Medicine excels when we treat people who ask for our help. Preventing people from needing our help is much tougher. The DANCAVAS trial, presented at the European Society of Cardiology (ESC) meeting and published in the New England Journal of Medicine, did not shy away from this high bar.
DANCAVAS: A Unique Trial
DANCAVAS was a population-based randomized trial of 45,000 men aged 65 to 74 years from 15 municipalities in Denmark. Researchers randomly assigned one third of them to an invitation to attend comprehensive cardiovascular disease (CVD) screening and two thirds to no invitation. Of those invited to screening, only 63% attended. The main comparison was between the invited and uninvited men.
The screening process was unique. Primary investigator Axel Diederichsen told me that all screening was done in one session and took about 40 minutes per person. Sessions were usually scheduled after clinic hours from 4 PM to 8 PM twice a week.
On arrival to screening, participants completed a questionnaire and then had their height, weight, and blood pressures in both upper and lower extremities (ankle-brachial index) measured. They then underwent CT starting at the jaw and panning down to the femoral region. The scans assessed only for coronary calcium and aortic aneurysms. A rhythm strip was taken during the scan. The patient then had blood drawn for lipids and glucose.
If there were no abnormalities, participants were informed by regular mail. Those who had abnormalities attended follow-up visits and were offered lifestyle recommendations, smoking cessation advice, medications (including aspirin, statins, and anticoagulants), and vascular surgery. Follow-up via the national Danish health registry was planned for 10 years. This report was the 5-year update.
In a previous pilot screening study, the researchers found that women had much lower rates of coronary calcium than men. This led them to include only men in the main study. Participants were about 68 years old. At trial entry, many individuals were already taking preventive therapy, including antiplatelet agents (25%), lipid-lowering drugs (40%), and antihypertensives (50%).
Five Major Results
The lower rate of death in the invited to screening group barely missed the threshold of statistical significance.After a median follow-up of 5.6 years, 12.6% of the screened group died vs 13.1% of the nonscreened group (hazard ratio [HR], 0.95; 95% CI, 0.90 - 1.00; P = .06).
Secondary outcomes, such as stroke, myocardial infarction (MI), aortic dissection, and rupture, all favored the screened arm.
Subgroups yielded provocative findings. Invitation to screening was associated with significantly reduced all-cause mortality in men age 65 to 70 years (HR, 0.89; 95% CI, 0.83 - 0.96) but not in those older than 70 years (HR, 1.01; 95% CI, 0.94 - 1.09).
Invitation to screening led to more prescriptions for antiplatelet drugs and lipid-lowering drugs (15% and 32%, respectively). Use of percutaneous coronary intervention, coronary artery bypass surgery, or vascular surgery did not differ between groups.
In a separate paper, the authors reported that the average difference in healthcare costs between the two groups was €207 per invitee.
Comments
Despite its P value, DANCAVAS was a positive trial. The majority of the 95% CI includes a lower rate of death. Some may disagree with this take. My response would be that they measured death, not a composite endpoint of surrogates. And, statistically speaking, nothing is materially different at P values of .06 or .04.
The subgroup analysis that found men younger than age 70 years had a greater reduction in death is persuasive. Slightly younger men would stand to benefit more from cardiac screening because they have fewer competing causes of death than older men. The effect of competing causes of death was shown (and widely accepted) in the subgroup analysis of the DANISH trial of internal cardiac defibrillators in nonischemic cardiomyopathy, in which younger patients garnered substantial benefit from the implantable cardioverter-defibrillator while older patients did not.
I would also compare the DANCAVAS screening strategy to the accepted and codified annual health check. Cochrane reviewed 17 trials of general health checks and found (with high certainty) little to no effect on the risk for death from any cause.
We should also speculate how the DANCAVAS protocol led to lower death rates. At ESC, I heard some mention the higher use of statins and antiplatelets. I doubt it. Recent data have found little to no net benefit for aspirin in patients without a previous event, and the benefit with statins over 5 years in this cohort would primarily be a reduction of nonfatal events.
There must be something more. I speculate it's a performance bias—a purposeful one. The interaction (or caring signal) from screening may have motivated individuals to stop smoking, adapt a healthy lifestyle, or better adhere to medications. The sum of motivation, statins, and a lack of harm may explain the death reduction.
Something Special in the State of Denmark
This was a special trial. One of the most remarkable parts of the screening program was that technologists read the CT scans. Diederichsen told me that the costs of radiologists were prohibitive. Yet this is a feature, not a bug. If you measure only calcium scores and aortic size, you avoid the downstream cascades from incidentalomas—a drag on both cost and outcomes.
Trial environment always factors into how we apply results. In DANCAVAS, the avoidance of overdiagnosis and overtreatment cannot be understated.
No one should be tempted to use DANCAVAS to support coronary artery calcium (CAC) screening outside of this setting. In our lengthy conversation, Diederichsen emphasized that Danish doctors do not feel compelled to look for ischemia in asymptomatic patients—even if they have a high calcium score. I may not have believed him had I not seen healthcare firsthand in that country.
Imagine such a pragmatic screening trial in the United States, where CAC-driven stress tests, angiography, percutaneous coronary intervention, and even coronary artery bypass grafting are ensconced as therapeutic fashions. The screened group in a U.S. trial would surely undergo more downstream procedures. And because these procedures have no benefit in stable patients, and come with a risk for complications, harm would likely counter any favorable effects from screening.
DANCAVAS authors have shown proponents of CAC screening that an outcomes trial is feasible. I'd urge them to replicate these data in a different environment.
Summary
In a country known for good health and a good healthcare system (a super-strong control arm), the DANCAVAS authors still found that a highly efficient screening program could extend life—at a very low cost. This is remarkable because mortality reductions with screening are exceedingly rare.
The methods and results of DANCAVAS should be studied and appreciated but not overextended. It's not a roadmap for what to do tomorrow; rather, it's a reason to question our status quo and plan more studies. This is what good science does.
Finally, the more I learn about Denmark and this trial, the more I wonder whether preventive efforts in the United States would improve if every medical trainee had to spend time rotating in Denmark. We could even study that idea in a randomized trial.
John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence.
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Cite this: John M. Mandrola. Judicious CVD Screening May Work in Men: DANCAVAS - Medscape - Sep 02, 2022.
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