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Analysis: PCSK9 inhibitors not cost-effective, could greatly increase US health care costs

PCSK9 inhibitors are associated with substantial LDL lowering and could lead to reductions in MI, stroke and CV mortality in patients with heterozygous familial hypercholesterolemia and atherosclerotic CVD, but they do not meet the threshold for cost-effectiveness, according to a new analysis.

The researchers called the high cost of PCSK9 inhibitors “uniquely challenging … because PCSK9 inhibitors are meant to be lifelong therapy not only for the relatively small number of patients with [familial hypercholesterolemia] but also for a large and growing population with [atherosclerotic] CVD. As a result, the potential increase in health care expenditures at current or even moderately discounted prices could be staggering, despite cost savings from averted [atherosclerotic] CVD events,” Dhruv S. Kazi, MD, MSc, MS, from the departments of medicine, epidemiology and biostatistics at the University of California, San Francisco, and colleagues wrote.

Using the Cardiovascular Disease Policy Model, the researchers evaluated the cost-effectiveness of the two PCSK9 inhibitors approved in the United States — alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen) — as well as ezetimibe (Zetia, Merck) compared with statin therapy in patients with heterozygous familial hypercholesterolemia (HeFH) and atherosclerotic CVD. The 2015 annual PCSK9 inhibitor mean wholesale cost of $14,350 was included in the model. The primary endpoint was the incremental cost-effectiveness ratio over lifetime analytic horizon.

FH analysis

According to the analysis, the addition of ezetimibe to statin therapy for patients with HeFH would result in 214,400 fewer major adverse CV events and add an additional 475,100 quality-adjusted life-years (QALYs) at an incremental cost-effectiveness ratio (ICER) of $152,000 per QALY.

However, adding a PCSK9 inhibitor would result in 316,300 fewer major adverse CV events and 628,500 additional QALYs. The researchers determined the cost of treating all patients with HeFH aged 35 to 74 years during their lifetime would cost $323 billion more than it would to treat them with ezetimibe. With an offset of about $17 billion for a decreased cost of CV care, the net cost would be $503,000 per QALY (80% uncertainty interval, 493,000-1,737,000), according to the researchers.

Atherosclerotic CVD analysis

In patients with atherosclerotic CVD, the addition of ezetimibe to statin therapy would prevent 2.7 million major adverse CV events and produce 5.3 million QALYs at an ICER of $154,000 per QALY, Kazi and colleagues wrote.

With the addition of a PCSK9 inhibitor to statin therapy, an additional 4.3 million major adverse CV events would be averted and an additional 7.9 million QALYs were generated. However, according to the researchers, treatment with a PCSK9 inhibitor would cost $3.3 trillion more during a lifetime in this population than ezetimibe. Despite an offset of $155 billion from averted events, there would still be a net of $414,000 per QALY (80% uncertainty interval, 277,000-1,539,000), Kazi and colleagues wrote.

Multiple scenario analyses suggest that reducing the price of PCSK9 inhibitors is the best way to increase their value, the researchers wrote, noting that if the annual price of PCSK9 inhibitors were reduced by 68% to 70% to $4,536, the cost-effectiveness threshold of $100,000 per QALY could be achieved.

Kazi and colleagues determined that using 2015 prices, use of PCSK9 inhibitors would lower costs of CV care by $29 billion over 5 years but increase prescription drug costs by $592 billion (38%), whereas using statins during the same period in all high-risk patients who could tolerate them would save $12 billion.

“In the face of limited health care resources, payers must consider the potential trade-off between paying for new drug treatments like PCSK9 inhibitors and investing in interventions known to improve access, physician prescription rates and patient adherence to statin therapy among those at high [atherosclerotic] CVD risk,” the researchers wrote.

Study criticized

In a letter to Cardiology Today, Joshua J. Ofman, MD, MSHS, senior vice president of Amgen, wrote that the study “provides an inaccurate portrayal of the value of PCSK9 inhibitors and may be used to support payer policies that make it difficult for patients to access them.”

Ofman wrote that while the FDA mandates that use of the drugs be limited to patients with atherosclerotic CVD or FH, “most … payers assume that all patients with elevated LDL will be treated.”

He also wrote that the study estimate of $120 billion in annual costs added by PCSK9 inhibitors is “around 400 times higher than the 2016 analyst consensus estimates for PCSK9 inhibitors. Compared to other economic analyses, this paper appears to focus on a population at a three to four times lower risk of CV events and uses list prices rather than the prices actually negotiated with payers after rebates and discounts. In addition, the model overestimates the number of patients who will receive PCSK9 inhibitors. … All this inflates the cost estimates.”

He concluded that “health experts must not focus on scare tactics, but rather on how we can collaborate and agree on how to assess value … with the shared goal that patients get access to the medicines they need.”

Sanofi/Regeneron in an email message to Cardiology Today stated that “while we welcome a thoughtful discussion of value, this is the latest in a series of analyses that do a major disservice to patients via dramatically overstated predictions on the cost burden of PCSK9 inhibitors.  In response to these misleading analyses, U.S. health plans have put in place unprecedented utilization management restrictions. Today, approximately 75% of patients prescribed Praluent (alirocumab) injection have been denied access.

“Overall, these analyses are based on a number of invalid assumptions,” the message from Sanofi/Regeneron continued. “The utility measures do not accurately reflect the substantial disability associated with CV events that have been used in previously published cost-effectiveness analyses in the U.S., and the event rates understate the likelihood of events as seen in the real world.  Similarly, there are no formal cost effectiveness thresholds in the U.S. — the literature on these thresholds varies greatly but a more generally accepted baseline threshold is $150,000 per QALY.  The analysis is based on total eligible patients, which greatly exaggerates real-world use of PCSK9 inhibitors; consider that statins, which are effective, oral and generic, are only used by about half of patients who can benefit.” by Tracey Romero and Erik Swain

Disclosure: Kazi reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. Ofman is an employee of Amgen.

PCSK9 inhibitors are associated with substantial LDL lowering and could lead to reductions in MI, stroke and CV mortality in patients with heterozygous familial hypercholesterolemia and atherosclerotic CVD, but they do not meet the threshold for cost-effectiveness, according to a new analysis.

The researchers called the high cost of PCSK9 inhibitors “uniquely challenging … because PCSK9 inhibitors are meant to be lifelong therapy not only for the relatively small number of patients with [familial hypercholesterolemia] but also for a large and growing population with [atherosclerotic] CVD. As a result, the potential increase in health care expenditures at current or even moderately discounted prices could be staggering, despite cost savings from averted [atherosclerotic] CVD events,” Dhruv S. Kazi, MD, MSc, MS, from the departments of medicine, epidemiology and biostatistics at the University of California, San Francisco, and colleagues wrote.

Using the Cardiovascular Disease Policy Model, the researchers evaluated the cost-effectiveness of the two PCSK9 inhibitors approved in the United States — alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen) — as well as ezetimibe (Zetia, Merck) compared with statin therapy in patients with heterozygous familial hypercholesterolemia (HeFH) and atherosclerotic CVD. The 2015 annual PCSK9 inhibitor mean wholesale cost of $14,350 was included in the model. The primary endpoint was the incremental cost-effectiveness ratio over lifetime analytic horizon.

FH analysis

According to the analysis, the addition of ezetimibe to statin therapy for patients with HeFH would result in 214,400 fewer major adverse CV events and add an additional 475,100 quality-adjusted life-years (QALYs) at an incremental cost-effectiveness ratio (ICER) of $152,000 per QALY.

However, adding a PCSK9 inhibitor would result in 316,300 fewer major adverse CV events and 628,500 additional QALYs. The researchers determined the cost of treating all patients with HeFH aged 35 to 74 years during their lifetime would cost $323 billion more than it would to treat them with ezetimibe. With an offset of about $17 billion for a decreased cost of CV care, the net cost would be $503,000 per QALY (80% uncertainty interval, 493,000-1,737,000), according to the researchers.

Atherosclerotic CVD analysis

In patients with atherosclerotic CVD, the addition of ezetimibe to statin therapy would prevent 2.7 million major adverse CV events and produce 5.3 million QALYs at an ICER of $154,000 per QALY, Kazi and colleagues wrote.

With the addition of a PCSK9 inhibitor to statin therapy, an additional 4.3 million major adverse CV events would be averted and an additional 7.9 million QALYs were generated. However, according to the researchers, treatment with a PCSK9 inhibitor would cost $3.3 trillion more during a lifetime in this population than ezetimibe. Despite an offset of $155 billion from averted events, there would still be a net of $414,000 per QALY (80% uncertainty interval, 277,000-1,539,000), Kazi and colleagues wrote.

Multiple scenario analyses suggest that reducing the price of PCSK9 inhibitors is the best way to increase their value, the researchers wrote, noting that if the annual price of PCSK9 inhibitors were reduced by 68% to 70% to $4,536, the cost-effectiveness threshold of $100,000 per QALY could be achieved.

Kazi and colleagues determined that using 2015 prices, use of PCSK9 inhibitors would lower costs of CV care by $29 billion over 5 years but increase prescription drug costs by $592 billion (38%), whereas using statins during the same period in all high-risk patients who could tolerate them would save $12 billion.

“In the face of limited health care resources, payers must consider the potential trade-off between paying for new drug treatments like PCSK9 inhibitors and investing in interventions known to improve access, physician prescription rates and patient adherence to statin therapy among those at high [atherosclerotic] CVD risk,” the researchers wrote.

Study criticized

In a letter to Cardiology Today, Joshua J. Ofman, MD, MSHS, senior vice president of Amgen, wrote that the study “provides an inaccurate portrayal of the value of PCSK9 inhibitors and may be used to support payer policies that make it difficult for patients to access them.”

Ofman wrote that while the FDA mandates that use of the drugs be limited to patients with atherosclerotic CVD or FH, “most … payers assume that all patients with elevated LDL will be treated.”

He also wrote that the study estimate of $120 billion in annual costs added by PCSK9 inhibitors is “around 400 times higher than the 2016 analyst consensus estimates for PCSK9 inhibitors. Compared to other economic analyses, this paper appears to focus on a population at a three to four times lower risk of CV events and uses list prices rather than the prices actually negotiated with payers after rebates and discounts. In addition, the model overestimates the number of patients who will receive PCSK9 inhibitors. … All this inflates the cost estimates.”

He concluded that “health experts must not focus on scare tactics, but rather on how we can collaborate and agree on how to assess value … with the shared goal that patients get access to the medicines they need.”

Sanofi/Regeneron in an email message to Cardiology Today stated that “while we welcome a thoughtful discussion of value, this is the latest in a series of analyses that do a major disservice to patients via dramatically overstated predictions on the cost burden of PCSK9 inhibitors.  In response to these misleading analyses, U.S. health plans have put in place unprecedented utilization management restrictions. Today, approximately 75% of patients prescribed Praluent (alirocumab) injection have been denied access.

“Overall, these analyses are based on a number of invalid assumptions,” the message from Sanofi/Regeneron continued. “The utility measures do not accurately reflect the substantial disability associated with CV events that have been used in previously published cost-effectiveness analyses in the U.S., and the event rates understate the likelihood of events as seen in the real world.  Similarly, there are no formal cost effectiveness thresholds in the U.S. — the literature on these thresholds varies greatly but a more generally accepted baseline threshold is $150,000 per QALY.  The analysis is based on total eligible patients, which greatly exaggerates real-world use of PCSK9 inhibitors; consider that statins, which are effective, oral and generic, are only used by about half of patients who can benefit.” by Tracey Romero and Erik Swain

Disclosure: Kazi reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. Ofman is an employee of Amgen.

    Perspective
    Seth J. Baum

    Seth J. Baum

    There are several ways in which this analysis is flawed. No. 1, the use of $14,350 per patient per year as the cost of PCSK9 inhibitors is wrong. The authors do not consider the many discounts built into the system. There are even value-based contracts that have been created providing not only deep initial discounts for drug, but rebates should the drugs fail to perform as promised. The researchers assume lifelong use of the drug, which is a poor assumption because of new drugs that emerge, patients being unable to tolerate the drug, and other reasons. They also assume constant costs of a drug, which is obviously not true. Interestingly, they also underestimated the LDL-lowering capacity of the medications.

    No. 2, the use of QALYs as the metric for value is flawed. In fact, QALYs are prohibited to be used for drug-policy decisions under the Affordable Care Act. Also, QALYs are considered so flawed by the European Commission Project that they recommend universal abandonment of the construct.

    No. 3, long-term health impacts and social/emotional impacts to families are not considered in the analysis. Imagine the trauma experienced by an adolescent when his mother has a MI or stroke, or even dies during his formative years. A lot of these patients, especially those with familial hypercholesterolemia, have their events when they’re extremely young. Such issues are not considered.

    The Institute for Clinical and Economic Review predicted a $7.2 billion price tag for the PCSK9 inhibitors in their first year on the market. The actual cost will be $83 million, about 1.2% of the prediction. The even bigger question is whether ICER’s predictions actually cause reduced approval of medication, thereby keeping the drugs from those who most need them. I have patients with LDL levels > 300 mg/dL and a history of MI and CABG well before age 30 who have been denied PCSK9 inhibitors. Time is plaque for these people, and I feel comfortable hypothesizing that individuals have died or suffered adverse events as a consequence of inappropriate drug denials. There is a lot of misrepresentation of the costs of these drugs, and of why the costs are high, and this is causing a lot of problems in health care.

    It is very difficult to create an honest cost-benefit scale. Currently, there is not one that is agreed on. Tom Frieden, MD, who was director of the CDC in 2013, stated that “even one preventable death is one too many.” You could thus argue that we cannot and should not place a monetary value on a life. Still, if we try to examine cost-effectiveness, we must include many aspects that have not been considered, such as the social, economic, and emotional effects an event has on not only the victim but also his or her family. 

    We need to create true transparency. I’d like to see how pharmacy benefit managers get rebates and how much money drugs really cost. I’d like to understand the impact that current regulations have on impeding innovations. A statistic I read states that a 45-year-old man today has a 3-year longer life expectancy compared with a 45-year-old man in the 1970s. This 3-year advantage has largely been attributed to medical advances. Stifling innovation will dampen our growth and development in the CVD arena. Novel drugs in atherosclerotic CVD have dropped significantly over the past 20 years, largely a consequence of regulatory and financial barriers. We need to understand the relationships between bodies such as the FDA, the Office of Inspector General, the CMS, pharmacy benefit managers and pharmaceutical companies as they relate to and impact drug costs.

    The patient-doctor relationship is being terribly eroded. It used to be sacrosanct; now it’s démodé. It needs to be resurrected. If doctors were simply permitted to follow the FDA’s indications for the PCSK9 inhibitors, we’d be in a much better place. The lack of utilization of the drugs is a consequence of the high rate of denials, not doctors’ need for outcomes data. Also, the 80% to 90% denial rate is a consequence of capricious denials. Compounding the problem, appealing denials is becoming much more difficult. In some states insurance companies are even charging doctors $250 simply to make a second appeal for their patients. This has got to stop.

    • Seth J. Baum, MD, FACC, FACPM, FAHA, FNLA, FASPC
    • Medical Director, Women’s Preventive Cardiology Christine E. Lynn Women’s Health & Wellness Institute Boca Raton Regional Hospital, Florida Affiliate Associate. Professor of Clinical Biomedical Science Dept. of Integrated Medicine, Charles E. Schmidt College of Medicine Florida Atlantic University, Boca Raton Founder and Chief Medical Officer Excel Medical Clinical Trials, LLC President, American Society for Preventive Cardiology

    Disclosures: Baum reports receiving research grants from, consulting for and/or speaking for Aegerion, Amgen, Esperion, Madrigal, Merck, Regeneron and Sanofi.

    Perspective
    Rita Redberg

    Rita Redberg

    I agree with the JAMA analysis. I think we need to have clinically meaningful outcomes data to know what the benefits of the new drugs will be. They were approved on the basis of a surrogate marker, LDL lowering, which does not always predict clinical outcomes, and the prices are too high to be cost-effective in any imaginable scenario. The prices should come down substantially.

    • Rita Redberg, MD
    • Cardiology Today Editorial Board Member Professor of Medicine, Division of Cardiology University of California

    Disclosures: Redberg reports receiving an honorarium for participation in an FDA mock panel for Amgen in April 2015.