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PCSK9 inhibition, atherosclerotic cardiovascular disease, and health economics: Challenges at the crossroads

      Highlights

      • Reduction of LDL-C to recommended goal is critical in very-high-risk patients.
      • Cost vs benefit balance impacts PCSK9 inhibitor use in very-high-risk patients.
      • Timing of initiation of PCSK9 therapy is critical to disease trajectory.
      • Health economics criteria should reflect clinical reality in these patients.
      • Economic models should account for event and treatment sequences and nonadherence.

      Background

      Improved survival after a cardiovascular event has led to an expanding patient population at very high risk of recurrent events. Reduction in low-density lipoprotein cholesterol, and thus implicitly non–high-density lipoprotein cholesterol, to guideline-recommended goals is a key tenet of secondary prevention. Yet, standard-of-care treatment with statin (with or without ezetimibe) often leaves a high risk of preventable cardiovascular events. Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9), highly efficacious lipid-lowering treatments that confer reduction in cardiovascular events and death, clearly have a role in the personalized management of these very-high-risk patients. Given budget constraints, however, their integration into the health care pathway merits health economic considerations. Consequently, it is important to identify challenges at the crossroads of the clinical and economic dimensions.

      Findings and conclusion

      Health economic analyses involve application of modeling scenarios integrating multiple parameters to ultimately yield values for quality-adjusted life-years and cost-effectiveness ratios. To date, these analyses have led to widely variable estimates of these benchmarks for PCSK9 inhibitors, causing confusion among stakeholders in the health care pathway. Clearly, a consensual approach to the conduct and reporting of health economic analyses involving all players, including noneconomists such as clinicians and patient advocates, is essential to bridge the gap between the clinical needs of patients and financial access to PCSK9 inhibition.

      Keywords

      Introduction

      A growing burden of atherosclerotic cardiovascular disease in the era of personalized medicine

      Atherothrombosis, characterized by atherosclerotic lesion disruption with superimposed thrombus formation, is the primary cause of cardiovascular death, the leading cause of mortality worldwide.
      World Health Organization
      Cardiovascular diseases. Fact sheet.
      The burden of atherosclerotic cardiovascular disease (ASCVD) is not, however, confined to mortality. With aging populations, morbidity and disability associated with cardiovascular complications become increasingly relevant. Heart failure is the endpoint of a variety of cardiovascular disease trajectories, key examples being (i) ischemic heart disease in developed regions,
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      and (iii) cerebrovascular accidents; each of these trajectories confers a high risk for hospital (re)admission, polymedication, and interventional procedures. Improved management in the acute MI setting means that a greater proportion of individuals are surviving and thus remain at very high risk of recurrent events.
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      Consequently, ASCVD is not only a health issue but also a major economic burden to society, doubling when indirect costs attributable to loss of productivity among patients and caregivers are incorporated.
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      Renewed efforts are needed to address the burden of ASCVD. Inherent to such efforts is a move to personalized management approaches that allow clinicians to target treatments to patients at highest risk. An urgent priority is to adapt public health approaches to risk estimation to reflect changing patient characteristics; incorporation of the SMART (second manifestations of arterial disease) score, which enables clinicians to differentiate the risk of recurrent events in individuals with clinical ASCVD, is one approach.
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      This will facilitate precise targeting of innovative therapies to individuals at highest risk, in whom the benefits are likely to be commensurate with the cost.
      How can we determine the optimal treatment strategy for patients at highest risk? Stakeholders in the health care pathway include a wide spectrum from patients and carers, to clinical staff and infrastructures (both public and private), pharmaceutical manufacturers, patient advocacy groups, public health system managers (whose mandate may vary across countries), and ultimately organizations involved in meeting the cost of health care (including insurance carriers, third-party payers, health plan sponsors, and national health insurance programs). A critical choice facing payers is between preexisting vs innovative therapies. Such choices involve detailed consideration of both benefit vs harm and benefit vs cost. The classical and recommended approach to address these questions is to perform cost-effectiveness analysis, in which two interventions are compared and the results expressed as a ratio of incremental cost to incremental effect. Cost-effective analyses have contributed substantially to achievement of optimized patient care in a wide range of pathologies. Nonetheless, as recently emphasized by Sanders et al. (2019),
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      there are a number of limitations and qualifications to be taken into account when using cost-effectiveness analyses, several of which were addressed by the Second Panel on Cost-Effectiveness in Health and Medicine in 2016.
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      Moreover, to allow clinicians and patient advocates to understand and interpret the results of such analyses, we believe that improvements can be made in the way cost-effectiveness analyses are presented.
      The aim of this critical appraisal focused on stakeholders involved in the management of patients presenting with ASCVD is to aid identification of the challenges at the crossroads between the introduction of an innovative and efficacious lipid-lowering therapy, in this instance PCSK9 inhibition, with the health economic dimension.

      Clinical challenges in preventing ASCVD by LDL-cholesterol lowering

      The challenges in ASCVD prevention are multi-tiered. From a public health perspective, promotion of cardiovascular health specifically targeting smoking prevention/cessation, diet quality, and physical inactivity is a prerequisite and cost-effective base component of any program; indeed, such a strategy would maintain low cardiovascular risk. Such approaches are feasible to implement on a population basis, are inexpensive, and confer important societal benefits, both in terms of health care cost savings and loss of productivity associated with ASCVD disability and death. It is, however, evident that maintenance of low cardiovascular risk does not eliminate the development of preclinical ASCVD,
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      highlighting the need to target intervention with nonpharmacological approaches as early as warranted.
      In both primary and secondary prevention settings, lowering low-density lipoprotein cholesterol (LDL-C), or the alternative target of non–high-density lipoprotein cholesterol (non-HDL-C), which has the added advantage of capturing the risk inherent to all atherogenic lipoproteins, must be a central part of any program for adults.
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      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.
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      National lipid association recommendations for patient-centered management of dyslipidemia: part 1--full report.
      Support for this is provided both by evidence for the cumulative arterial burden of LDL and by genetic data for the beneficial impact of lifelong exposure to lower LDL-C levels on lifetime cardiovascular risk.
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      Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes.
      One of the major challenges in the primary prevention setting is to identify and treat individuals at the highest risk, including those with familial hypercholesterolemia (FH), before the onset of clinical complications, and non-FH individuals with preclinical atherosclerosis.
      • Fernández-Friera L.
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      • et al.
      Prevalence, vascular distribution, and multiterritorial extent of subclinical atherosclerosis in a middle-aged cohort: the PESA (Progression of Early Subclinical Atherosclerosis) Study.
      Indeed, detection of subclinical carotid or coronary atherosclerosis with noninvasive imaging may be one cost-effective strategy to improve targeting of therapeutic intervention appropriately, with the potential for gains in healthy life years.
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      • Peñalvo J.L.
      • Fernández-Ortiz A.
      • et al.
      Prevalence, vascular distribution, and multiterritorial extent of subclinical atherosclerosis in a middle-aged cohort: the PESA (Progression of Early Subclinical Atherosclerosis) Study.
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.
      • Wiegman A.
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      • et al.
      European Atherosclerosis Society Consensus Panel
      Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      Yet, it is clear that the clinical reality lags far behind what is required.
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      European Atherosclerosis Society Consensus Panel
      Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      For individuals with clinical ASCVD, the major challenge is to reduce the risk of recurrent events and the associated burden of hospitalization, revascularization, and intensive clinical management.
      For both primary and secondary prevention, statins are established first-line therapy for preventing cardiovascular events
      • Collins R.
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      Interpretation of the evidence for the efficacy and safety of statin therapy.
      ; the addition of ezetimibe provides further benefit.
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      • et al.
      IMPROVE-IT Investigators
      Ezetimibe added to statin therapy after acute coronary syndromes.
      Yet, even on optimally tolerated statin therapy, with or without ezetimibe, a proportion of high-risk patients fail to attain guideline-recommended LDL-C goal, in part due to lack of adherence, interindividual variability in treatment response, and/or inability to tolerate statin therapy, in large part due to muscle symptoms.
      • Reiner Ž.
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      Lipid lowering drug therapy in patients with coronary heart disease from 24 European countries--Findings from the EUROASPIRE IV survey.
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      Percent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents.
      • Stroes E.S.
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      European Atherosclerosis Society Consensus Panel
      Statin-associated muscle symptoms: impact on statin therapy-European atherosclerosis society consensus panel statement on assessment, aetiology and management.
      These individuals have unmet clinical needs, requiring additional potent therapeutic options to attain LDL-C goal and thus reduce the risk of recurrent cardiovascular events.
      There is now evidence from randomized controlled trials (RCTs) that new treatments such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors—which lower LDL-C levels on top of intensive statin therapy in patients with clinical ASCVD—can regress atherosclerosis as exemplified by the GLAGOV trial and equally improve clinical outcomes significantly, with no evidence to suggest an LDL-C threshold for clinical benefit.
      • Sabatine M.S.
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      FOURIER Steering Committee and Investigators
      Evolocumab and clinical outcomes in patients with cardiovascular disease.
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      FOURIER Investigators
      Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial.
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      Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial.
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      ODYSSEY OUTCOMES Committees and Investigators
      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
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      SPIRE Cardiovascular Outcome Investigators
      Cardiovascular efficacy and safety of bococizumab in high-risk patients.
      Moreover, the benefit in preventing total nonfatal cardiovascular and fatal events was even greater, of relevance to a longer-term horizon for efficacy from PCSK9 inhibition.
      • Szarek M.
      • White H.D.
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      • et al.
      Alirocumab reduces total Nonfatal cardiovascular and fatal events: the ODYSSEY OUTCOMES Trial.
      The key question, then, is how cost-effective these treatments are, prompting the publication of a slew of analyses with varying conclusions. Some have indicated that the incremental cost of adding a PCSK9 inhibitor is prohibitive without significant discounting,
      • Arrieta A.
      • Hong J.C.
      • Khera R.
      • Virani S.S.
      • Krumholz H.M.
      • Nasir K.
      Updated cost-effectiveness assessments of PCSK9 inhibitors from the perspectives of the health system and private payers: insights derived from the FOURIER Trial.
      • Kazi D.S.
      • Penko J.
      • Coxson P.G.
      • et al.
      Updated cost-effectiveness analysis of PCSK9 inhibitors based on the results of the FOURIER trial.
      • Fonarow G.C.
      • Keech A.C.
      • Pedersen T.R.
      • et al.
      Cost-effectiveness of evolocumab therapy for reducing cardiovascular events in patients with atherosclerotic cardiovascular disease.
      whereas others claimed that incorporation of PCSK9 inhibitor treatment in patients with clinical ASCVD or with heterozygous FH would be below the benchmark or willingness to pay threshold for a quality-adjusted life-year (QALY) gained (typically $50,000 to $100,000/year).
      • Shah P.
      • Glueck C.J.
      • Jetty V.
      • et al.
      Pharmacoeconomics of PCSK9 inhibitors in 103 hypercholesterolemic patients referred for diagnosis and treatment to a cholesterol treatment center.
      • Villa G.
      • Lothgren M.
      • Kutikova L.
      • et al.
      Cost-effectiveness of evolocumab in patients with high cardiovascular risk in Spain.
      These contrasting findings may be due to a number of factors, including the setting (US or a single country in Europe), drug costs, patient characteristics (clinical setting, baseline age, background therapy, and baseline LDL-C levels), the estimated LDL-C and event reductions (either modeled, or based on registry or trial data), the extent to which indirect costs (which are related to productivity losses due to cardiovascular events) were incorporated, and the time horizon and perspective of the health economic analysis. There are health systems around the world, in Australia for example, where the use of this class of drugs in non-FH is only available by private prescription at this stage.
      • Scherer D.J.
      • Nelson A.J.
      • O'Brien R.
      • et al.
      Status of PCSK9 Monoclonal Antibodies in Australia.
      Furthermore, the 2018 ACC/AHA guidelines incorporated an economic value statement for the use of PCSK9 inhibitors (relevant to mid-2018 prices), recommending that they have a low value.
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.
      However, as this interpretation of value is intertwined with pricing, with the decreasing cost of PCSK9 inhibitors, this needs to be reassessed. Ideally, every health economic model should envisage sensitivity analyses on the price of the investigated medicine or technology, so that these analyses do not become invalid as the price changes.
      In addition to questions of pricing, however, clinicians are clearly confused by the different approaches used in these analyses. Is it possible to simplify the health economics modeling to anticipate the projected impact of these innovative treatments on CVD trajectory over a decade or more?

      Health economic challenges of PCSK9 inhibitors

      Health economic models have been used for decades to evaluate the potential economic benefit of innovative agents. Not surprisingly, these models have also been applied in assessment of the value of PCSK9 inhibitors. The prevailing perception among clinicians, however, is that the final cost per QALY seems to have “fallen from the sky.” In large part, this is due to the lack of (i) clear information on the parameters considered essential for integration into modeling scenarios and (ii) the necessary support to explain the results of these assessments. Furthermore, large differences in the results reported for different studies do not generate confidence. Many, many questions emerge when clinicians try to understand and interpret these models, as highlighted below.
      • Is the considered target population a real-life population or clinical trial population? Clinical trial populations are usually more homogeneous than those seen in routine practice due to screening procedures that tend to exclude patients with multiple morbidities, who are likely to be more susceptible to adverse effects. Thus, the trial population may not reflect the clinical reality as shown by event rates that are usually lower than those seen in practice. Sometimes, however, the opposite is true if the clinical trial requires a minimal risk level for patient inclusion.
      • Which clinical trial data have been used to express the benefits of a new treatment? Are treatment effects assumed beyond the duration of the trial, and if so, is there the same relative risk reduction, a waning effect or something else?
      • How long is the prediction period and does this make clinical sense? Many models use a lifetime horizon, which is often perceived by clinicians as beyond a realistic scope (“who are you to predict the trajectory of cardiovascular disease in my patient over the next 30 to 40 years?”).
      • How many events are predicted in the scenario without and with the innovation? Clinicians prefer to see the predicted clinical benefit of the models, not just a cost per QALY. For instance, over a period of 5 years, how many MIs are predicted in the scenario without the new medicine and how many in the scenario with the new medicine?
      • What are the assumed consequences of the events and which management patterns have been applied? For example, if the patient suffers a stroke, what is the probability that this is disabling and how does this correspond to the clinical reality? How many patients are in permanent residential care following that stroke? What is the assumed follow-up care?
      • Which disease and treatment trajectories have been assumed? Will avoiding an MI lead to less heart failure in the future? And if so, will only heart failure of ischemic origin be affected or is there an impact on all types of heart failures (including valvular heart failure)?
      • Are composite endpoints in clinical trials concealing benefit—or the lack thereof—on specific events that are included in that endpoint? Should the composite endpoint strategy be revised in this context?
      • What is the assumed impact on mortality when the duration of the clinical trial is too short or insufficiently powered to show a statistically significant effect? Will avoiding strokes lead to reduced cardiovascular mortality? What are the patterns of fatal events and mortality overall over time?
      • And finally, what is the impact of treatment on the profile of nonfatal cardiovascular events that lead to fatal noncardiovascular events (for example, a nonfatal stroke, which results in hospitalization due to aspiration pneumonia and subsequent death)?
      So long as health economists fail to clearly answer these questions, clinicians will be tempted to ignore the reported findings and therefore not to adapt their practice as a consequence.

      Health economics scenarios in ASCVD for the 21st century: impact on disease trajectory

      To be relevant to clinicians, health economic models should comply with several requirements (see Box 1). Briefly, the model should be clinically validated, transparent, use real-world data to provide event rates in the target population and RCT data to provide the relative reduction in risk of these events with any new therapy, and should also consider the clinical realities of the condition and its consequences. In the context of prevention of ASCVD events in very-high-risk patients, an extended time horizon of the analysis is critical to capture a true estimate of benefit vs costs.
      • Basu A.
      • Maciejewski M.L.
      Choosing a time horizon in cost and cost-effectiveness analyses.
      Moreover, if the real-world population has different characteristics compared with the clinical trial population (eg, is older and has more comorbidities or higher LDL-C) and the relative risk reduction has been shown to be influenced by some of these characteristics, then the relative risk needs to be adjusted. Furthermore, if data on clinically relevant endpoints such as MIs and strokes are lacking, then the assumed relationship between the intermediate endpoint (in this case, LDL-C reduction) and the endpoints (cardiovascular events) should be documented and justified. Table 1 evaluates recent heath-economic analyses for PCSK9 inhibitors in the context of these proposed requirements.
      • Arrieta A.
      • Hong J.C.
      • Khera R.
      • Virani S.S.
      • Krumholz H.M.
      • Nasir K.
      Updated cost-effectiveness assessments of PCSK9 inhibitors from the perspectives of the health system and private payers: insights derived from the FOURIER Trial.
      • Kazi D.S.
      • Penko J.
      • Coxson P.G.
      • et al.
      Updated cost-effectiveness analysis of PCSK9 inhibitors based on the results of the FOURIER trial.
      • Kazi D.S.
      • Penko J.
      • Coxson P.G.
      • Guzman D.
      • Wei P.C.
      • Bibbins-Domingo K.
      Cost-effectiveness of alirocumab: a just-in-time analysis based on the ODYSSEY Outcomes Trial.
      • Korman M.
      • Wisløff T.
      Modelling the cost-effectiveness of PCSK9 inhibitors vs. ezetimibe through LDL-C reductions in a Norwegian setting.
      • Stam-Slob M.C.
      • van der Graaf Y.
      • de Boer A.
      • Greving J.P.
      • Visseren F.L.J.
      Cost-effectiveness of PCSK9 inhibition in addition to standard lipid-lowering therapy in patients at high risk for vascular disease.
      As indicated, these vary in meeting criteria for a clinically validated structure and also in terms of the degree to which they reflect the clinical reality for very-high-risk patients. Moreover, none of these analyses appeared to take account of the impact of nonadherence.
      Essential requirements of health economic models
      Tabled 1
      • Clinically validated structure, which correctly reflects the (combination of) clinical outcomes in the target population
      • Transparency, with disclosure and justification of clinical and economic inputs and assumptions
      • Derived from real-world data and randomized controlled trial data
      • Use of age-adjusted event rates, with explanation of the adjustment
      • Reflect the clinical reality in terms of event and treatment sequences
      • Account for nonadherence
      • A sensitivity analysis on the price of the investigated medicine should be envisaged, thereby avoiding invalidation of the model findings as the price changes
      Table 1Evaluating recent cost-effectiveness analyses against recommended criteria given in Box 1
      Recommended criteriaRecent cost-effectiveness analyses
      Patient-level data were employed in the analyses of Korman et al35 and Stam-Slob et al,36 whereas study-level data were used by Arrieta et al,27 Kazi et al,28 and Kazi et al.34
      Kazi (2019)
      • Kazi D.S.
      • Penko J.
      • Coxson P.G.
      • Guzman D.
      • Wei P.C.
      • Bibbins-Domingo K.
      Cost-effectiveness of alirocumab: a just-in-time analysis based on the ODYSSEY Outcomes Trial.
      Korman (2018)
      • Korman M.
      • Wisløff T.
      Modelling the cost-effectiveness of PCSK9 inhibitors vs. ezetimibe through LDL-C reductions in a Norwegian setting.
      Stam-Slob (2018)
      • Stam-Slob M.C.
      • van der Graaf Y.
      • de Boer A.
      • Greving J.P.
      • Visseren F.L.J.
      Cost-effectiveness of PCSK9 inhibition in addition to standard lipid-lowering therapy in patients at high risk for vascular disease.
      Arrieta (2017)
      • Arrieta A.
      • Hong J.C.
      • Khera R.
      • Virani S.S.
      • Krumholz H.M.
      • Nasir K.
      Updated cost-effectiveness assessments of PCSK9 inhibitors from the perspectives of the health system and private payers: insights derived from the FOURIER Trial.
      Kazi (2017)
      • Kazi D.S.
      • Penko J.
      • Coxson P.G.
      • et al.
      Updated cost-effectiveness analysis of PCSK9 inhibitors based on the results of the FOURIER trial.
      Clinically validated structureNot reportedNot reportedNot reportedNot reportedNot reported
      TransparencyPartialPartialYesYesPartial
      Derived from real-world and RCT dataYesYesYesNoNo
      Age-adjusted event ratesModeledNot clearModeledModeledModeled
      Reflect clinical realityPartialNot testedNot testedNot testedNot tested
      Account for non-adherenceNoNoNoNoNo
      Patient-level data were employed in the analyses of Korman et al
      • Korman M.
      • Wisløff T.
      Modelling the cost-effectiveness of PCSK9 inhibitors vs. ezetimibe through LDL-C reductions in a Norwegian setting.
      and Stam-Slob et al,
      • Stam-Slob M.C.
      • van der Graaf Y.
      • de Boer A.
      • Greving J.P.
      • Visseren F.L.J.
      Cost-effectiveness of PCSK9 inhibition in addition to standard lipid-lowering therapy in patients at high risk for vascular disease.
      whereas study-level data were used by Arrieta et al,
      • Arrieta A.
      • Hong J.C.
      • Khera R.
      • Virani S.S.
      • Krumholz H.M.
      • Nasir K.
      Updated cost-effectiveness assessments of PCSK9 inhibitors from the perspectives of the health system and private payers: insights derived from the FOURIER Trial.
      Kazi et al,
      • Kazi D.S.
      • Penko J.
      • Coxson P.G.
      • et al.
      Updated cost-effectiveness analysis of PCSK9 inhibitors based on the results of the FOURIER trial.
      and Kazi et al.
      • Kazi D.S.
      • Penko J.
      • Coxson P.G.
      • Guzman D.
      • Wei P.C.
      • Bibbins-Domingo K.
      Cost-effectiveness of alirocumab: a just-in-time analysis based on the ODYSSEY Outcomes Trial.
      Health economic models should also avoid the pitfalls of overclaiming or underclaiming benefits. An example of the former is assumption that effects from LDL-C reduction impact directly the incidence of heart failure despite the lack of evidence for any such relationship. In contrast, underestimating the impact of stroke on quality of life has consequences, as for example, on the calculation of the incremental cost-effectiveness ratio in the US analyses when stroke was assumed to decrease quality of life by only 3%.
      • Kazi D.S.
      • Penko J.
      • Coxson P.G.
      • et al.
      Updated cost-effectiveness analysis of PCSK9 inhibitors based on the results of the FOURIER trial.
      A key question is how best to relate the impact of innovative treatments on the trajectory of ASCVD. In middle-aged individuals with a first MI, attainment of very low LDL-C levels with early initiation of a PCSK9 inhibitor on the background of statin or statin plus ezetimibe treatments has the potential for large gains in life expectancy and QALYs. Models should clarify what the health benefits are for those patients for whom more aggressive treatment really makes a difference. In those patients where MIs and strokes are prevented, what will be the impact on their lives? These benefits for the patient will undoubtedly translate to societal benefits arising from reduced morbidity and loss of productivity associated with cardiovascular complications. If, however, the requirements for access to such new treatments are restrictive, then such a promising scenario is unlikely.
      • Doshi J.A.
      • Puckett J.T.
      • Parmacek M.S.
      • Rader D.J.
      Prior authorization requirements for proprotein convertase subtilisin/kexin type 9 inhibitors across US private and public payers.
      Indeed, some have suggested that despite their established clinical value, perceived costs and budgetary concerns relating to the use of PCSK9 inhibitors in the target patient groups have led to lower than expected uptake of these treatments.
      • Sabatine M.S.
      Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors: comparing and contrasting guidance across the Atlantic.
      This is a simplistic approach, however, which does not integrate possible rebates and discounts that may be offered by the manufacturers (It is noteworthy that, in the US, both manufacturers of PCSK9 inhibitors have lowered their price recently by 60%); indeed, recent developments suggest that the budget impact of such treatments is lower than anticipated,
      • Mallya U.G.
      • Boklage S.H.
      • Koren A.
      • Delea T.E.
      • Mullin C.D.
      Budget impact analysis of PCSK9 inhibitors for the management of adult patients with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease.
      especially when weighed against the burden of cardiovascular complications.
      Importantly, the outcomes of the model should be clearly reported and validated, using graphs that reflect the predicted number of clinical events over time in the model, both for the control arm (in this case, background statin or statin plus ezetimibe therapy) and the intervention arm (add-on PCSK9 inhibitor). The extent to which the model prediction for the control arm corresponds to the observed event rate in real-world data sets should be assessed. If the model underestimates the event rates in the control arm (either single or composite events), then the absolute benefit of the better therapy will also be underestimated, which will in turn result in a worse cost-effectiveness estimate, whereas if baseline event rates are overestimated, then this will result in overestimation of cost-effectiveness. In either case, the model cannot be considered as validated.
      A recommended approach is cross-validation. If the results of model X widely deviate from model Y, the input parameters in X can be modified sequentially to reflect those in Y. The extent to which the results of X evolve toward the results of Y for each modified parameter provides insights into the key drivers of the deviation in results. The onus is on health economists to clarify this, instead of making unconditional claims about the level of cost-effectiveness of medicines.

      Balancing benefit vs cost for very-high-risk patients: light at the end of the tunnel?

      With increasingly finite resources, the use of innovative therapies needs to be balanced against their cost relative to the substantial burden of associated cardiovascular sequelae. Health economic modeling needs to adapt to the evolving characteristics of patients, in particular taking account of the impact of new therapies, as well as the timing of initiation of such treatments, on the trajectory of ASCVD (Fig. 1). By following these proposed recommendations, health economic models can become informative rather than create confusion. To achieve this, it is imperative that all stakeholders in the health care pathway are involved in the production and interpretation of economic models to ensure appropriate patient access to innovative therapies, and in this instance, those targeting LDL-C reduction, for prevention of cardiovascular events.
      Figure thumbnail gr1
      Figure 1Essential components of a health economic model for assessment of the cost-effectiveness of an innovative therapy, in this instance PCSK9 inhibition, for prevention of cardiovascular events in very-high-risk patients. ASCVD, atherosclerotic cardiovascular disease; RCT, randomized controlled trial; QALY, quality-adjusted life-year.

      Acknowledgments

      The authors are indebted to Dr Henry Ginsberg for insightful discussion and to the PCSK9 Education and Research Forum for the award of an educational grant for logistical support. Responsibility for all opinions, conclusions, and interpretation of data lies with the authors.
      Authors' contributions: All authors approve the final manuscript and have made substantial contributions to the following: (1) the conception of the review and critical appraisal and interpretation of data and (2) drafting the article and revising it critically for important intellectual content.

      Financial disclosure

      This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Furthermore, no author received any honoraria in composing this manuscript. The PCSK9 Education and Research Forum has been supported by educational grants from the following: Alexion Pharmaceuticals, Amarin Pharma, Amgen (Europe) GmbH, AstraZeneca AB, Eli Lilly and Company, Daiichi Sankyo Europe GmbH, Kowa Pharmaceutical Europe Co Ltd, Regeneron Pharmaceuticals, Inc, Sanofi-Aventis Groupe, The Medicines Company, and Pfizer Ltd.

      Disclosures

      LA has received honoraria for lectures and advisory boards from Amgen and Sanofi. MJC has received research grants from Amgen, Kowa Europe, and Pfizer and honoraria for participation on speakers' bureau and advisory boards from Akcea, Alexion, Amarin, Amgen, Daiichi Sankyo, Kowa Europe, Merck/MSD, Pfizer, Sanofi, Regeneron, and Unilever. JKS consults with the PCSK9 Education and Research Forum, which has been supported by educational grants as detailed but reports no direct disclosures. The authors have no competing interests to declare.

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