Early combination lipid-lowering therapy is associated with greater achievement of goal LDL-C: Insights from the OPTIMIZE PAD-1 trial

Low-density lipoprotein cholesterol (LDL-C) lowering reduces ischemic risk in patients with peripheral artery disease (PAD).^1,2 Large outcomes trials have demonstrated that ‘lowest is best’ for LDL-C and ischemic risk reduction, and guidelines have recommended increasingly lower thresholds for high-risk patients, including goal LDL-C < 55 mg/dL and/or ⩾ 50% reduction from baseline.^1,2 Despite supporting evidence, lipid-lowering therapies remain underutilized in patients with PAD. ³

Implementation studies, such as OPTIMIZE PAD-1 (Implementation of Vascular Care Team to Improve Medical Management of Peripheral Artery Disease Patients, ClinicalTrials.gov ID: NCT04400409), have been designed to evaluate models of care that may address treatment gaps. OPTIMIZE PAD-1 demonstrated that a vascular care team using a clinical pharmacist-driven algorithm-based treatment was more effective than provider education for achieving LDL-C goals in patients with PAD. ⁴ One aspect of the OPTIMIZE PAD-1 algorithm was an emphasis on early prescription of combination therapy consisting of concomitant use of therapies from two or more different medication classes to achieve goals rather than a strategy of initial statin prescription with titration over time, including subsequent adjuncts to statin therapy. After accounting for baseline LDL-C and lipid-lowering medications, combination therapy was prescribed upfront for vascular care team patients for whom it was deemed necessary to achieve goal LDL-C but was not necessarily required for all patients, including some patients not on any lipid-lowering medications at baseline. Whether combination therapy, as opposed to high-intensity statin monotherapy, was associated with improved achievement of LDL-C goals has not been described.

In OPTIMIZE PAD-1, medications and LDL-C values were collected at baseline, 6 months, and 12 months. Combination therapy at baseline, month 6, or month 12 was defined as concurrent use of two or more of the following classes of medications: statin, ezetimibe, or proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i). High-intensity statin was defined according to clinical practice guidelines. ⁵ The proportions of patients with achieved LDL-C according to the lipid-lowering regimen were compared using chi-squared tests. The protocol was approved by the Colorado Institutional Review Board, and all participants provided informed consent.

Among 114 randomized patients, the mean age was 66 years, 36.0% were women, 84.2% were White, 30.7% had diabetes, and 35.1% had coronary artery disease. Baseline combination therapy was used in none of the 57 vascular care team patients and 2 (3.5%) of the 57 usual care patients. At 6 and 12 months, combination therapy was prescribed in 61.4% (n = 35) of the vascular care team and 5.3% (n = 3) of the usual care patients, representing absolute increases of 61.4% and 1.8% from baseline, respectively (Figure 1A). Among patients on combination therapy, 44.7% (n = 17) had ezetimibe added to statin, 26.3% (n = 10) had PCSK9i added to statin, and 26.3% (n = 10) had both added, usually in sequence; 2.6% (n = 1) received combination ezetimibe and PCSK9i.

Figure 1.

(A) The absolute change in combination therapy use from baseline to 12 months in vascular care team patients versus usual care patients. (B) The 12-month achieved LDL-C in patients on combination therapy versus high-intensity statin monotherapy.

Twelve-month LDL-C levels according to the prescribed lipid-lowering regimen were examined among 105 patients (at 12 months, four patients died, and five were alive but without available LDL-C). Among 37 patients on combination therapy, the mean LDL-C was 44.1 mg/dL; LDL-C levels were < 55 mg/dL for 78.4% (n = 29), 55–69 mg/dL for 10.8% (n = 4), and ⩾ 70 mg/dL for 10.8% (n = 4). Among 68 patients not on combination therapy, the mean LDL-C was 86.7 mg/dL; LDL-C levels were < 55 mg/dL for 16.2% (n = 11), 55–69 mg/dL for 20.6% (n = 14), and ⩾ 70 mg/dL for 63.2% (n = 43). A comparison of 12-month LDL-C levels among patients on combination therapy (n = 37) versus high-intensity statin monotherapy (n = 33) similarly demonstrated lower LDL-C and greater LDL-C goal achievement with combination therapy (Figure 1B).

In OPTIMIZE PAD-1, combination lipid-lowering therapy was associated with lower LDL-C and higher likelihood of achieving goal LDL-C compared with non-combination therapy. Current guidelines recommend the initiation of high-intensity statin therapy for patients with PAD and the addition of nonstatin therapies if not at goal. However, this analysis demonstrates that high-intensity statin monotherapy is insufficient to achieve goal LDL-C in the majority (~80% using a 55 mg/dL threshold) of patients. Taken together, these results demonstrate that the guideline-recommended strategy of statin monotherapy and ‘wait and see’ titration is only successful in ~20% of patients over 1 year, leaving four out of five patients with unaddressed residual LDL-C-related risk. In contrast, early algorithm-based combination therapy directed by a clinical pharmacist achieved LDL-C goals in ~80% in as little as 1 month from evaluation. These findings support algorithm-driven combination therapy delivered through an interprofessional vascular care team as an effective strategy for getting patients on combination therapy to achieve their goal LDL-C.