Residual Inflammatory Risk on Treatment With PCSK9 Inhibition and Statin Therapy

Background: The combination of statin therapy and PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition markedly lowers low-density lipoprotein cholesterol (LDL-C) and reduces cardiovascular event rates. Whether residual inflammatory risk as measured by on-treatment high sensitivity C-reactive protein (hsCRP) remains an important clinical issue in such patients is uncertain. Methods: We evaluated residual inflammatory risk among 9738 patients participating in the SPIRE-1 and SPIRE-2 cardiovascular outcomes trials (Studies of PCSK9 Inhibition and the Reduction in Vascular Events), who were receiving both statin therapy and bococizumab, according to on-treatment levels of hsCRP (hsCRPOT) and LDL-COT measured 14 weeks after drug initiation. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death. Results: At 14 weeks, the mean percentage change in LDL-C among statin-treated patients who additionally received bococizumab was −60.5% (95% confidence interval [CI], −61.2 to −59.8; P<0.001; median change, −65.4%) as compared to 6.6% (95% CI, −1.0 to 14.1; P=0.09; median change, 0.0%) for hsCRP. Incidence rates for future cardiovascular events for patients treated with both statin therapy and bococizumab according to hsCRPOT <1, 1 to 3, and >3 mg/L were 1.96, 2.50, and 3.59 events per 100 person-years, respectively, corresponding to multivariable adjusted hazard ratios of 1.0, 1.16 (95% CI, 0.81–1.66), and 1.62 (95% CI, 1.14–2.30) (P-trend=0.001) after adjustment for traditional cardiovascular risk factors and LDL-COT. Comparable adjusted hazard ratios for LDL-COT (<30, 30–50, >50 mg/dL) were 1.0, 0.87, and 1.21, respectively (P-trend=0.16). Relative risk reductions with bococizumab were similar across hsCRPOT groups (P-interaction=0.87). Conclusions: In this post hoc analysis of the SPIRE trials of bococizumab in a stable outpatient population, evidence of residual inflammatory risk persisted among patients treated with both statin therapy and proprotein convertase subtilisin-kexin type 9 inhibition. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01975376, NCT01975389.

[1]  P. Ridker.  Mortality Differences Associated With Treatment Responses in CANTOS and FOURIER: Insights and Implications. , 2017, Circulation.

[2]  P. Libby,et al.  Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease , 2017, The New England journal of medicine.

[3]  C. Cannon,et al.  Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration , 2017, European heart journal.

[4]  P. Ridker,et al.  Lipid‐Reduction Variability and Antidrug‐Antibody Formation with Bococizumab , 2017, The New England journal of medicine.

[5]  P. Ponikowski,et al.  Cardiovascular Efficacy and Safety of Bococizumab in High‐Risk Patients , 2017, The New England journal of medicine.

[6]  A. Keech,et al.  Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease , 2017, The New England journal of medicine.

[7]  P. Ridker.  How Common Is Residual Inflammatory Risk? , 2017, Circulation research.

[8]  Paul M Ridker,et al.  Residual inflammatory risk: addressing the obverse side of the atherosclerosis prevention coin. , 2016, European heart journal.

[9]  Deepak L. Bhatt,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. , 2014, American heart journal.

[10]  P. Libby,et al.  Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. , 2013, American heart journal.

[11]  E. Braunwald.  Creating controversy where none exists: the important role of C-reactive protein in the CARE, AFCAPS/TexCAPS, PROVE IT, REVERSAL, A to Z, JUPITER, HEART PROTECTION, and ASCOT trials. , 2012, European heart journal.

[12]  Børge G Nordestgaard,et al.  Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial , 2009, The Lancet.

[13]  P. Libby,et al.  Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. , 2008, The New England journal of medicine.

[14]  Amy Shui,et al.  Clinical Relevance of C-Reactive Protein During Follow-Up of Patients With Acute Coronary Syndromes in the Aggrastat-to-Zocor Trial , 2006, Circulation.

[15]  E. Tuzcu,et al.  Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease , 2005 .

[16]  M. Pfeffer,et al.  C-reactive protein levels and outcomes after statin therapy. , 2005, The New England journal of medicine.

[17]  P. Libby,et al.  CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: report from the clinical practice discussion group. , 2004, Circulation.

[18]  Paul M. Ridker,et al.  Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. , 2001, The New England journal of medicine.

[19]  M. Pfeffer,et al.  Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. , 1998, Circulation.