Lipid-lowering therapy in a real-world setting : eligibility, utilization, and goal attainment

Introduction

Low-density lipoprotein cholesterol (LDL-C), and other lipid fractions containing apolipoprotein B, have been identified as key components in the process of atherogenesis and consequently the progression to cardiovascular disease (CVD). Lowering LDL-C with lipid-lowering therapy has been identified as an important aspect in the reduction of the incidence of atherosclerotic CVD (ASCVD) events. The European Society of Cardiology (ESC) have published guidelines on LDL-C and provided recommendations on the use of lipid-lowering therapy. This thesis aimed to evaluate the implementation and potential implications of these recommendations in a real-world setting.

Methods and results

In study I, the attainment of the LDL-C goals of the 2011 (<1.8 mmol/L or ≥50% reduction from baseline levels) and the 2016 (<1.8 mmol/L and >50% lowering from baseline levels) ESC guidelines were evaluated. Using nationwide registers, including the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART), we identified all adult patients <75 years with MI registered in SWEDEHEART between 2013 and 2017. We included those with available lipid data at follow-up visits 6-10 weeks (n=25,466) and 12-14 months (n=17,117) after the index MI. At both follow-ups, 84% (6-10 weeks) and 69% (12-14 months) of the patients were receiving high-intensity stain monotherapy. The fulfillment of the LDL-C goals of the 2011 guidelines were 64% at both follow-up visits. The proportion of patients that fulfilled the goals of the 2016 guidelines was 32%, at both follow-ups. When the goal attainment at follow-up visits before vs. after the publication of the 2016 guidelines were compared, the goal attainment improved from 30% to 35% (6-10-week visit), and from 28% to 38% (12-14-month visit), after the release of the 2016 guidelines.

In study II, the potential implications of implementing the 2019 ESC dyslipidemia guidelines and the eligibility of combination lipid-lowering therapy were evaluated. Using data from SWEDEHEART and other national registries, the application of the 2019 ESC guideline goals (<1.4 mmol/L and >50% baseline level reduction) and recommendations were assessed in a cohort of patients at 6-10 weeks after the index MI (n=25,466). Using a Monte Carlo simulation model, the effects of maximizing and escalating treatment with lipid-lowering therapies on the attainment of the 2019 LDL-C goals were estimated. Despite most patients (87%) receiving high-intensity statin therapy, 83% of the cohort were still eligible for escalation of their lipid-lowering therapy since they had not attained the 2019 LDL-C goals. Simulating the use of maximized high-intensity statin therapy, 20% of the cohort reached the goals, and adding therapy with ezetimibe an additional 29% percent reached the goals. Thus, 51% of the cohort were still eligible for additional therapy with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. After therapy with PCSK9 inhibitors were simulated, approximately 90% of all patients reached the LDL-C goals.

In study III, in accordance with the 2021 ESC guidelines, the prevalence of CVD risk categories and the proportion potentially eligible for lipid-lowering therapy were assessed in apparently healthy individuals. Using the Swedish Cardiopulmonary Bioimage Study (SCAPIS), which randomly invited individuals in Sweden aged 50- 64 years, apparently healthy individuals were identified. Applying the Systemic Coronary Risk Estimation 2 (SCORE2) equation to these individuals (n=26,570), 32% and 4% were estimated as having high and very high 10-year risk of fatal and nonfatal CVD, respectively. Among these individuals, 99% had LDL-C levels above the guidelines' targets, resulting in 35% of the total cohort being eligible for lipid- lowering therapy as per the 2021 guidelines. In individuals eligible for lipid-lowering therapy, 38% had no evidence of atherosclerosis in their coronary arteries according to computed tomography. When the SCORE2 multicell chart was used, the proportion eligible for lipid-lowering therapy was 52%, in which 44% had no evidence of coronary atherosclerosis. The use of lipid-lowering therapy was reported in 7% of those with high and very high risk, and an additional 11% received lipid-lowering therapy within 6 months after participating in SCAPIS.

In study IV, utilization and discontinuation rates of secondary preventive medications (statins, renin-angiotensin-aldosterone system (RAAS) inhibitors, beta-blockers, and low-dose aspirin) after an MI were evaluated. We identified all adult patients with a first-time MI that survived >30 days and were registered in SWEDEHEART during 2006-2021. Information on filled prescriptions were collected from national registries, and each drug class was analyzed separately for initiation, discontinuation, reinitiation, and the proportion of patients with ongoing therapy within 1-12 years after the index MI. We identified 122,288 patients discharged with a first statin prescription, 79,968 with a RAAS inhibitor, 105,095 with a beta-blocker, and 127,463 with low-dose aspirin. After discharge from the index MI, the proportion of patients filling a first prescription ranged from 95%-97% across the drugs. Using a grace period of 90 days, 12%-14% of those who initiated therapy discontinued it at 1 year, 79%-82% at 5 years, and 74%-79% at 12 years after the index MI. Among the patients who discontinued therapy, the rates of reinitiation ranged from 28% to 46% at 1 year, 42% to 62% at 5 years, and 47% to 67% at 12 years. The proportions of patients who were alive and had ongoing treatment (regardless of previous discontinuation) were 91%-92% at 1 year, 79%-82% at 5 years, and 74%-79% at 12 years after the index MI.

Conclusions

In a nationwide real-world setting in Sweden, the LDL-C goals of the 2011 and 2016 ESC dyslipidemia guidelines were not attained in many patients with a recent MI. When applying the 2019 ESC dyslipidemia guidelines on patients with an MI, despite maximizing the use of high-intensity statins and ezetimibe, eligibility for PCSK9 inhibitors was estimated to be present in approximately half of the patients. In apparently healthy middle-aged individuals, application of the 2021 ESC guidelines resulted in 35% being eligible for lipid-lowering therapy, with many having no signs of coronary atherosclerosis. After a first-time MI, many patients discontinue therapy with CVD preventive medications during a period of 1-12 years. However, many patients later reinitiate previously discontinued therapy, and among alive patients many have ongoing treatment at 1-12 years after the MI.

List of scientific papers

This thesis is based on the following papers, which will be referred to by their corresponding Roman numerals:

I. Ali Allahyari*, Tomas Jernberg, Dominik Lautsch, Pia Lundman, Emil Hagström, Jessica Schubert, Robert Boggs, Stina Salomonsson, Peter Ueda. Low-density lipoprotein-cholesterol target attainment according to the 2011 and 2016 ESC/EAS dyslipidaemia guidelines in patients with a recent myocardial infarction: nationwide cohort study, 2013-17. European Heart Journal - Quality of Care and Clinical Outcomes. Volume 7, Issue 1, January 2021, Pages 59-67. https://doi.org/10.1093/ehjqcco/qcaa016

II. Ali Allahyari*, Tomas Jernberg, Emil Hagström, Margret Leosdottir, Pia Lundman, Peter Ueda. Application of the 2019 ESC/EAS dyslipidaemia guidelines to nationwide data of patients with a recent myocardial infarction: a simulation study, European Heart Journal. Volume 41, Issue 40, 21 October 2020, Pages 3900-3909. https://doi.org/10.1093/eurheartj/ehaa034

III. Ali Yari, Peter Ueda, Pia Lundman, Joakim Alfredsson, Annica Ravn- Fischer, Stefan Söderberg, Troels Yndigegn, Emil Hagström, Tomas Jernberg. Eligibility for lipid-lowering therapy when applying systemic coronary risk estimation 2 according to guidelines on apparently healthy middle-aged individuals. European Journal of Preventive Cardiology. Volume 31, Issue 15, October 2024, Pages 1890-1897. https://doi.org/10.1093/eurjpc/zwae190

IV. Ali Yari, Carl-Emil Lim, Emil Hagstrom, Pia Lundman, Jessica Schubert, Tomas Jernberg, Peter Ueda. Utilization and discontinuation of secondary preventive medications after myocardial infarction: a nationwide cohort study. [Manuscript]

*Former last name