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Highlight on Gaps in Evidence in the 2016 European Guidelines on CVD Prevention in Clinical Practice

One of the latest changes in ESC Guidelines is to insert a section about gaps in evidence. The latest European Guidelines on CVD Prevention deal with various risk factors and their integration into a risk score, in which, although we are improving, we still have gaps in our evidence-based knowledge.

In the following article the most important gaps in evidence from the 2016 European Guidelines on CVD Prevention in Clinical Practice will be highlighted.

Risk Factors and Prevention

Total Cardiovascular Risk

  • There are no recent RCTs of a total risk approach to risk assessment or risk management.
  • The young, women, older people and ethnic minorities continue to be underrepresented in clinical trials.
  •  A systematic comparison of current international guidelines is needed to define areas of agreement and the reasons for discrepancies.

Family History - Epigenetics

  • The impact of adding family history to the current SCORE risk equation should be assessed.
  • Future studies should assess the power of different genetic risk scores to improve CVD risk prediction in several different populations, the number of events prevented and the cost effectiveness of including genetic data in the risk assessment

Psychosocial risk factors

  • It remains unknown whether routine screening for psychosocial risk factors contributes to fewer future cardiac events.

Circulating and urinary biomarkers

  • Biomarkers may be useful in specific subgroups, but this has been addressed in only a limited number of studies.
  • The role of metabolomics as risk factors for CVD and to improve CV risk prediction beyond conventional risk factors should be further assessed.

Measurement of preclinical vascular damage

  • Currently, most imaging techniques have not been rigorously tested as screening tools in CV risk assessment; more evidence on calibration, reclassification and cost-effectiveness is still needed.
  • The reduction of CVD risk in patients treated with lipid- or BP-lowering drugs because of reclassification with, for example, CAC or ABI remains to be demonstrated

Patients treated for cancer

  • Evidence on the effect of early preventive measures to reduce type I cardiotoxicity is inconclusive.
  • The most appropriate strategy to improve risk stratification and prevent CVD in patients treated for cancer needs to be tested prospectively.

Autoimmune disease

  • The association between non-RA immune inflammatory disease and CVD is less clear than for RA.
  • The relationship between anti-rheumatic drugs and CV risk is unknown.

Individuals <50 years of age

  • Age to commence formal CV risk estimation.
  • Whether and how to screen populations for FH.

Female specific conditions

  • The degree to which increased CVD risk associated with several of the female-specific conditions occurs independent of conventional CVD risk factors is unknown.
  • Information on whether female-specific conditions improve risk classification in women is unknown.

Ethnic minorities

  • Studies focusing on CVD risk and the prevalence of CVD risk factors among minorities in Europe are needed.
  • Validation of the SCORE risk estimation among ethnic minorities is needed.
  • Ethnicity-specific thresholds to define high risk (based on the SCORE evaluation) should be identified.
  • Alternatively, ethnicity specific CVD risk equations should be developed.

Psychosocial factors

  • Evidence that treatment of clinically significant depression and anxiety alone will prevent CVD and improve outcomes is inconclusive.

Sedentary behaviour and Physical Activity

  • The lower and upper limit of aerobic PA intensity, duration and frequency to exert a beneficial effect is unknown.
  • The effectiveness of PA monitoring vs. simple counselling to optimize the motivation of patients to adhere to active lifestyle is unknown.
  • The role and sustainability of modern technology (such as wearable technology, ‘exergaming’ and smartphone apps) for motivating people to undertake more PA has not been established.


  • The biggest challenge in dietary prevention of CVD is to develop more effective strategies to make people change their diet (both quantitatively and qualitatively) and to maintain that healthy diet and a normal weight.
  • Research into the substances in foods that underlie the protective effects is ongoing.

Body Weight

  • Knowledge and implementation of effective strategies to achieve weight loss and maintain a long-term healthy weight.
  • Identification of the relative roles of diet, exercise and behavior modification in the management of overweight and obese people.
  • The optimal level of BMI over the life course (at older ages and after a CV event).

Lipid Control

  • Triglyceride or HDL-C values as a target for therapy.
  • Whether Lp(a) lowering against background statin therapy can reduce the risk of CVD.
  • How to increase adoption of non-HDL-C and non-fasting samples in clinical practice.
  • Whether functional foods and food supplements with a lipid-lowering effect can safely reduce the risk of CVD.

Diabetes Mellitus

  • There is a need to examine whether a type 2 DM CV risk score based on either 10 year or lifetime risk helps to improve targeting of preventative therapies and leads to a reduction in CV risk or a gain in lifetime years free from disease.
  • Further trial data are needed to establish if the empagliflozin outcome findings hold for other classes of SGLT2 inhibitors and to better understand the mechanisms of benefit. It would also be useful to know if SGLT2 inhibitors lessen CV mortality and HF risks in patients with DM but without CVD.
  • More research on the benefits of glucagon-like peptide 1 (GLP-1) receptor agonists on CVD risk is needed and trials are due to be reported in subsequent years. Early evidence suggests no CVD benefit with short-term use of dipeptidyl peptidase4 (DPP-4) inhibitors in people at high risk for CVD, as reviewed.


  • Drug treatment in white coat hypertension.
  • If and when drug treatment should be started in the high-normal BP range.
  • The optimal office BP values (i.e. the most protective and safe) for patients to achieve by treatment in different demographic and clinical conditions.
  • The optimal out-of-office (home and ambulatory) BP targets and whether the treatment strategies based on control of out-of-office BP provide an advantage over strategies based on conventional (office) BP control.

Cerebrovascular Disease

  • For patients with cryptogenic stroke, it is uncertain whether nonvitamin K antagonist oral anticoagulants reduce the risk of future CV events more than antiplatelet drugs.
  • The optimal secondary prevention strategy after subarachnoid haemorrhage is uncertain.

Peripheral Arterial Disease

  • There are few studies specific for the PAD population. Most often data comes from CAD patients with concomitant PAD. More specific data on the PAD population are needed


For some of these gaps there are trials already in progress, other gaps will be more difficult to get an answer in the near future.

Read the 2016 European Guidelines on CVD Prevention in Clinical Practice