A naturally randomized trial comparing the effect of long-term exposure to lower LDL-C, lower SBP, or both on the risk of cardiovascular disease

Presented at the ESC congress 2016 by:Brian A Ference (Plymouth, MA, USA)

Background

Mendelian randomisation studies have shown that both LDL-c and systolic blood pressure (SBP) have both a causal and a cumulative effect on the risk of CVD. Considering the cumulative effects over time, a simple preventive strategy directed at stimulating long term exposure to both low LDL-c levels and low SBP might be a highly effective prevention strategy.
The causal effect of combined exposure to LDL-c and SBP on CVD is still unknown, but prospective epidemiological studies suggest that it is more than an additive effect, but less than a multiplicative effect. The recent 2x2 factorial randomised HOPE-3 study suggested that the benefit of combined LDL-c and SBP-lowering was not larger than that of LDL-c with a statin alone.
This study aimed to assess the causal effect of combined exposure to lower LDL-c and SBP on the risk of CV events. Moreover, the potential clinical benefit was estimated of a parsimonious prevention strategy that focuses on promoting long-term exposure to combination of one mmol/L lower LDL-C and 10 mmHg lower SBP.
Genetic LDL and BP scores were used, as an instrument to ‘naturally randomise’ 102.000 participants to lower LDL-c, lower SBP, both or none, using a 2x2 factorial Mendelian randomisation study protocol. The genetic scores were calculated based on the number of alleles of polymorphisms with a known association with LDL-c or SBP. The study used genetic and risk factor data of participants of 14 prospective cohort or case-control studies.
The genetic scores were not used to predict risk, instead they allowed evaluation of the causal effect of random allocation to exposure to lower LDL-c, lower SBP or the combination of both risk factors, without confounding, on the risk of CV events, in a way analogous to a long term randomised study.

Main results

• 14368 major vascular events (MVE: CHD mortality, MI, stroke or coronary revascularisation) occurred during 32 years follow-up.
• When present simultaneously, lower LDL-c and lower SBP had independent, multiplicative and cumulative causal effects on the risk of CV events.
• Long term exposure to the combination of 1 mmol/L lower LDL-c and 10 mmHg lower SBP was associated with 86.1% lower risk of MVE (OR: 0.139, 95%CI: 0.114-0.170, p=1.6x10-83).
• Combined exposure to lower LDL-c and lower SBP was associated with a significantly greater reduction in the risk of MVE as compared with lower LDL-c alone (OR: 0.458, P=1.4x10-14) and lower SBP alone (OR: 0.553, P=1.8x10-23).
• The effect of combined exposure to lower LDL-c an lower SBP was consistent among various CV endpoints (including CHD mortality).
• The effect was comparable for men and women, smokers and non-smokers, diabetics and non-diabetics, persons with LDL-c above and below 3.5 mmol/L, and persons with SBP above and below 120 mmHg.

Conclusion

This study shows that LDL-c and SBP have independent, multiplicative and cumulative causal effects on the risk of CV events. As a result of the effects being multiplicative and cumulative, long term exposure to the combination of even moderately lowered LDL-c and SBP has the potential to dramatically lower the risk of CV events, even in persons with apparently normal cholesterol and blood pressure levels.
This study confirms that CV events are largely preventable. Prevention of CV events can be substantially improved and simplified by setting up prevention programmes that focus on stimulating exposure to lower LDL-c levels and lower SBP on the long run, starting in early adulthood.

Our reporting is based on the information provided during the ESC congress