R3i Editorial

It is increasingly clear that the benefits of pharmacotherapeutic intervention on the atherosclerotic process may extend beyond the period of active treatment. Such an effect has already been demonstrated for statins. Long-term follow-up data from the West of Scotland Coronary Prevention Trial (WOSCOPS) ¹ indicated that statins could have a legacy effect in preventing cardiovascular events in individuals with elevated low-density lipoprotein (LDL) cholesterol but without overt evidence of atherosclerotic disease. At 20-year follow-up, the risk of cardiovascular events was 27% lower in the group allocated statin compared with placebo during the trial, irrespective of whether treatment was continued after the trial. This benefit was also evident in elderly patients after the end of the PROSPER trial ². Such findings suggest the possibility of ongoing, carry-over effects on the atherosclerotic disease process and/or the stabilization of existing coronary artery plaques.

The question, then, is whether other cardiovascular preventive strategies offer similar legacy effects? Perhaps, given the prevalence of atherogenic dyslipidaemia among high risk patients ^3,4, lipid-modifying therapies targeting this dyslipidaemia should be considered?

From this year’s American Heart Association Scientific Sessions, we now have information on long-term follow-up of the Action to Control Cardiovascular Risk in Diabetes (ACCORDION) study. Four or more years after the end of the ACCORD study, there was a similar lack of statistically significant benefit on major cardiovascular events in the total study population, as observed at the end of the trial ^5,6. However, there was a significant macrovascular benefit for patients with atherogenic dyslipidaemia (as defined in the original trial), with 27% reduction in risk versus no benefit in patients without this dyslipidaemia (p=0.048). Such findings might suggest the possibility of a legacy-type effect with add-on fenofibrate in type 2 diabetes patients with atherogenic dyslipidaemia. While we wait for full publication of these data, these findings reinforce the need to manage this dyslipidaemia appropriately to reduce long-term residual cardiovascular risk.

ACCORDION also provided information on the effects of long-term follow-up of type 2 diabetes patients allocated initially to an intensive versus standard blood pressure lowering regimen ⁷. While there was evidence of benefit for intensive blood-pressure lowering in subjects randomized to standard glycaemic control, broadly consistent with the findings from SPRINT ⁸, the significant reduction in stroke seen in the ACCORD trial was no longer apparent at the end of follow-up, when the difference in blood pressure between the intensive and standard control groups had narrowed from 14 mmHg to about 4 mmHg ^7,9. Thus, these findings suggest that unlike the effects of statins, and possibly other lipid-lowering therapy, there is no legacy effect of blood-pressure reduction.

What do these findings indicate for the future of cardiovascular prevention?
While we undoubtedly also need new therapeutic approaches to treat atherogenic dyslipidaemia, it is also clear that we need to focus on the trajectory of the atherosclerotic disease process. To do this, we will need to develop new metrics for gauging the success of therapeutic intervention if we adopt the shift to a primordial type approach. In this context, the findings of Avanzini et al ¹⁰, discussed in this month’s Focus, have important impact. In this study, improvement in just one of the major modifiable cardiovascular risk factors, assessed using a simple health metric, at one year, translated to a 6% reduction in risk for cardiovascular events over the following 4 years in a high-risk patient group. Given that atherogenic dyslipidaemia was likely prevalent in a substantial proportion of these patients, the addition of treatment specifically targeting this dyslipidaemia may offer further benefit in terms of long-term impact on the morbidity, mortality and disability associated with cardiovascular disease.

References

1. Packard C, Ford I, Murray HM, McCowan C. Lifetime clinical and economic benefits of statin-based LDL lowering in the 20-year followup of the West of Scotland Coronary Prevention Study. Circulation 2014 130:2105-26.
2. Lloyd SM, Stott DJ, de Craen AJ et al. Long-term effects of statin treatment in elderly people: extended follow-up of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). PLoS One 2013;8(9):e72642.
3. Halcox JP, Roy C, Henriksson KM. Assessing the prevalence of atherogenic dyslipidemia in EURIKA patients. Circulation 2015; 132: A17096.
4. Reiner Ž, De Bacquer D, Kotseva K et al. Treatment potential for dyslipidaemia management in patients with coronary heart disease across Europe: findings from the EUROASPIRE III survey. Atherosclerosis 2013;231:300-
5. Elam MB, Lovato LC2, Ginsberg HN on behalf of the ACCORD/ACCORDION Study Group. The effect of combined statin/fibrate therapy on cardiovascular disease is influenced by sex and dyslipidemia: ACCORDION-Lipid Long-Term Follow-up. Abstract 15997, American Heart Association Scientific Sessions, 2015.
6. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
7. Cushman WC, Evans GW, Cutler JA; ACCORD/ACCORDION Study Group. Long-term Cardiovascular Effects of 4.9 Years of Intensive Blood Pressure Control in Type 2 Diabetes Mellitus: The Action to Control Cardiovascular Risk in Diabetes Follow-On Blood Pressure Study. AHA Scientific Sessions 2015.
8. SPRINT showed significant benefit associated with intensive blood pressure control (<120 mmHg systolic blood pressure [SBP]) in patients at high cardiovascular risk but without diabetes. The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Eng J Med 2015; Epub 9th November 2015.
9. ACCORD Study Group, Cushman WC, Evans GW, Byington RP et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-85.
10. Avanzini F, Marzona I, Baviera M et al; Risk and Prevention Study Collaborative Group. Improving cardiovascular prevention in general practice: Results of a comprehensive personalized strategy in subjects at high risk. Eur J Prev Cardiol 2015 [Epub ahead of print].