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Updated: Feb 4, 2026
In Silico Clinical Trials for Cardiovascular Disease
Published on: May 27, 2022
Increased Mortality Despite Successful Multifactorial Cardiovascular Risk Reduction in Healthy Men: 40-Year Follow-Up
T E Strandberg1, K Räikkönen, V Salomaa
1Timo E. Strandberg, MD, PhD, Professor of Geriatric Medicine, University of Helsinki, Clinicum, Haartmaninkatu 4, PO Box 340, FIN-00029 Helsinki, Finland; email: timo.strandberg@oulu.fi; tel: +358 40 672 4533.
Insights
A cardiovascular disease (CVD) intervention trial unexpectedly showed higher mortality in the intervention group. This excess mortality was linked to shorter vacation times, suggesting lifestyle factors interact with preventive measures.
Area of Science:
- Cardiovascular disease research
- Preventive medicine
- Longitudinal health studies
Background:
- A 5-year intervention aimed to reduce cardiovascular disease (CVD) risk factors in healthy men.
- The intervention involved health education and drug treatments for dyslipidemia and hypertension.
- Unexpectedly higher mortality was observed in the intervention group during initial follow-up.
Purpose of the Study:
- To investigate the reasons for increased mortality in the intervention group.
- To examine baseline characteristics that contributed to total mortality.
- To conduct a long-term follow-up of a controlled intervention trial.
Main Methods:
- Analysis of previously unpublished baseline data on risk factors and lifestyle.
- Long-term mortality follow-up (40 years) through national death registers.
- Examination of cause-specific mortality and subgroup analyses.
Main Results:
- The intervention group showed a 46% reduction in CVD risk but higher total mortality up to 25 years post-trial.
- Increased mortality was driven by cardiovascular disease and accidental deaths.
- Shorter yearly vacation time at baseline interacted with the intervention, increasing 30-year mortality (HR 1.37).
Conclusions:
- A multifactorial intervention led to unexpectedly increased mortality in healthy men with CVD risk factors.
- This adverse outcome was particularly noted in individuals with shorter vacation times.
- Further investigation is warranted to understand this response in high-status men with subclinical CVD.
Objectives:
In a 5-year multifactorial risk reduction intervention for healthy men with at least one cardiovascular disease (CVD) risk factor, mortality was unexpectedly higher in the intervention than the control group during the first 15-year follow-up. In order to find explanations for the adverse outcome, we have extended mortality follow-up and examined in greater detail baseline characteristics that contributed to total mortality.
Design:
Long-term follow-up of a controlled intervention trial.
Setting:
The Helsinki Businessmen Study Intervention Trial.
Participants And Intervention:
The prevention trial between 1974-1980 included 1,222 initially healthy men (born 1919-1934) at high CVD risk, who were randomly allocated into intervention (n=612) and control groups (n=610). The 5-year multifactorial intervention consisted of personal health education and contemporary drug treatments for dyslipidemia and hypertension. In the present analysis we used previously unpublished data on baseline risk factors and lifestyle characteristics.
Main Outcome Measures:
40-year total and cause-specific mortality through linkage to nation-wide death registers.
Results:
The study groups were practically identical at baseline in 1974, and the 5-year intervention significantly improved risk factors (body mass index, blood pressure, serum lipids and glucose), and total CVD risk by 46% in the intervention group. Despite this, total mortality has been consistently higher up to 25 years post-trial in the intervention group than the control group, and converging thereafter. Increased mortality risk was driven by CVD and accidental deaths. Of the newly-analysed baseline factors, there was a significant interaction for mortality between intervention group and yearly vacation time (P=0.027): shorter vacation was associated with excess 30-year mortality in the intervention (hazard ratio 1.37, 95% CI 1.03-1.83, P=0.03), but not in the control group (P=0.5). This finding was robust to multivariable adjustments.
Conclusion:
After a multifactorial intervention for healthy men with at least one CVD risk factor, there has been an unexpectedly increased mortality in the intervention group. This increase was especially observed in a subgroup characterised by shorter vacation time at baseline. Although this adverse response to personal preventive measures in vulnerable individuals may be characteristic to men of high social status with subclinical CVD, it clearly deserves further investigation.
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