The data from the ELITE study presented here reveal the distribution of Lp(a) in the north-western German population for the first time. At just under 21%, the population studied here is in line with other northern European regions [13]. The increasing number of CVE in recent years highlights the urgent need for a comprehensive prevention strategy. Data already published from the ELITE study show that, in addition to elevated Lp(a), modifiable cardiovascular risk factors are disproportionately prevalent in the risk group and that adequate prevention is often inadequately implemented [18]. The five-year evaluation now available allows the successful outcomes of the intervention and the distribution of endpoints to be analyzed for the first time. The main findings from this analysis were as follows: (1) The number of CVEs (CHD with/without MI, stroke, PAD, carotin stenosis, AF) were significantly more frequent with elevated Lp(a). (2) without significant differences in the expression of the other risk factors in both groups, this difference is mainly due to the elevated Lp(a). (3) the majority of those affected were unaware of their elevated Lp(a) (4) Despite repeated risk communication and education, only a minority of at-risk patients were referred to a specialist. (5) 40% of those affected reported anxiety or worry about their elevated Lp(a), making Lp(a) a previously unknown psychological risk factor.
CVEs with and without mortality occurred significantly more frequently in patients with elevated Lp(a) (p < 0.001). Total mortality and cardiovascular mortality did not differ. The collective was relatively young on average and the follow-up period was only 4.4 years. This is likely to be the reason for the lack of difference in overall and cardiovascular mortality. The most common CVD in both groups was CHD, without significant difference. Due to the existing trends, with a percentage-wise but not significant overrepresentation of newly occurring CHD, the evaluation was performed according to Lp(a) concentration. This confirmed that a significantly elevated Lp(a) level of >120 nmol/l is associated with a significantly higher incidence of new CHD [Lp(a) < 120 nmol/l: 4.0%, Lp(a) >120 nmol/l: 6.1%, p = 0.030]. The differences in heart failure, stroke and atrial fibrillation were not significant. In contrast, carotid stenosis and PAD were significantly more common in patients with elevated Lp(a). It is possible that PAD and carotid stenosis manifest themselves before the onset of ischemic events such as stroke or CHD. Only LDL-C was significantly higher upon admission to Gr2, which is partly due to the LDL-C content of Lp(a) [20]. However, LDL-C fell significantly in both groups, which can be explained by a significant increase in the prescription of lipid-lowering drugs, especially statins, with the increase in prescriptions of lipid-lowering drugs being significantly higher in Gr2. Conversely, a significant increase in Lp(a) levels was observed in patients taking statins. A smaller but still significant increase in Lp(a) levels was also observed in the group not receiving statin therapy. Overall, an increase in Lp(a) levels was evident in both groups and in all subgroups. Significant increases in Lp(a) were also observed when the data were broken down by gender. One reason for this could be that people with elevated Lp(a) were made very aware of the significance of elevated LDL cholesterol and were urgently advised to see a doctor. Early LDL-C reduction in Lp(a) patients has been shown by Ferrence et al. to be a potential strategy to reduce overall risk in an analysis of 445,765 patients from the UK Biobank [21]. Overall, the relevance of under-treatment of hypercholesterolemia is clear. This was also confirmed in the SANTORINI study (Treatment of High and Very High riSk Dyslipidemic pAtients for the PreveNTion of CardiOvasculaR Events). Around 2,000 patients (average age 66) from Germany were analysed. Overall, 80% of patients with high risk and very high risk did not achieve the defined target value. At the start of the study, one fifth of patients did not take lipid-lowering drugs [22]. In our cohort, statin therapy was significantly increased through intensive written recommendations, although it remains alarmingly rare at approximately 20% in the pathological Lp(a) group. One limitation here is that participants were referred to their general practitioner for further treatment with the recommendations. Even though the majority of patients with hyperlipoproteinemia reported having discussed the findings with their GP, the reasons preventing lipid-lowering therapy cannot be fully identified. It remains to be postulated that outpatient management of LDL cholesterol in patients with hyperlipoproteinemia is inadequate.
Of course, the care provided is completely unacceptable. However, this applies equally to the whole of Germany and Europe, as recent data and also surveys from Germany show. In addition, the study was conducted in a predominantly rural region in north-west Germany with a low density of doctors and relatively long distances.
The same applies to further lipid modifying therapies. Only one person was treated with an PCSK9 Inhibitor. Patients with apheresis were not included in the study. These comparatively low figures are most likely due to cost and structural limitations in Germany as only specific patients were eligible for treatment, and initially only certain specialists were permitted to administer these therapies.
The risk of elevated Lp(a) in relation to LDL-C was clearly illustrated by an analysis of the Copenhagen General Population Study. Hedegaard et al. attempted to make the risk of hyperlipoproteinemia more tangible in comparison to familial hypercholesterolemia. An Lp(a) level above 150 nmol/L is equivalent to the risk of clinically diagnosed familial hypercholesterolemia. At plasma levels above 180 nmol/L, participants had an identically high risk of myocardial infarction as genetically diagnosed familial hypercholesterolemia [23].
Overall, the repeated prevention recommendations in ELITE significantly improved the number of risk factors per person in both groups. However, the extent of the reduction is not yet sufficient to achieve a sustained reduction in cardiovascular events. Ultimately, despite improved risk factors, Gr2 with elevated Lp(a) showed significantly more cardiovascular events after 4.4 years.
Strict and early control of all CVRFs is therefore essential. In our cohort, written prevention recommendations improved mean blood pressure in either group, even though the combination of high blood pressure and elevated Lp(a) has also been shown to dramatically increase cardiovascular risk. In a prospective study spanning almost 14 years, Liu et al. showed that patients with elevated Lp(a) and additional hypertension had the highest risk of cardiovascular disease compared to patients with isolated hypertension or isolated hyperlipoproteinemia. The authors therefore hypothesized that hypertension causes vascular damage, allowing Lp(a) to exert its proatherogenic properties [24]. “The Mesa” study also demonstrates this impressively. In this prospective study by Rikhi et al., the cardiovascular risk of isolated hyperlipoproteinemia was not increased compared to a reference group, but only increased significantly when high blood pressure occurred simultaneously [25].
In particular, a lack of physical exercise is a missed opportunity for evidence-based preventive medicine. Although repetitive written information has significantly increased physical activity, the potential of sport is still far from being fully exploited. It has been clearly and repeatedly proven that physical activity at the recommended level leads to a better cardiovascular risk profile [26, 27]. In this cohort, adequate physical activity was also associated with better blood pressure, lower BMI, healthier diet and less psychological stress than in physically inactive individuals [28]. Despite this, only about 43% of the cohort were physically active enough.
The 3 F studies already demonstrated that regular exercise can safely optimise blood pressure profiles. In this study, patients were introduced to exercise through regular physical activity as part of a modified football training program, and their vital signs were evaluated during training and in everyday life [29, 30].
There is also clear room for improvement in terms of education and awareness. The majority of participants with elevated Lp(a) were unaware of its pathogenicity, and only about 30% were referred by their general practitioner to specialists. For the vast majority of participants with elevated Lp(a), the pathological finding had no impact on their medication or lifestyle. This leads to the subjective assessment of those affected that they do not feel adequately cared for by their doctors, which in turn leads to anxiety in almost 40% of participants. However, some results regarding psychosocial issues have not yet been fully evaluated. Since the Elite Study placed particular emphasis on psychosocial factors, further analyses of the influence of these factors will follow based on the data collected here.
The significant reduction in nicotine abuse in both groups is encouraging. The literature shows that smoking in combination with elevated Lp(a) increases cardiovascular risk [31, 32]. This group therefore benefits greatly from giving up nicotine. The success of the therapy is attributed to intensive education and regular reminders about the significantly increased risk of cardiovascular disease. Other studies have also shown that the prevention of cardiovascular disease is not being implemented optimally. In a systematic review Álvarez-Bueno et al. found that the effectiveness of primary prevention of cardiovascular disease in primary care has only limited to moderate success [33]. In addition, a study in the USA showed that around half of doctors do not follow guidelines for the prevention of cardiovascular disease in 50% of cases [34].
The debate surrounding adequate, comprehensive cardiovascular prevention in Germany (similar to various oncological diseases) is currently louder than ever. The DANCAVAS study investigated whether cardiovascular screening tests can reliably and effectively identify people with heart disease. To this end, 46,000 people in Denmark between the ages of 65 and 75 with no previous cardiovascular disease were randomly assigned (2:1) to a screening group (cardio CT, cholesterol, blood sugar) and a non-screening group. In a relatively short observation period of approximately 5 years, the mortality risk in the screening group was reduced (from 13.1% to 12.6%) [35]. It is hoped that Lp(a) will be included in future preventive studies. However, this poses a problem, as established risk scores do not currently include Lp(a). In this regard, Nurmohamed et al. conducted an evaluation in which they included Lp(a) in the SMART Score and SCORE. When Lp(a) was taken into account, 31% of primary prevention patients and 62.5% of secondary prevention patients with elevated Lp(a) had to be reclassified into a higher risk category [36]. Again, the authors suggest routine testing.
Although the data available from the ELITE study demonstrate the effectiveness and success of regular, individual counselling in controlling CVRF, they also highlight major shortcomings in outpatient care. This is particularly relevant for the patient group with elevated Lp(a), which is already an intrinsic high-risk group. The high-risk group of patients with elevated Lp(a) requires even more attention with regard to the control of all modifiable CVRF. The most prominent example here is the lack of adherence to lipid-lowering therapy as also shown in EUROASPIRE [37]. These results give cause not only to educate patients about the benefits and necessity of treatment with lipid lowering therapy, but also to seek dialogue with the treatment general practitioners in order to ensure adequate therapy. This has been done in the ELITE study.
In the ÄSP study, Schneider et al. already investigated cardiovascular prevention work carried out by general practitioners in Germany. This revealed concerning deficits in cardiovascular risk communication and prevention. The main reason given is, in the eyes of the general practitioners, the intervention is unlikely to be successful. The data from the ELITE study prove the opposite. This makes it all the more important to communicate the successes of adequate risk prevention in the outpatient sector as well. Good risk communication works [38].
Limitations and strengths
One limitation of this registry study is the lack of a randomized control group. Majority of the data collected is based on information provided by the participants, which means that the accuracy of the information cannot be verified. In any case, the majority of data were collected primarily through letters from clinics, specialists and general practitioners. This ensured a high level of expertise regarding new diagnoses and changes in patients’ health. However, this is offset by the fact that all participants were regularly examined and interviewed in person. Where possible, the reasons for changes in responses were also investigated. The close contact and personal visits provide a relative assurance that the information provided by the participants is truthful. For the accurate recording of cardiovascular events, we relied on the corresponding findings of the treating physicians. Therefore, in the event of missing data, research was carried out at hospitals, with physicians and also with the participants or their relatives. The strengths of this study lie in the systematic and thorough recording of all CVRF and the repeated personal visits. In addition, the personal situation and lifestyle (physical activity, stress, depression, well-being) were also recorded. A particular strength is the personal visits and conversations, including written recommendations.
link