Introduction
Cardiovascular disease (CVD) is the most frequent cause of death in Austria, claiming 31,403 lives in 2021 [
1]. One of the main risk factors for CVD is high low-density lipoprotein cholesterol (LDL-C), which is associated with increased cardiovascular (CV) events [
2]. There is strong evidence that the larger the reductions of LDL‑C, the greater the reduction in the CV event rate [
3‐
5]. Evidence from Mendelian randomization studies suggests that there is no risk in lowering LDL‑C to very low levels [
6,
7]. Therefore, it is important to manage elevated LDL‑C levels effectively and early in patients at risk of CVD [
3,
8,
9], as shown by the FOURIER open-label extension study [
10]. According to the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines on LDL‑C goals and lipid lowering therapy (LLT), patients with very high CV risk should achieve LDL‑C levels of < 55 mg/dL, and those with high CV risk should achieve < 70 mg/dL, with an LDL‑C reduction by ≥ 50% from baseline or estimated untreated levels in both groups. In individuals with extremely high CV risk, i.e. those with preexisting atherosclerotic cardiovascular disease (ASCVD) who experience a second vascular event within 2 years despite taking maximally tolerated statin therapy, an LDL‑C goal of < 40 mg/dL may be considered [
11]. In the past, and prior to the widespread availability of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), studies consistently demonstrated the difficulty of achieving the recommended goals [
12‐
17]. There is compelling evidence that patients with insufficient LDL‑C reduction need a combination of high-intensity statins and other LLTs [
8,
9,
11,
17‐
19]. Moreover, maintaining attained LDL‑C reductions is important for preventing CV events [
20,
21]. LDL‑C stability over time depends on persistence with therapy and on response variability to the administered treatments [
22].
The HEYMANS (cHaractEristics of hYperlipidaeMic pAtieNts at initiation of evolocumab and treatment patternS) study [
16,
23], showed large and sustained LDL‑C reductions and high persistence to evolocumab on a population level in the real-world setting across 12 European countries. Data from the Austrian HEYMANS cohort are reported here.
Discussion
Previous studies have consistently demonstrated inadequate LDL‑C goal attainment across regions and healthcare settings. LDL‑C goal attainment mainly depends on two factors: the severity of dyslipidemia and the treatment intensity. Treatment intensity not only depends on the prescribed medication but also on adherence to treatment. In the Austrian HEYMANS cohort, the median baseline LDL‑C was 142 mg/dL, which was reduced by 59% within the first 3 months of evolocumab therapy. Sixty-five percent achieved the LDL‑C goal of < 55 mg/dL. Patients receiving evolocumab with background LLT had higher levels of LDL‑C goal attainment (76% versus 55%, respectively).
In Austria, patients received evolocumab mostly in secondary prevention (i.e. after they had already experienced a CV event). This is in accordance with the Austrian reimbursement regulations, which restricts PCSK9i use to secondary prevention in patients on maximally tolerated statin/ezetimibe therapy. At the onset of the study, reimbursement regulations further required patients to meet certain LDL‑C levels before (> 100 mg/dL) and during treatment (target of < 70 mg/dL), based on the 2016 ESC/EAS dyslipidemia guidelines in force at the time [
25]. During the enrolment period, initial PCSK9i prescriptions and thus high-intensity combination therapy, could only be provided in 27 specialized centers of endocrinology and metabolic diseases appointed by the Austrian Federation of Social Insurances [
24]. However, in July 2022, after this study was completed, the Austrian health authorities allowed more specialties (cardiologists and neurologists) to prescribe evolocumab, the numbers of appointed centers increased to 100, and the treatment reimbursement threshold was lowered to > 70 mg/dL with an on-treatment target of < 55 mg/dL [
26], as recommended by the 2019 ESC/EAS guidelines [
11]. These changes represent an important step to improve access to intensified LLT for patients at very high CV risk in Austria.
The DA VINCI study was a multinational survey that examined how well patients with high or very high CV risk achieved their LDL‑C goals. The study was conducted before PCSK9i were widely used (only 1% used a PCSK9i in DA VINCI). In the Austrian DA VINCI cohort, only 38% reached their risk-based LDL‑C goals, which were < 55 mg/dL for very high CV risk and < 70 mg/dL for high CV risk. Among secondary prevention patients, only 23% attained LDL-C < 55 mg/dL, despite receiving high-intensity statins (45%), moderate-intensity statins (34%) or a statin-ezetimibe combination (14%) as the most frequently prescribed LLTs [
12]. While there were some differences in goal achievement between men (75%) and women (50%) in Austria, it should be noted that women had a higher baseline LDL‑C and were less likely to receive a high-intensity statin or combination with ezetimibe. In the Austrian DA VINCI cohort [
12], women were also less likely to attain their LDL‑C goals. In the FOURIER trial, LDL‑C reductions were greater in men (58%) than women (52%,
p < 0.001) but absolute CV risk reduction was similar [
27].
In HEYMANS Austria, approximately two-thirds (66%) received evolocumab after they were found to be intolerant to at least one statin; 94% of patients were in secondary prevention. The findings from HEYMANS indicate that adding evolocumab to the LLT regimen increases the proportion of secondary prevention patients who achieve their LDL‑C goal of < 55 mg/dL. The 65% of patients who attained this goal in HEYMANS marks a vast improvement over the 23% in secondary prevention in DA VINCI Austria [
12]. The overall DA VINCI study, which included 18 countries and 5888 patients, allowed identification of key clinical insights, such as the importance of highly intensive combination therapy to attain recommended LDL‑C goals [
17]. The HEYMANS study confirms these insights from DA VINCI that intensive combination therapy is necessary to reach recommended LDL‑C levels.
In the Austrian HEYMANS cohort, more than half of patients did not receive a statin and/or ezetimibe. The Austrian reimbursement criteria mandate documentation of indicators of statin intolerance, defined as therapeutic attempts with more than one statin (at minimum atorvastatin and rosuvastatin) which led to myopathies and exceeding creatinine kinase normal values by at least 5 times or occurrence of a severe hepatopathy [
24]. In the study setting, where all patients were treated in PCSK9i centers with extensive knowledge and experience in dyslipidemia management, it must be assumed that patients received the best possible treatment combination in their respective circumstance of very high CV risk and often combined with statin intolerance.
As stated above, the LDL‑C level at treatment initiation is an important factor in achieving recommended LDL‑C goals. The higher the initial LDL‑C level, the more difficult it becomes to reach LDL-C < 55 mg/dL, which is recommended for very high-risk patients. This leads to the question of why physicians did not refer patients to specialized PCSK9i centers for initiation of highly intensive combination therapy as early as possible when they were not attaining their LDL‑C goals despite taking statins. In clinical practice, individuals with high LDL‑C levels are often first identified in primary care. General practitioners initiate statins as a first step to lower lipid levels and advise on life-style changes. It can be assumed that referrals to specialized clinics often involve only those patients who have LDL‑C levels farthest away from the goal (i.e. those with the highest LDL‑C levels). This is supported by the finding that most patients in our analysis had no background LLT before (62%) or at the start of evolocumab (52%). In patients not receiving background LLT at baseline, LDL‑C was substantially higher than in those with background LLT, which can be considered a contributor to the lower goal attainment in these patients. As evolocumab was relatively new at the time of the study, the population enrolled may be biased towards patients for whom there was no adequate treatment as the time. Across the countries participating in HEYMANS, it was consistently found that patients were often started on evolocumab when their LDL‑C levels were above the threshold set by the insurers or the government [
16]. In addition to the barriers within general practice, patients released from hospitals after an acute vascular event and receiving an initial LLT prescribed by the hospital, are not always adequately followed-up to monitor if they have reached their recommended target LDL‑C levels. Therefore, their LLT might not be intensified as needed. It is therefore essential to raise awareness on the importance of starting intensive LLT as soon as possible after a vascular event, ideally high-intensity statins ± ezetimibe with intensification using PCSK9is. For patients who cannot tolerate statins and are receiving evolocumab monotherapy, additional options for treatment intensification could include low dose statins, ezetimibe, bempedoic acid, or a combination of bempedoic acid and ezetimibe.
This study has some limitations. In Austria, recruitment started in May 2016 when PCSK9is were relatively newly reimbursed. Therefore, the patients selected for evolocumab treatment and subsequently enrolled into this study may have been those who had persistently high LDL‑C levels despite previous therapies. A selection of more difficult-to-treat patients may have impacted on the findings. Evolocumab persistence may have been slightly overestimated by two factors: patients who were receiving evolocumab for a longer period before enrolment (maximum 6 months) may have been more likely to continue with their treatment than those who initiated treatment closer to the enrolment date. The centers participating in the HEYMANS study were the first to prescribe PCSK9is and had high expertise in all aspects of dyslipidemia management. Such specialists may have been more likely to motivate patients to continue with treatment and to monitor them more closely than a typical scenario in primary care. Nevertheless, our results are similar to those of previous studies on evolocumab persistence [
23,
28,
29] and adherence [
30]. The study protocol was amended to extend the observation period from 12 to 30 months. Some study centers declined to participate in the extension phase. However, treatment centers in Austria generally follow the same therapeutic principles. Therefore, possible bias resulting from the discontinuation of some study centers is unlikely. Finally, all observational studies carry a risk of potential data misclassification.
Declarations
Conflict of interest
C. Ebenbichler received research grants from NovoNordisk, Sanofi and AAS, consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Novartis and Sanofi, and gave lectures for Amgen, Novartis and Sanofi. H. Toplak has received research grants from Amgen, Sanofi, Novartis, MSD and Regeneron, consulting fees from Amgen, Sanofi, Novartis, Mylan, Takeda, Servier and AstraZeneca, and has lectured for Amgen, Sanofi, NovoNordisk, Mylan, AstraZeneca and Pfizer. M. Hemetsberger received consulting fees from Amgen and owns Amgen shares. K.K. Ray reports grants from Amgen during the conduct of the study; personal fees from AbbVie, Aegerion, Akcea, Algorithm, AstraZeneca, Bayer, Boehringer Ingelheim, Cerenis, Cipla, Dr Reddys, Esperion, Kowa, Lilly, Novartis, Silence Therapeutics, Takeda, The Medicines Company, and Zuelling Pharma; and grants and personal fees from Amgen, Daiichi Sankyo, MSD, Sanofi–Regeneron, and Pfizer, outside the submitted work. I. Bridges, N.N. Dhalwani and R. Hoelzl are employees of Amgen and own Amgen shares. H. Drexel and U. Hanusch declare that they have no competing interests.
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