Bring Back LDL Targets Back to Manage Cost and Use of PCSK9 Inhibitors, Says CVS Health

August 21, 2015

WOONSOCKET, RI — CVS Health, a large pharmacy benefits manager with nearly 70 million plan members in the US, is asking the American College of Cardiology and American Heart Association (ACC/AHA) to return to goal-based cholesterol targets to limit the massive costs of the new PCSK9 inhibitors[1].

In a perspective published last week in the Journal of the American Medical Association, Drs William Shrank, Jane Barlow, and Troyen Brennan, all employees with CVS Health, argue the costs of alirocumab (Praluent, Sanofi/Regeneron), which was approved by the Food and Drug Administration (FDA) in early August and is priced at $14,600 per year, and evolocumab (Repatha, Amgen), which is expected to be approved later this month, would dwarf those of high-priced specialty hepatitis-C drugs.

"The $64,000 question, or maybe the $64 billion question, is exactly how many patients are going to go on these medications," Brennan told heartwire from Medscape. "Some of that is going to be related to the views of the cardiology community about how effective the medications are, and obviously a lot of that relates to the guidelines. Given the pricing, we know what they cost now, and we know how many people are on statins, and when you look at those two facts put together, the costs are astounding. It all depends of what fraction of people on statins also go on a PCSK9 inhibitor."

With more than 73 million adults in the US with elevated LDL-cholesterol levels, and with both alirocumab and perhaps evolocumab approved not as a cure but rather a lifelong treatment for managing chronic hypercholesterolemia, the CVS executives argue that "if used broadly, the PCSK9 inhibitors would likely be the most costly class of medications marketed thus far."

The worst-case, doomsday scenario envisioned by CVS? The PCSK9 inhibitors would add anywhere from $100 billion to $200 billion per year in costs to the US healthcare system, a number that includes treating all patients with familial hypercholesterolemia (FH) and severe hypercholesterolemia, statin-intolerant patients, and those with a history of coronary artery disease[2].

CVS is so concerned about the costs of the new PCSK9 inhibitors it has not added alirocumab to any of its formularies. As reported by Reuters last week, CVS will wait until evolocumab is approved before making a coverage decision on either drug. Delaying gives CVS time to see in whom evolocumab is indicated, but the second approval also gives CVS more room to negotiate price discounts with another manufacturer in the picture. Brennan previously said "all bets are off" when it comes to negotiating contracts with either Sanofi/Regeneron or Amgen.

Dr Donald Lloyd-Jones (Northwestern University Feinberg School of Medicine, Chicago, IL), cochair of the guidelines on assessment of cardiovascular risk, expressed sympathy with CVS and other providers about the costs of the drugs. Express Scripts, the largest pharmacy benefit manager in the United States, has also said that the cost of the PCSK9 inhibitors could "wreak financial havoc" on its business.

"There is broad consensus that we need a very thoughtful approach to understanding when these PCSK9 drugs should be used and in whom, particularly given the costs," said Lloyd-Jones. "We have very limited follow-up data. It was enough to get one drug approved, and we're still waiting on the second one, but in the absence of large-scale randomized, controlled clinical trials, we have to reserve these drugs for niche situations."

Given the emergence of PCSK9 inhibitors and the challenge they pose for healthcare payers, CVS believes a reasonable solution is to return to a utilization-management strategy that relies on lipid goals. The lipid goals, such as treating patients to an LDL-cholesterol target of less than 100 mg/dL or less than 70 mg/dL for high-risk patients would help support "rational decision making" about using the PCSK9 inhibitors.

The absence of a clinical target might have made sense when only statins were available, but the therapeutic landscape has changed, according to the company. For example, CVS is worried physicians will misinterpret the guidelines and prescribe the potent LDL-lowering PCSK9 inhibitors to high-risk patients instead of starting with a high-intensity statin. They are also worried about lower-risk patients needlessly receiving the drugs when a generic statin will do.

Brennan said they are supportive of clinical guidelines and the experts' reliance upon evidence-based medicine in making certain recommendations, but the 2013 cholesterol guidelines "probably don't suit us as well as they might have when we just had statins available, especially when we're thinking about things from the point of view of cost of drugs."

As reported by heartwire, the ACC/AHA guidelines moved away from cholesterol targets because there was no scientific evidence to support their use. While there is an abundance of randomized, controlled, clinical-trial data supporting the use of moderate- or high-intensity statins in various patient populations, no outcomes trial to date has taken an approach of titrating medication dosing to achieve a certain LDL level.

Although sympathetic to the issue of cost, Lloyd-Jones doesn't have much compassion for payers lamenting the loss of LDL-cholesterol targets as a utilization-management tool. Used as such a tool, a target LDL would help payers ensure a patient started with a cheaper, generic statin. Only those unable to get to goal with other therapies would be covered for the newer, more expensive PCSK9 inhibitors.

I think it's a slippery slope to say the guidelines need to conform to payer metrics rather than the other way around. Dr Donald Lloyd-Jones

As a metric, the LDL-cholesterol targets lacked scientific evidence, said Lloyd-Jones, so it was essentially measuring the wrong variable. "I think it's a slippery slope to say the guidelines need to conform to payer metrics rather than the other way around," said Lloyd-Jones. "Change the metric, but don't tell us what the evidence says so that your metrics work."

Brennan readily acknowledges the lack of evidence but said physicians continue to fall back on the use of cholesterol thresholds. He points out that various organizations, including the European Atherosclerosis Society (EAS), the American Association of Clinical Endocrinologists (AACE), and the National Lipid Association (NLA) still maintain specific LDL-cholesterol targets.

"From a scientific point of view, it's absolutely correct there hasn't been a randomized controlled trial [RCT] on this issue," said Brennan. "But from the point of view of rational and cost-effective use of medications, it might be that we'd endorse thresholds even though we don't have RCTs around them."

CVS Misreading the Cholesterol Guidelines, Say Experts

The ACC/AHA cholesterol guidelines, which were developed in conjunction with the National Heart, Lung, and Blood Institute (NHLBI), currently identify four major primary- and secondary-prevention patient groups who should be treated with either a high- or moderate-intensity statin, depending on the patient's baseline risk.

Speaking with heartwire, Dr Neil Stone (Northwestern University Feinberg School of Medicine, Chicago, IL), the chair of the guideline writing committee, took issue with CVS's interpretation of the guidelines and its call for bringing back LDL-cholesterol targets. He pointed out that Shrank, Barlow, and Brennan contend the guidelines call for the use of the "most effective therapy" once the patient has been stratified by risk, but statins, most of which are available as generics, absolutely remain first-line therapy, and this is explicitly stated in the guidelines.

"We didn't say lower is better," he said, emphasizing the role of statins as the mainstay of LDL-cholesterol–lowering therapy. "We actually said, lower is better, but it matters how you get there and whether the benefits outweigh the risks for that particular patient."

Stone said the return of LDL-cholesterol treatment targets might have an unintended effect, namely the overutilization of PCSK9 inhibitors. With an artificial target, physicians would strive to get all of their patients to goal without considering the means they used to achieve those LDL-cholesterol levels. Statins have such a strong designation in the guidelines not because they are effective at lowering LDL cholesterol but because of the ample RCT data showing their net benefit in terms of reducing hard clinical outcomes with a low risk of adverse events.

He added that recent studies of alirocumab and evolocumab, which were published in March 2015 in the New England Journal of Medicine and showed significant reductions in LDL-cholesterol levels, would have been ineligible for the guideline literature review because these trials are "not definitive at all." They were too short and lacked hard clinical outcomes to make any expert statement about widespread use, said Stone. The drugs are extremely effective at lowering LDL-cholesterol levels but the outcomes trials, which are ongoing, have not yet been completed.

When you see a large marketing budget, you realize there's going to be a lot of push for broad distribution of the medication. Dr Troyen Brennan

"At present, it is important to note that there are longer-term safety data supporting the use of ezetimibe (Zetia, Merck/Schering-Plough) in the IMPROVE-IT study as an add-on to moderate-intensity statin therapy in very high-risk coronary patients that reduced hard clinical events than there are for the new class of PCSK9 inhibitors," said Stone.

Lloyd-Jones agreed. He also took issue with CVS Health's contention that the lack of targets muddied the LDL-cholesterol treatment waters. For the patient at high risk with a less-than-anticipated response to statins, the patient unable to tolerate the recommended statin intensity, or the patient completely statin intolerant, the guidelines recommend the addition of nonstatin therapy, but that is not a green light for alirocumab or evolocumab.

"When that's the case, the guidelines explicitly say physicians should [preferentially select] drugs that have been shown in RCTs to provide a risk-reduction benefit that outweighs the potential for adverse events."

Dr Mark Creager (Dartmouth-Hitchcock Medical Center, Lebanon, NH), the current president of the AHA, said guidelines are continually evolving and will be updated in the future, as all guidelines are. Such updates will likely include a role for ezetimibe, which demonstrated efficacy in the IMPROVE-IT study. If the large-scale, randomized clinical trials with alirocumab and evolocumab were positive—known as ODYSSEY Outcomes and FOURIER, respectively—then the guidelines would be updated to include a role for those drugs, too.

"The PCSK9 inhibitors are clearly a very effective mechanism at lowering LDL cholesterol using a therapeutic intervention distinct from statins and other cholesterol-lowering medications," said Creager. "I think there's considerable promise with the PCSK9 inhibitors, but keep in mind the outcomes trials are still in progress. Let's see what they show."

He added that if clinical trials were to show a benefit of treating to a specific target, then the guidelines would reflect that, too, but right now there is no such evidence.

Creeping Indications

To heartwire, as well as in their JAMA viewpoint, Brennan and the CVS physicians expressed concern about "indication creep" with alirocumab, especially given the extent of marketing with the drugs. He said that while physicians can argue alirocumab should be used as a niche drug and only for those indicated, widespread advertising for the PCSK9 inhibitors, including at the major cardiology conferences, betrays such an intention.

"You never saw that for a niche drug like lomitapide (Juxtapid, Aegerion Pharmaceuticals), which is used to treat familial hypercholesterolemia," said Brennan. "When you see a large marketing budget, you realize there's going to be a lot of push for broad distribution of the medication."

Stone agrees with Lloyd-Jones and stressed the PCSK9 inhibitors should remain a niche agent, one reserved potentially for specific circumstances. These circumstances include patients with severe heterozygous or homozygous FH where existing statin therapy is not enough to lower LDL-cholesterol levels enough or the stable-CAD patient unable to tolerate a high-intensity statin.

"But even in those patients, you should first add ezetimibe to see where you're at," he told heartwire. "And it should be absolutely clear to everyone that this new class of drug, as exciting as it is, should not be used for lower-risk primary-prevention patients."

The authors are employees of CVS Health. Stone, Lloyd-Jones, and Creager report no relevant financial relationships.


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