How Low Should We Decrease LDL-Cholesterol in a Cost-Effective Manner?
The association between blood cholesterol and cardiovascular (CV) disease has been consistently demonstrated in epidemiological studies within all ranges of studied cholesterol levels.1 Statins have been the mainstay therapy for low-density lipoprotein-cholesterol (LDL-C) reduction and subsequent prevention of CV events. In fact, after the first year of statin use, each 1 mmol/L (38.6 mg/dL) of reduction in LDL-C leads to a 20-25% relative reduction of global CV risk, including a 20% decrease in coronary mortality.2,3
Whereas this degree of relative risk reduction is largely independent of baseline characteristics,2,4,5 the net benefit or absolute risk reduction achieved with lowering LDL-C levels is highly dependent on baseline CV risk. As an example, a reduction in LDL-C of 1 mmol/L and subsequent 25% relative reduction in CV risk will translate into 1% versus 5% absolute risk reduction (and numbers needed to treat of 100 vs. 20) in patients with a 10-year estimated risk of 4% and 20%, respectively. For this reason, guidelines across the globe recommend CV risk assessment and tailoring the aggressiveness of lipid lowering therapies to such risk.6-10
The 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Treatment of Blood Cholesterol did not recommend the routine use of non-statin drugs for the reduction of CV events.8 However, more recently, randomized data for ezetimibe and the proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor evolocumab demonstrated improved CV outcomes through LDL-C reduction in patients already treated with a statin.
In the IMPROVE-IT (Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatintrial) Trial, 18,144 patients with a recent acute coronary syndrome and baseline LDL-C 50-125 mg/dL were randomized to daily placebo or ezetimibe 10 mg, in addition to simvastatin 40 mg. Ezetimibe targets the Niemann-Pick like protein on intestinal cells, reducing the absorption of cholesterol. During a median follow-up of 6 years, the average LDL-C was 16 mg/dL (0.4 mmol/L) lower in the ezetimibe group: 54 versus 70 mg/dL. The observed ~6% relative risk reduction in the composite CV outcome is consistent with the expected risk reduction seen with statins and similar degrees of LDL-C reduction.11
In FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), 27,564 patients with atherosclerotic cardiovascular disease (ASCVD) and LDL-C ≥70 mg/dL while on statin therapy were randomized to bi-weekly or monthly injections of placebo or evolocumab. After a median follow-up of 2.2 years, evolocumab reduced LDL-C by 59% or 56 mg/dL (1.4 mmol/L), as compared to placebo, from a baseline of 92 mg/dL to 30 mg/dL.This resulted in a relative risk reduction of 15% for the primary composite CV endpoint, consistent with the expected risk reduction per LDL-C lowering over two years as predicted by the Cholesterol Treatment Trialists.12 The ongoing ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial is evaluating alirocumab, another PCSK9 inhibitor, for secondary prevention of CV outcomes.13
Although randomized trials of lipid-lowering therapies were not specifically aimed at achieving specific LDL-C goals, data from high- versus moderate-intensity statin therapy, ezetimibe, and PCSK9 inhibitor trials indicate that lower on-treatment levels of LDL-C are in fact associated with CV risk reduction, which may be particularly important for secondary prevention patients as well as for primary prevention patients at high baseline risk (e.g., familial hypercholesterolemia). This notion of "lower is better" begets the question of how low we should push our patients' LDL-C. The answer to this is highly dependent on a patient's baseline risk, but one also must consider two other principles: 1) safety of aggressive anti-lipid therapies and very low LDL-C levels; and 2) cost-effectiveness of such therapies.
Notably, myopathy, new-onset diabetes and a slight increase in hemorrhagic strokes can be seen with statins. Myalgias, weakness and other non-specific muscular symptoms can occur in up to 1/3 of statin-treated patients, but this incidence is no different or only slightly higher than the observed with placebo controls.5,14 True myopathy with elevated creatinine kinase levels and rhabdomyolysis are exceedingly rare, with incidences of 1-5/10,000 and 2-5/100,000, respectively.2,3,15 There is an approximate 10% relative risk increase of new-onset diabetes in statin-treated patients.16 Such risk is primarily restricted to patients who are overweight, glucose intolerant or with metabolic syndrome.17
Results from the Cholesterol Treatment Trialists showed an odds-ratio of 1.21 for hemorrhagic stroke in statin versus placebo control trials.2 This finding was not confirmed in a larger meta-analysis comprising >180,000 patients from randomized trials.18 Importantly though, there is still a large net benefit of statins even in populations at risk for new-onset diabetes or hemorrhagic stroke.2,17 Observational data suggesting increased risk of cognitive impairment with statins or very low LDL-C levels have not been confirmed in randomized studies.12,14 Similarly, ezetimibe and PCSK9 inhibitors have not shown significant safety hazards in clinical trials.11,12
The cost-effectiveness of lipid-lowering therapies is highly dependent on drug costs. With statin therapy, the cost ranges widely, from a newer branded agent like Livalo with an average retail price of ~$320 per month ($3,840 per year) to $4-10 per month ($48-120 per year) generic statins. If generic statins were effectively employed in practice, this may not only be cost-effective, but also cost-saving in higher risk individuals. Heller and colleagues estimated that over a 10-year period, the 2013 ACC/AHA cholesterol guidelines would result in 12.3 million additional statin users, a gain of 183,000 quality-adjusted life-years (QALYs), and the United States would save $3.8 billion as compared to the previous Adult Treatment Panel III guidelines. Further, a strategy of universal treatment for all men 45-74 years-old and women 55-74 years old would result in nearly 29 million more statin users, an additional 269,000 QALYs, and cost savings of $11.5 billion as compared to the 2013 ACC/AHA guidelines.19
The high cost of non-statin therapies yields a less favorable cost-effectiveness profile. In a model of the US adult population, it was found that ezetimibe has the potential to prevent 2.7 million major adverse CV events over 5 years if taken by the eligible population of patients with clinical ASCVD. Despite these encouraging results, ezetimibe would not be considered cost-effective ($154,000 per QALY) at the average annual cost of $2,878.20 It has been estimated that ezetimibe would only be cost-effective beyond an 80% reduction of the brand price in a lifetime horizon model.21 Generic ezetimibe was FDA-approved in December 2016. At goodrx.com, the costs of generic ezetimibe range from $552 to $2,544/year, although available coupons can decrease the price to as low as $140/year at select pharmacies (within cost-effectiveness range). Dedicated cost-effectiveness studies of generic ezetimibe are warranted.
Similarly, although there is some heterogeneity in the PCSK9 inhibitor cost-effectiveness models, studies agree that these drugs are not considered cost-effective at the current listed price of approximately $14,000 per year.20,22,23 Heterogeneity stems mostly from differences in: 1) estimated drug costs over future years; 2) baseline CV risk of the population; and 3) inclusion versus exclusion of particular CV outcomes. Baseline risk in real-world data (US claims data, national surveys, insurance claims, etc.) is typically higher than that of similar populations enrolled in clinical trials (strict inclusion and exclusion criteria). Therefore, models including baseline risk of US clinical practice data typically have more favorable cost-effectiveness results as compared to trial-based models.23 Coronary revascularization is not included in all models, as some authors assume it does not affect CV risk or quality of life. Models including revascularization yield more favorable cost-effectiveness results.22,23 Despite these differences, models agree that in order to achieve willingness-to-pay cost-effectiveness thresholds of $100,000/QALY or $150,000/QALY, substantial cost reductions would be required, below ranges of $4,215-$5,459/year and $6,780-$9,669/year, respectively.22-24
The 2017 ACC Focused Update on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering recommends adding ezetimibe or PCSK9 inhibitors for patients with clinical ASCVD with ≤50% LDL-C reduction from baseline or with absolute levels of LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL despite maximally tolerated statin therapy. Shared-decision making should include discussions about desired % reduction in LDL-C, patient preferences, route of administration, costs and potential adverse events. In particular, ezetimibe is favored in patients who require <25% additional lowering of LDL-C, whereas PCSK9 inhibitors are better suited for patients with clinical ASCVD and additional comorbidities who require >25% additional lowering of LDL-C since they lower LDL-C ~60% (three times the effect of ezetimibe).25
In summary, patients at high risk of adverse CV outcomes benefit the most from aggressive LDL-C lowering to levels well below 70 mg/dL. For these individuals, "lower is better" despite the absence of trial-oriented LDL-C targets, and approved lipid-lowering therapies should be used as guided by the results of clinical trials and practice guidelines. Statins, ezetimibe, and PCSK9 inhibitors are safe and effective therapies for reduction of blood cholesterol levels and the prevention of adverse CV outcomes. Whereas certain generic statins are relatively cheap and therefore not only cost-effective, but cost-saving, the equation is less straightforward for more expensive branded statins, ezetimibe and especially for PCSK9 inhibitors. More broadly, the high costs of prescription drugs in the US is a well-recognized problem and it is a national priority to address this. The particularly high costs of PCSK9 inhibitors is bringing even more immediate attention to this issue. If ongoing national conversations can lead to lower drug prices and greater acceptability by payers and health care systems, then this will improve access for patients in need of additional LDL-C lowering to prevent CV events.
- Prospective Studies Collaboration, Lewington S, Whitlock G, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007;370:1829-39.
- Cholesterol Treatment Trialists' (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-81.
- Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532-61.
- Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trails. Lancet 2012;380:518-90.
- Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2021-31.
- Jacobson TA, Ito MK, Maki KC, et al. National lipid association recommendations for patient-centered management of dyslipidemia: part 1--full report. J Clin Lipidol 2015;9:129-69.
- Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members. An international Atherosclerosis Society position paper: global recommendations for the management of dyslipidemia--full report. J Clin Lipidol 2014;8:29-60.
- Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol 2014;63:2889-934.
- Piepoli MF, Hoes AW, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: the sixth joint task force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315-81.
- Anderson TJ, Gregoire J, Pearson GJ, et al. 2016 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol 2016;32:1263-82.
- Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
- Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
- Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J 2014;168:682-9.
- Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.
- Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol 2006;97:52C-60C.
- Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735-42.
- Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 2012;380:565-71.
- McKinney JS, Kostis WJ. Statin therapy and the risk of intracerebral hemorrhage: a meta-analysis of 31 randomized controlled trials. Stroke 2012;43:2149-56.
- Heller DJ, Coxson PG, Penko J, et al. Evaluating the impact and cost-effectiveness of statin use guidelines for primary prevention of coronary heart disease and stroke. Circulation 2017;136:1087-98.
- Kazi DS, Moran AE, Coxson PG, et al. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA 2016;316:743-53.
- Almalki ZS, Guo JJ, Alahmari A, Alotaibi N, Thaibah H. Cost-effectiveness of simvastatin plus ezetimibe for cardiovascular prevention in patients with a history of acute coronary syndrome: analysis of results of the IMPROVE-IT trial. Heart Lung Circ 2017. [Epub ahead of print]
- Arrieta A, Hong JC, Khera R, Virani SS, Krumholz HM, 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. JAMA Cardiol 2017;2:1369-74.
- Fonarow GC, Keech AC, Pedersen TR, et al. Cost-effectiveness of evolocumab therapy for reducing cardiovascular events in patients with atherosclerotic cardiovascular disease. JAMA Cardiol 2017;2:1069-78.
- Kazi DS, Penko J, Coxson PG, et al. Updated cost-effectiveness analysis of PCSK9 inhibitors based on the results of the FOURIER trial. JAMA 2017;318:748-50.
- Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2017 focused update of the 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology task force on expert consensus decision pathways. J Am Coll Cardiol 2017;70:1785-1822.
Keywords: Acute Coronary Syndrome, American Heart Association, Antibodies, Monoclonal, Azetidines, Cholesterol, Cholesterol, LDL, Comorbidity, Cost Savings, Cost-Benefit Analysis, Creatinine, Decision Making, Diabetes Mellitus, Drug Costs, Epidemiologic Studies, Follow-Up Studies, Glucose, Goals, Health Care Costs, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Incidence, Hyperlipoproteinemia Type II, Metabolic Syndrome, Myalgia, Numbers Needed To Treat, Odds Ratio, Outcome Assessment, Health Care, Overweight, Patient Preference, Pharmacies, Prescription Drugs, Primary Prevention, Proprotein Convertases, Quality of Life, Quality-Adjusted Life Years, Rhabdomyolysis, Risk, Risk Assessment, Risk Factors, Risk Reduction Behavior, Secondary Prevention, Simvastatin, Stroke, Subtilisins, Dyslipidemias
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