Our study investigated a Canadian cohort of patients with ASCVD and a history of MI, IS, or PAD, and LDL-C above the current recommended threshold on moderate-high intensity statin therapy, making them high-risk for subsequent CV events. Patients had a mean LDL-C value of 2.08 mmol/L, which is also above the previous guidelines’ goal of less than 2.0 mmol/L [14,15,16], and above the current recommended threshold of 1.8 mmol/L [3]. Results demonstrated that CV outcome rates were high for this cohort of patients with ASCVD, and patients continued to experience high total CV outcome rates during the follow-up period. Exploratory subgroup analyses of very high-risk patients with ASCVD identified in the recent CCS guidelines [3] revealed higher CV event rates in patients with recurrent MI and comorbid diabetes compared to the overall cohort. Furthermore, patients with ACS and recent MI had very high rates of additional CV outcomes over time, reinforcing the very high risk of recurrent events. MI and CV death were the most common individual CV events over follow-up, in the overall population and across all very high-risk subgroups. Our findings highlight the sobering high morbidity and mortality rates for patients with ASCVD who remain above recommended LDL-C threshold, despite statin treatment.

The evidence linking reduction in LDL-C to subsequent reduction in CV outcomes has increased substantially over time [17], leading to global adoption of guidelines further lowering recommended thresholds/targets of LDL-C in patients with ASCVD [18, 19]. The lower LDL-C threshold for the use of additional lipid lowering drugs of 1.8 mmol/L has recently been recommended by the CCS to reduce CV risk in patients with ASCVD already receiving maximally tolerated statin [20]. Evidence contributing to this recommendation includes CV outcome clinical trials with non-statin therapies such as ezetimibe (IMPROVE-IT) [21] and PCSK9is (FOURIER [4, 6, 22] and ODYSSEY OUTCOMES [5, 23]). These trials demonstrated the CV benefit of non-statin therapies when added to statin in secondary prevention patients compared to placebo-treated patients. In the FOURIER trial, whose patient characteristics are emulated in our study, the addition of evolocumab to statin therapy resulted in a rapid and sustained reduction in LDL-C down to levels lower than previously reported in other lipid-lowering trials (median achieved LDL-C 0.78 mmol/L). Event rates were 9.8% and 11.3% in the evolocumab and placebo-treated groups, respectively, for the primary endpoint (a composite of CV death, MI, stroke, hospitalization for UA, or coronary revascularization), resulting in significant reduction in CV events (20% relative risk reduction in the composite of CV death, MI and stroke; p < 0.001) [4]. A linear relationship between achieved LDL-C and reduction in CV events was also established [24]. Long-term follow-up with PCSK9i treatment has reinforced this concept [25]. This current analysis captures a similar patient population to the FOURIER study and demonstrates, in a real-world population, the high morbidity and mortality that occurs in these high-risk patients in an era where PCSK9i treatment was not available.

Despite this growing body of evidence, a large care gap still exists in Canada. A recent analysis in Alberta found that 53% of patients with ASCVD and 30% of patients with acute MI were not treated with a statin; less than 3% were treated with ezetimibe [1]. In a population-based cohort of post-percutaneous coronary intervention (PCI) patients in Ontario, over 40% of patients with an LDL-C test remained above 1.8 mmol/L 6 months post-PCI [12]. This was correlated with a significantly higher risk of CV outcomes, which increased the further away from the threshold that patients were [12]. Further, in an analysis of very high-risk patients with recent ACS in Alberta, approximately 80% of patients had an LDL-C above 1.8 mmol/L or non-HDL-C above 2.6 mmol/L within 90 days post-discharge [26]. The authors determined that approximately 40% of the patients assessed in this real-world cohort would have been eligible for treatment intensification with PCSK9i, which could have reduced their risk of further CV events [26]. Indeed, a recent analysis in a post-MI population found that the proportion of patients achieving below the 1.8 mmol/L threshold increased by 77.7% in patients treated with statins and PCSK9i in combination after their MI [27]. This was substantially higher than in patients treated with ezetimibe and statin (45.4%) or with high-intensity statin alone (32.4%) [27]. Taken together, these results reiterate the urgent need to further reduce residual LDL-C-related risk in Canadian patients with ASCVD and support clinical guidelines [3, 18, 19] for therapeutic intensification with non-statin therapies in patients who are unable to attain LDL-C recommended thresholds on statin therapy alone.

In our study, of patients with LDL-C or non-HDL-C level above guideline-recommended thresholds, despite being on moderate to high-intensity statins, ezetimibe use was very low. As a result of the inclusion criteria, the median LDL-C was 1.88 (IQR 1.42–2.55) mmol/L in this cohort and approximately half of these patients had an LDL-C above the currently recommended 1.8 mmol/L. We demonstrated that over the course of follow-up (mean of 41 months), approximately 1 in 5 patients experienced a CV event and nearly 1 in 10 died. This risk is amplified among the very high-risk subgroups in this cohort; patients with ACS and recent MI were identified as having the highest risk of recurrent CV events, with both higher proportions and rates of additional events over follow-up. Notably, approximately half of patients with ACS and recent MI experienced additional CV events, while approximately one-quarter of patients experienced CV death. These results highlight that patients with ACS and recent MI require swift and intensive LDL-C intervention to reduce CV morbidity and mortality. The addition of evidence-based non-statin therapies in line with current Canadian guideline recommendations has the potential to decrease the impact of this care gap. Indeed, this significant reduction in events has been demonstrated with PCSK9is in ODYSSEY OUTCOMES (a 1–12-month post-ACS population) and in a pre-specified analysis of patients with recent MI (< 12 months) in FOURIER [5, 6]. Future research should focus on better understanding how to optimize non-statin therapy use in very high-risk patients with ASCVD, particularly those with ACS and recent MI.

Our study had the strength of examining a large, trial-like population of patients identified with ASCVD in Alberta, Canada; however, some limitations should be considered. First, administrative data are not collected specifically for research; rather, they are for billing, monitoring, and hospital administrative purposes. This may have introduced potential misclassification bias of the study cohort and CV outcomes due to incorrect ICD coding and lack of independent adjudication. CV events were assessed on the basis of inpatient or ED deaths, and Vital Statistics, but as a result of the lag time in the Vital Statistics dataset for out-of-hospital death, rates of CV deaths at the end of our study period may be underestimated. Additionally, administrative health data do not include certain patient and clinical characteristics such as lifestyle factors and behaviors (e.g., smoking), which can impact CV event rates. There are other residual risk factors for CV outcomes including other lipoproteins (i.e., lipoprotein(a), triglycerides), inflammatory risk factors, and smoking, which were not assessed in this analysis. Testing of lipids was not done in a central laboratory, which could lead to variability. Furthermore, the use of a fixed index date could potentially exclude patients who died prior to the three fixed index dates, leading to a reduced sample size and potential selection bias. Another limitation is that the study focused on LDL-C/non-HDL-C levels at baseline; these were not examined over time. Our study also did not track LLTs over time, only at baseline, where the potential of non-adherence or removal of statin/ezetimibe therapy could have inflated incidence rates. Statins could also have been uptitrated, or ezetimibe added, which may have reduced CV outcome rates over time. Finally, other secondary prevention medications were not captured at baseline or during follow-up.