Highlights
- •FH patients had nominal cardiac event reduction with PCSK9 inhibition.
- •Among FH patients, PCSK9 inhibition resulted in a hazard ratio of 0.83.
- •The effects were greater in magnitude for patients with LDL-C > 160 mg/dL (HR 0.74).
- •Risk reduction was greater in FH patients with stronger LDL-C response (HR 0.68)
Background
Familial hypercholesterolemia (FH) is a dominant genetic disorder associated with
elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic
events. Although therapeutic monoclonal antibodies that inhibit proprotein convertase
subtilisin-kexin type 9 (PCSK9) are indicated for LDL-C reduction among adult patients
with FH, placebo-controlled outcome data among FH patients are scant.
Objective
Directly compare the efficacy of PCSK9 inhibition as compared to placebo on hard cardiovascular
outcomes in FH patients enrolled in the Studies of PCSK9 Inhibition and the Reduction
of vascular Events (SPIRE) program.
Methods
We estimated the efficacy of PCSK9 inhibition with bococizumab on future cardiovascular
event rates among 1578 FH patients and 15,959 patients without FH who were selected
for comparable lipid levels (on-statin levels of LDL-C >100 mg/dL or non–high-density
lipoprotein cholesterol > 130 mg/dL). All patients were randomized by computer generated
codes to bococizumab 150 mg subcutaneously every 2 weeks or to matching placebo in
the SPIRE clinical trials program and were followed over a median period of 11.2 months
for major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal
stroke, or cardiovascular death). Analysis is by intention to treat. The SPIRE trials
are closed and registered at ClinicalTrials.gov: NCT01968954, NCT01968967, NCT02100514, NCT01968980, NCT01975376, and NCT01975389.
Results
Compared to non-FH patients, FH patients enrolled in the SPIRE trials were on average
younger (58 vs 63 years), more likely to be women (42 vs 35%), more likely to be primary
prevention patients (42 vs 23%), had higher mean baseline LDL-C levels (151 vs 127 mg/dL),
and lower rates of diabetes (25 vs 52%) and hypertension (59 vs 82%). FH and non-FH
patients both had 55% reductions in LDL-C with bococizumab. Among FH patients, major
adverse cardiovascular events occurred among 18 of 781 allocated to bococizumab and
22 of 797 allocated to placebo (hazard ratio 0.83; 95% confidence interval 0.44–1.54,
P = .55). This best estimate of effect was similar in magnitude to that observed in
the much larger group of patients without FH (hazard ratio 0.79, 95% confidence interval
0.64–0.97, P = .023) with no statistically significant evidence of heterogeneity between groups
(P = .87). Incidence rate ratios comparing bococizumab to placebo for adverse events
were similar among those with and without FH. The proportion of patients developing
antidrug antibodies was higher among those with FH compared to those without FH (43%
vs 36%, P < .001).
Conclusions
In these randomized placebo-controlled data, the subgroup of statin-treated FH patients
had a similar magnitude of risk reduction for hard cardiovascular events with the
PCSK9 inhibitor bococizumab as did patients without FH, with no evidence of statistical
heterogeneity between groups.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Clinical LipidologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association.Circulation. 2015; 132: 2167-2192
- 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.Eur Heart J. 2013; 34: 3478-3490a
- LDL cholesterol: controversies and future therapeutic directions.Lancet. 2014; 384: 607-617
- Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES).Circulation. 2016; 133: 1067-1072
- Cholesterol evaluation in young adults: absence of clinical trial evidence is not a reason to delay screening.Ann Intern Med. 2017; 166: 901-902
- Two years after molecular diagnosis of familial hypercholesterolemia: majority on cholesterol-lowering treatment but a minority reaches treatment goal.PLoS One. 2010; 5: e9220
- The biology and therapeutic targeting of the proprotein convertases.Nat Rev Drug Discov. 2012; 11: 367-383
- Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial.Lancet. 2012; 380: 29-36
- Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial.Circulation. 2012; 126: 2408-2417
- Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia.Circulation. 2013; 128: 2113-2120
- PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.Lancet. 2015; 385: 331-340
- Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial.Lancet. 2015; 385: 341-350
- ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia.Eur Heart J. 2015; 36: 2996-3003
- Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study.Lancet Diabetes Endocrinol. 2017; 5: 280-290
- Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody alirocumab vs placebo in patients with heterozygous familial hypercholesterolemia.J Clin Lipidol. 2017; 11: 195-203
- Evolocumab and clinical outcomes in patients with cardiovascular disease.N Engl J Med. 2017; 376: 1713-1722
- Cardiovascular efficacy and safety of bococizumab in high-risk patients.N Engl J Med. 2017; 376: 1527-1539
- Lipid-reduction variability and antidrug-antibody formation with bococizumab.N Engl J Med. 2017; 376: 1517-1526
- Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: a study of a cohort of 14,000 mutation carriers.Atherosclerosis. 2014; 233: 219-233
- Statins in familial hypercholesterolemia consequences for coronary artery disease and all-cause mortality.J Am Coll Cardiol. 2016; 68: 252-260
- Prevalence and significance of cardiovascular risk factors in a large cohort of patients with familial hypercholesterolaemia.J Intern Med. 2003; 253: 161-168
- Low-density lipoprotein cholesterol lowering for the primary prevention of cardiovascular disease among men with primary elevations of low-density lipoprotein cholesterol levels of 190 mg/dL or above: analyses from the WOSCOPS (West of Scotland Coronary Prevention Study) 5-Year Randomized Trial and 20-Year Observational Follow-Up.Circulation. 2017; 136: 1878-1891
- Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia.J Am Coll Cardiol. 2016; 67: 2578-2589
- Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis.JAMA. 2016; 316: 1383-1391
- Interpretation of the evidence for the efficacy and safety of statin therapy.Lancet. 2016; 388: 2532-2561
Article info
Publication history
Published online: April 03, 2018
Accepted:
March 29,
2018
Received:
January 2,
2018
Footnotes
Trial Registration clinicaltrials.gov: NCT01968954, NCT01968967, NCT02100514, NCT01968980, NCT01975376, NCT01975389.
Identification
Copyright
© 2018 National Lipid Association. All rights reserved.
