Provocative Findings of the DANCAVAS Trial Should Inform Future Cardiovascular Screening Trials
- The DANCAVAS trial's primary results for a reduction in all-cause mortality were negative, but the findings of reduced mortality for men 65-69 years of age and a reduction in major adverse cardiovascular events are promising for future study designs.
- The results of the trial support the concept of cardiovascular screening among appropriately selected individuals, but further studies are needed before US guidelines are changed.
- Increased use of statin therapy and aspirin in those with subclinical cardiovascular disease likely explain the benefits in the subgroup of men aged 65-69.
The utility of comprehensive population wide screening for cardiovascular disease (CVD) has long been a matter of debate. While CVD remains the leading cause of morbidity and mortality around the globe, there is no consensus on the most appropriate or cost-effective screening approach.1 Importantly, screening is different from CVD risk estimation, as screening aims to diagnose subclinical or undiagnosed diseases. The recently published DANCAVAS trial sheds new light on this topic.2
CVD risk estimation in both the United States (US) and Europe is primarily based on risk scores developed from traditional CVD risk factors. An individual's estimated CVD risk is then used as the primary tool for allocation of primary prevention pharmacotherapies. However, there are important limitations to the use of traditional risk factor-based risk scores. This is especially true among older patients.
For example, the US pooled cohort equations risk score classifies nearly all men over the age of 65 as intermediate to high risk based on age alone even if they have an ideal risk factor profile. However, identification of the absence, presence, and magnitude of subclinical atherosclerosis can significantly improve risk estimation beyond traditional risk factors and guide treatment.1
In 2015, the Danish Cardiovascular Screening Trial (DANCAVAS) enrolled 46,611 men aged 65-74 years living in Southern and Central Denmark.2 Initially, investigators planned to include both men and women, but ultimately included only men as they concluded women of the same age had a significantly lower CVD event rate for short-to-intermediate follow-up.3 All participants were randomized in two groups with one third assigned to screening arm (16,736 men) of which 63% (10,471) agreed to participate.
Importantly, the screening protocol was multifaceted and screened for multiple types of CVD, which included CAC scoring, aortic/iliac aneurysms, brachial and ankle blood pressure (BP) index for diagnosis of peripheral arterial disease (PAD) and hypertension (systolic [S]BP>160 or diastolic [D]BP >100), and finally assessment of atrial fibrillation with electrocardiogram (ECG) during the computed tomography (CT) scan, in addition to lipid profile and plasma glucose levels. The other two thirds were treated according to usual care. Recommended treatment for those with coronary artery calcium (CAC) score above the sex and age specific median (e.g. 145 for a 70 year-old White man), or those with PAD, or aneurysm were started on atorvastatin 40 mg daily and aspirin 81 mg daily.4
The investigators chose all-cause mortality as the primary outcome. A prespecified subgroup analysis stratified by age 70 was also performed along with a post hoc defined composite of major adverse cardiovascular events (MACE). Over a median follow-up time of 5.6 years there was a borderline, but nonsignificant 5% reduction in the primary outcome of all-cause mortality (hazard ratio [HR] 95% confidence interval [CI] 0.95 [0.90 to 1.00], P=0.06).
When stratified by age, participants <70 years of age had a significant 11% reduction in total mortality (HR 0.89; 95% CI 0.83 – 0.96), while those ≥70 years of age did not (HR 1.01; 95% CI 0.94 – 1.09). Additionally, there was a significant 7% reduction in the risk for MACE (HR 0.93 [95% CI, 0.89 to 0.97]), and there were no significant between-group differences in safety outcomes including risk of incident of cancer.
The DANVACAS study utilized multiple different screening tests in same visit. Therefore, it can be difficult to directly attribute the observed results to any one of the specific screening protocols. However, the initiation of antiplatelet agents (-0.85) and lipid-lowering medications (-0.68) had the largest difference in restricted mean survival time for interventions that occurred after screening. This suggests that screening for subclinical atherosclerosis, such as by the CAC scan, likely had the largest impact on CVD risk reduction.
It is also important to note that not all of the screening protocols should be expected to have the same utility or efficacy for CVD risk reduction. For example, detection of above average for age CAC is likely to be associated with a greater total risk for CVD compared to detection of an aortic dilatation. Similarly, while there is no universally agreed-upon screening protocol for atrial fibrillation, detection of atrial fibrillation by ECG during CAC scan is much less likely to identify this arrhythmia compared to more commonly used screening protocol of 30-day event monitor. The prevalence of aortic aneurysm remained low (<5%) with even fewer participants eligible for any surgical referral. Therefore, these aspects of the screening protocol are unlikely to provide significant benefit.
Another important nuance of this study is that the results were performed as intention to treat; therefore, participants who were invited, but did not attend screening were included in the treatment group. There were significant differences in the risk factor burden between screened and non-screened individuals that may have impacted the results. Accordingly, the results of this study may be best interpreted as the potential CVD risk reduction among persons invited to have CVD screening performed.
The primary outcome of this study was all-cause mortality, which is rarely the primary outcome in CVD trials, because this is the most difficult outcome to prevent, especially over the typical trial follow-up period of approximately 5 years. However, in the prespecified analysis, participants less than 70 years of age did have a significant reduction in mortality.
A likely explanation for the difference in mortality outcomes by age is that older individuals had a much higher prevalence of primary prevention therapies (e.g., statin use) at baseline compared to younger individuals. Accordingly, younger participants with an abnormal/positive screening test were more likely to start an antiplatelet and lipid-lowering therapy compared to older persons, who may have already been on these pharmacotherapies.
Two other very noteworthy findings from this are that there was no increase in downstream CVD testing for the group that received screening nor was there any increase in adverse events, including bleeding. Furthermore, a complementary analysis by the authors showed that this CVD screening protocol was cost-effective for the younger men without CVD at baseline.5 These three findings indicate that the results of CVD screen testing were used appropriately for initiation of primary prevention strategies rather than leading to an increase in invasive and expensive testing.
While the DANCAVAS study's primary results for all-cause mortality were negative, the findings of significantly reduced mortality for men <70 years of age and a reduction in MACE for all participants should not be overlooked. Had the primary outcome for this study been the more traditional composite of MACE, most would have seen the trial results as positive. Accordingly, the overall results of this study provide support for the concept of targeted CVD screening among an appropriately selected group of individuals.
Additionally, a CVD screening protocol among appropriately selected individuals can be cost-effective and need not lead to an increased financial burden for the healthcare system. As with all good studies, the results raise important ideas for future research, which is needed to investigate a more focused screening approach among patients not on primary prevention medications (e.g., statin and aspirin), inclusion of only the highest efficacy screening protocols, and inclusion of women.
- Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;74:1376-1414.
- Lindholt JS, Sogaard R, Rasmussen LM, et al. Five-year outcomes of the Danish Cardiovascular Screening (DANCAVAS) trial. N Engl J Med 2022;387:1385-94.
- Kvist TV, Lindholt JS, Rasmussen LM, et al. The DanCavas pilot study of multifaceted screening for subclinical cardiovascular disease in men and women aged 65-74 years. Eur J Vasc Endovasc Surg 2017;53:123-31.
- Obel LM, Diederichsen AC, Steffensen FH, et al. Population-based risk factors for ascending, arch, descending, and abdominal aortic dilations for 60-74-Year-old individuals. J Am Coll Cardiol 2021;78:201-11.
- Sogaard R, Diederichsen ACP, Rasmussen LM, et al. Cost effectiveness of population screening vs. no screening for cardiovascular disease: the Danish Cardiovascular Screening trial (DANCAVAS). Eur Heart J 2022;43:4392-4402.
Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Noninvasive Imaging, Prevention, Atherosclerotic Disease (CAD/PAD), Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Computed Tomography, Nuclear Imaging, Hypertension
Keywords: Cardiovascular Diseases, Undiagnosed Diseases, Blood Pressure, Platelet Aggregation Inhibitors, Atrial Fibrillation, Iliac Aneurysm, Cost-Benefit Analysis, Risk Factors, Cardiometabolic Risk Factors, Blood Glucose, Coronary Vessels, Primary Prevention, Survival Rate, Tomography, Tomography, X-Ray Computed, Lipids, Risk Reduction Behavior, Neoplasms, Peripheral Arterial Disease, Hypertension, Calcium, Aspirin
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