Simulation of Lipid-Lowering Therapy Intensification in a Population With Atherosclerotic Cardiovascular Disease

Abstract

Importance: In patients with atherosclerotic cardiovascular disease (ASCVD), guidelines recommend optimizing statin treatment, and consensus pathways suggest use of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in patients with persistently elevated low-density lipoprotein cholesterol (LDL-C) levels despite use of statins. Recent trials have provided evidence of benefit in reduction of cardiovascular events with these agents.

Objective: To estimate the percentage of patients with ASCVD who would require a PCSK9 inhibitor when oral lipid-lowering therapy (LLT) is intensified first.

Design, setting, and participants: This simulation model study used a large administrative database of US medical and pharmacy claims to identify a cohort of 105 269 patients with ASCVD enrolled from January 1, 2012, through December 31, 2013, who met the inclusion criteria (database cohort). Patients were sampled with replacement (bootstrapping) to match the US epidemiologic distribution and entered into a Monte Carlo simulation (simulation cohort) that applied stepwise treatment intensification algorithms in those with LDL-C levels of at least 70 mg/dL. All patients not initially receiving a statin were given atorvastatin, 20 mg, and the following LLT intensification steps were applied: uptitration to atorvastatin, 80 mg; add-on ezetimibe therapy; add-on alirocumab therapy, 75 mg (a PCSK9 inhibitor); and uptitration to alirocumab, 150 mg. Sensitivity analyses included evolocumab as a PCSK9 inhibitor. Efficacy was estimated from published studies and incorporated patient-level variation. Data were analyzed from December 2015 to May 2017.

Exposures: Treatment intensification strategies with LLT.

Main outcomes and measures: Use of LLT among the population with ASCVD and distributions of LDL-C levels under various treatment intensification scenarios.

Results: Inclusion criteria were met by 105 269 individuals in the database cohort (57.2% male and 42.8% female; mean [SD] age, 65.1 [12.1] years). In the simulation cohort (1 million patients; 54.8% male and 45.2% female; mean [SD] age, 66.4 [12.2] years), before treatment intensification, 51.5% used statin monotherapy and 1.7% used statins plus ezetimibe. Only 25.2% achieved an LDL-C level of less than 70 mg/dL. After treatment intensification, 99.3% could achieve an LDL-C level of less than 70 mg/dL, including 67.3% with statin monotherapy, 18.7% with statins plus ezetimibe, and 14% with add-on PCSK9 inhibitor.

Conclusions and relevance: Large gaps exist between recommendations and current practice regarding LLT in the population with ASCVD. In our model that assumes no LLT intolerance and full adherence, intensification of oral LLT could achieve an LDL-C level of less than 70 mg/dL in most patients, with only a modest percentage requiring a PCSK9 inhibitor.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Cannon reports receiving research grants from Amgen, Arisaph, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Merck, and Takeda and consulting fees from Alnylam, Amarin, Amgen, Arisaph, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Kowa, Merck, Takeda, Lipimedix, Pfizer, Regeneron Pharmaceuticals Inc, and Sanofi. Dr Khan reports being an employee and stockholder of Sanofi. Ms Klimchak reports being an employee of Axtria. Dr Reynolds reports receiving consulting fees from Sanofi. Drs Sanchez and Sasiela are employees and stockholders of Regeneron Pharmaceuticals Inc. No other disclosures were reported.

Figures

Figure 1.. Logic of Lipid-Lowering Treatment Intensification and Proportion of Patients Flowing Through the Treatment Intensification Logic in the Simulation

Final treatment combinations are shown in orange. A20 indicates atorvastatin, 20 mg; A80, atorvastatin, 80 mg; ALI 75, alirocumab, 75 mg; ALI 150, alirocumab, 150 mg; ASCVD, atherosclerotic cardiovascular disease; EZE, ezetimibe; HIS, high-intensity statin; LDL-C, low-density lipoprotein cholesterol; and MIS, moderate- to low-intensity statin. To convert LDL-C levels to millimoles per liter, multiply by 0.0259.

Figure 2.. Use of Lipid-Lowering Treatment and Low-Density Lipoprotein Cholesterol (LDL-C) Level Distribution Before and After Treatment Intensification (Base-Case Scenario A)

The graphs depict base-case scenario A (for definition of scenarios, see Scenario Analyses subsection of the Methods). ALI 75 indicates alirocumab, 75 mg; ALI 150, alirocumab, 150 mg; EZE, ezetimibe; HIS, high-intensity statin; and MIS, moderate- to low-intensity statin. To convert LDL-C levels to millimoles per liter, multiply by 0.0259.

Figure 3.. Use of Lipid-Lowering Treatment and Low-Density Lipoprotein Cholesterol (LDL-C) Level Distribution After Treatment Intensification for Other Scenarios

Scenario B1 consists of patients with LDL-C goals of less than 70 mg/dL with comorbidities and less than 100 mg/dL without comorbidities; scenario B2, 50% reduction of LDL-C levels from baseline; scenario B3, scenario B1 or B2; scenario B4, scenarios B1 and B2; scenario C, threshold for adding alirocumab increased to LDL-C goal of less than 80 mg/dL; and scenario D, ezetimibe removed before adding alirocumab if LDL-C goal of less than 70 mg/dL was not achieved. ALI 75 indicates alirocumab, 75 mg; ALI 150, alirocumab, 150 mg; EZE, ezetimibe; HIS, high-intensity statin; and MIS, moderate- to low-intensity statin. To convert LDL-C levels to millimoles per liter, multiply by 0.0259. For additional information on scenarios, see the Scenario Analyses subsection of the Methods.

Figure 4.. Use of Lipid-Lowering Treatment (LLT) With Full Treatment Intensification Across All Scenarios

Scenarios are ordered by increasing use of proprotein convertase subtilisin/kexin type 9 inhibitor therapy (for definition of scenarios, see Scenario Analyses subsection of the Methods). Scenario A includes reduction of low-density lipoprotein cholesterol (LDL-C) levels to less than 70 mg/dL for all patients and LLT with alirocumab (ALI) as third-line therapy after statins and add-on ezetimibe (EZE). Scenarios B1-B4, C, and D are described in Figure 3. Scenarios A and C used ALI as third-line therapy after statins and add-on EZE. Other scenarios removed EZE before adding ALI if goal LDL-C level was not achieved. ALI75 indicates alirocumab, 75 mg; ALI150, alirocumab, 150 mg; HIS, high-intensity statin; and MIS, moderate-to-low intensity statin. To convert LDL-C levels to millimoles per liter, multiply by 0.0259.