key now is the data that will be coming from subgroup analyses from FOURIER to provide insight into whether certain groups of patients are at much higher risk and thus have greater benefit. Planned analyses include patients with coronary disease and diabetes, excess Lp(a) or familial hypercholesterolemia (FH). These data will help define the sweet spot for treatment – the right patient at the right level of risk for benefit. The hope is that a PCSK9i will be reasonably cost effective in patients at the very highest levels of risk.

Costs and Access: The Big Unknowns

Now we know what we didn’t know: cardiovascular events are reduced by a PCSK9i on top of statin therapy. Will this translate to a smoother and faster road to approvals by payers? Brown for one is skeptical, saying payer rejections have been an issue of documentation, not efficacy. If this remains true, this will be disappointing to the medical community which hung its hat on the perception it was about having the evidence from hard outcomes.

Ann Marie Navar, MD, PhD, says FOURIER provided compelling data about preventing events with a PCSK9i, but that she is mindful that “changes are likely to be incremental, and achieving full effectiveness of these therapies requires multiple components including uptake into guidelines, coverage from payers and acceptance of these new therapies by providers.”

The lack of transparency regarding cost is an issue and many related factors remain unknown. There’s also no clinical trial the medical community can conduct to get the answers. The actual cost of a PCSK9i to a specific patient or the health system is not known. The list price of $14,000 annually is generally reported. But, the cost varies by payer depending on the negotiated discounted price.

Navar and colleagues conducted a study of access to PCSK9i. Presented at ACC.17, it showed that 80 percent of prescriptions for PCSK9i are initially rejected by the payer. Ultimately, it is approved in nearly half of patients, but about a third never fill the prescription, presumably because of the high cost to the patient. Although the median time to dispensing was nearly 10 days, it was more than a month for 25 percent of patients.

Two other studies of access had similar findings. Seth J. Baum, MD, FACC, and colleagues reported at ACC.17 results that nearly mirror those from Navar and colleagues. The FH Optimal Care of the US (FOCUS) study just published online by Joshua W. Knowles, MD, PhD, FACC, et al., showed that even patients with presumed FH based on adjudicated claims data had rejection rates of 63 percent for a PCSK9i and nine percent for ezetimibe; 14 percent and 26 percent of approved prescriptions were abandoned.³ In patients with diagnosed ASCVD, the rates of rejection for a PCSK9i and ezetimibe were 58 percent and 8 percent, and rates for abandoned prescriptions were 16 percent and 24 percent.

“We need more than effective new therapies,” says Navar, “we need policies to get these proven and effective treatments to patients – which is true for all novel drugs.” She adds that without a synthesized process for approvals, the brunt of the work will fall on the clinic and there will be utilization management issues. The cost to the health system that is being absorbed for the time for the nurse and clinics for the approval process is often overlooked.

The lack of transparency regarding cost is an issue and many related factors remain unknown. There’s also no clinical trial the medical community can conduct to get the answers. The actual cost of a PCSK9i to a specific patient or the health system is not known. The list price of $14,000 annually is generally reported. But, the cost varies by payer depending on the negotiated discounted price. Anecdotal reports put the price for specialty pharmacies in the $5000-9000 range. In Europe, the list price is lower than the U.S. list price. Another factor is the sway held by the pharmacy benefit managers (PBMs). The numbers are tightly guarded and often subject to confidentiality agreements and it seems difficult to pull back the curtain to understand the costs to best help patients and even to do accurate cost-effectiveness analyses.

Interestingly, at least one insurer, Harvard Pilgrim, is reported to have negotiated a risk sharing deal with the manufacturer, in which they received an additional rebate, on top of their negotiated price if LDL levels are not lowered to the levels in the clinical trials. Also, there is another rebate if the drug is used more than an established level, essentially reducing their cost per prescription.

Another wrinkle in the fabric of trying to optimize treatment of patients who would benefit from a PCSK9i is the unknown of what’s ahead in the health care market in relation to the Affordable Care Act and possible changes to this legislation.

Other issues are the lack of transparency for the criteria used by payers for approval and the lack of uniformity in these criteria across payers – and even within payers. “Variability in rejection rates across different payers and PBMs suggests that factors other than clinical ones contribute to the decision to deny a pre-authorization request,” says Navar.

Clinicians continue to be frustrated by not knowing at the time of prescribing the PCSK9i the cost to that patient, because the formulary varies by payer and so does the patient’s copay and deductible. Equally problematic is the cumbersome pre-authorization forms that differ by payer. Minissian, a board-certified lipid specialist, highlights the value of adding her credentials to appeal letters and the need for stringent documentation and a streamlined pre-authorization process.

Many experts suggest a focus on obtaining uniform approval criteria and uniform pre-authorization forms. Navar encourages the clinical community to have a bigger voice on this issue and notes that the ACC is working to help address issues of access. “The current approval process is a very blunt instrument for discriminating appropriate from inappropriate prescriptions,” says Navar. “We have the capability to create a better system, but we need to be more vigorous in calling for it.”

"We need more than effective therapies, we need policies to get these proven and effective treatments to patients — which is true for all novel drugs." — Ann Marie Navar, MD, PhD

Baum and colleagues recommend the adoption of a simple evidence-based form that is uniform and more easily navigable, which will require consensus among payers, along with creating payer websites to expedite the pre-authorization process and case managers for direct and efficient communication between the payer and the physician office.⁴ Other recommendations from town halls held by several leading societies, including the ACC, are summarized in their recent article.

Evolving Strategies to Inhibit PCSK9

Research is underway for other strategies to inhibit PCSK9, some that are not a monoclonal antibody, and if effective may help to address the cost issue.

One approach, using a small interference RNA to block PCSK9 called inclisiran, was shown in the ORION-1 study to provide significant, dose-dependent and sustained reductions in LDL at 180 days (28-42 percent with one subcutaneous injection) and 240 days (36-53 percent with two injections).

Not only is there the potential that the twice yearly injection of inclisiran is less expensive, but it provides the opportunity for a comprehensive visit every six months to focus on risk modification and review medications, including for diabetes and hypertension, and reinforce lifestyle changes. Ballantyne suggests along with trials to prove the efficacy of a drug, there could be evaluation of the effectiveness of a treatment approach like this. Such an approach could also look at better personalizing treatment to the specific driver of the risk in a patient, whether it be heart failure or diabetes or LDL, etc, and using the range of new treatments available. This refinement of treating the driving risk also will be important because of the costs of these medications.

Bempedoic acid, which reduces cholesterol production higher upstream than HMG-coA reductase and has no effect on the muscles, added to statin therapy is being studied in a phase III trial. Other strategies are targeting triglycerides.

Inflammation continues to be a target to treat the substantial residual risk that remains despite the much lower levels of LDL. Methotrexate is being evaluated in the CIRT trial and canakinumab, an inhibitor of interleukin-1β, is being studied in CANTOS, which may be reported later in 2017.

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References

1. Colantonio LD, Huang L, Monda KL, et al. JAMA Cardiol 2017;April 19:[Epub ahead of print].
2. Virani SS, Akeroyd JM, Nambi V, et al. Circulation 2017;May 2:[Epub ahead of print].
3. Knowles JW, Howard WB, Karayan L, et al. Circulation 2017;April 26:[Eub ahead of print].
4. Baum SJ, Toth PP, Underberg JA, et al. Clin Cardiol 2017;40:243-54.

Read the full May 2017 issue of Cardiology at ACC.org/Cardiology

Keywords: ACC Publications, Cardiology Magazine, ACC17, ACC Annual Scientific Session, American Heart Association, Angina, Unstable, Antibodies, Monoclonal, Case Management, Cholesterol, Cognition, Confidentiality, Consensus, Coronary Disease, Deductibles and Coinsurance, Diabetes Mellitus, Type 2, Disease Progression, Fibrinogen, Follow-Up Studies, Heart Failure, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Hypertension, Inappropriate Prescribing, Injections, Subcutaneous, Insurance Carriers, Life Style, Medicare, Methotrexate, Myocardial Infarction, Patient Protection and Affordable Care Act, Pharmaceutical Preparations, Pharmacies, Plaque, Atherosclerotic, RNA, Small Interfering, Risk Reduction Behavior, Secondary Prevention, Stroke, Triglycerides, United States Department of Veterans Affairs, Veterans

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