When the death toll from atherosclerotic disease was significantly rising in the first half of the twentieth century [2] the first big research question was: why? The beginning of research in prevention was therefore defined by the risk factor hypothesis. In essence the concept of risk factors for diseases implies that any disease is associated with the presence of non-modifiable (e.g. gender, age, ethnicity) and modifiable risk factors (e.g. eating habits, exposure to certain environmental conditions, exercise frequency). The advantage of risk factor research is that it may identify potential areas for preventive intervention without the need to fully understand the pathophysiology of the disease itself. Risk factor studies are typically carried out in a large representative population sample of clinically healthy individuals who are characterized at baseline by a standardized interview and clinical examination and measurement of physiologic baseline values (i.e. blood pressure, heart rate, exercise capacity). This large cohort is then longitudinally followed and reexamined e.g. on an annual basis to confirm the vital status and the presence/absence of the disease under investigation. Typical clinical end-points in the first cardiovascular risk factor studies were death from any cause, cardiac death (as confirmed by autopsy or clinical assessment), myocardial infarction (as suspected by typical ECG changes like Q-waves).

The classical example of a prospective risk factor study that laid the foundation for future preventive strategies is the Framingham study [3]. In this study smoking, hypertension, and elevated cholesterol were identified as principal risk factors for cardiovascular disease [4]. Due to the difficult post-war situation in Europe the first prevalence studies in Europe did not appear before the 1960s [5]. The era of the large-scale risk factor studies saw a further landmark publication in 2004, when the results of the global INTERHEART study were published [6]. Risk factor studies evolved into two different directions during the last two decades: On the one hand, risk factor prevalence studies were pooled across Europe to develop a simple and valid risk prediction model (the SCORE model) [7]. On the other hand, researchers moved away from traditional environmental risk factors and used high-throughput genetic testing to identify genes variants such as 9p21 associated with increased cardiovascular risk [8].

Genetic studies have already lead to new therapeutic approaches in CVD prevention: In the 1970s cardiologists observed that members of a family with hypercholesterolaemia due to a mutation in the LDL-receptor had premature heart attacks in the second and third decades of life [9]. More recently, it was shown that African-Americans with a loss-of-function mutation of the PCSK9 gene had a 28 % reduction of class LDL-C levels and a reduction of 88 % in the risk of coronary artery disease [10].

Both observations stimulated the development and clinical prospective testing of statins and PCSK9 inhibitors, which lower LDL-C independent of statins. Landmark studies in this area were the 4S study (Scandinavian Simvastatin Survival Study [11] and many other statin studies. The first outcome studies of the new highly potent PCSK9 inhibitors have just begun (e.g. ODYSSEY Outcomes) but the large reductions by two thirds seen in statin-pretreated patients suggest major advances further reducing cholesterol-related CVD mortality [12].

Prospective randomised risk factor intervention studies are pivotal for proving that reversal of a risk factor actually results in reduced CVD mortality. They continue to play a significant role in determining target levels for optimal blood pressure, cholesterol levels, glucose levels and other parameters, which can be influenced by medications (Fig. 2).

During the last three decades regular physical exercise has received increased attention to its potent effects on reducing cardiovascular morbidity and mortality. However, physiological studies were needed to better understand the cardio- and vasculoprotective effects of the intervention. During the 1990s both animal and clinical studies showed that exercise led to improved endothelial function through repetitive increases in laminar are shear stress at the vascular vessel wall [13, 14].

Studies like these are important in two regards: (1) They replace a statistical association between increased exercise activity and reduce cardiovascular mortality by a causal mechanism. Better understanding of this mechanism, in turn, helps to optimise the treatment intervention in order to achieve greater gains in cardiovascular health. (2) Identifying specific mechanisms related to reduce cardiovascular events can ideally lead to targets for future pharmaceutical interventions.

Today, we have a well-established concept of non-modifiable and modifiable risk factors which are potential targets for interventions to prevent the development and progression of cardiovascular diseases. In PubMed we will find 5266 publications on clinical trials in statin therapy. However, no more than 144 articles have been published worldwide on clinical trials in cardiovascular prevention implementation.

Research in this area is fundamentally different from the traditional concept of full-spectrum multicentre randomised clinical studies. It focuses on testing an implementation strategy (i.e. a strategy to identify and treat risk factors in certain in hospital or outpatient environment) versus usual care in its effects on cardiovascular risk factors or outcomes. A recent example of such a study is a recent publication on “The impact of a bodyweight and physical activity intervention (BeWEL) initiated through a national colorectal cancer screening programme: randomised controlled trial.” [15] Studies like these are not just scarce but also quite recent: the first ones were not published before 1989 (Fig. 1).

What are the reasons for the current lack of effective prevention implementation?