The Anglo-Scandinavian Cardiac Outcomes Trial: 11-year mortality follow-up of the lipid-lowering arm in the UK

Response to Dr Ravnskov's letter

The Anglo-Scandinavian Cardiac Outcomes Trial: 11-year mortality follow-up of the lipid-lowering arm in the UK Peter S Sever, Choon L Chang, Ajay K Gupta, Andrew Whitehouse and Neil R Poulter, on behalf of the ASCOT investigators

We note the comments of Dr Ravnskov regarding our manuscript on long term benefits in subjects originally assigned atorvastatin in this trial, and we have been careful to the discuss the limitations of these analyses(1). Firstly, Dr Ravnskov is wrong in making the statement that during the 8 years after the trial was stopped, 37% of those in the active treatment group had stopped atorvastatin and 53% in the placebo group had commenced statin therapy. These data were collected at the end of the blood pressure-lowering arm of the trial (2.2 years after the end of LLA)(2). Secondly, we have no information on statin use in the following 6 years, during which mortality data were obtained. Dr Ravenskov's suggestion that our findings could be explained by differential withdrawal of statin use due to adverse effects, has no basis in fact. During ASCOT- LLA (a double blind trial) there was no difference between active treatment and placebo in rates of side effects or drug withdrawal(3). Finally, we did not propose that cholesterol- lowering protected against infectious disease. We cited several studies in which subjects receiving statins appeared to have reduced morbidity and mortality from infection, and speculated, as others have done, that possible mechanisms could include non lipid-lowering, pleiotropic actions of statins rather than an association with low blood cholesterol.

References

1. Sever PS, Chang CL, Gupta AK, Whitehouse A, Poulter NR; on behalf of the ASCOT investigators. The Anglo-Scandinavian Cardiac Outcomes Trial: 11-year mortality follow-up of the lipid-lowering arm in the UK. Eur Heart J 2011;32:2525-2532.

2. Sever P, Dahlof B, Poulter N, Wedel H. Beevers G, Caulfield M, Collins R, Kjeldsen S, Kristinsson A, Mehlsen J, Nieminem M, O'Brien E, Ostergren, ASCOT Steering Committee Members. The Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm: Extended Observations 2 Years After Trial Closure. Euro Heart J 2008;29:499-508.

3. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo- Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003:361;1149-1158.

Peter S Sever Professor of Clinical Pharmacology and Therapeutics Imperial College London 59 North Wharf Road London W2 1LA, UK. Email: [email protected] Tel: +44 (0)207 594 1100

Conflict of Interest:

Have served as a consultant or received travel expenses, or payment for speaking at meetings, or funding for research from one or more pharmaceutical companies that market blood-pressure-lowering or lipid-lowering drugs including Pfizer for ASCOT

In their report from the lipid-lowering arm of the ASCOT-LLA trial Sever et al concluded that statin treatment may have pleiotropic effects able to lower the risk of infection and respiratory illness even eight years after ending the trial.1 They mention a few unimportant limitations, but have ignored the most important one, the fact that during these eight years 37% in the treatment group had stopped the statin medication whereas 56% in the control group had started. It is not too farfetched to assume that those who stopped the treatment did it because of unpleasant adverse effects, and that many of those, who had started it, not yet had recognized that possible adverse effects were caused by the treatment. Thus, the higher incidence of infections and other pulmonary diseases in the control group could as well have been an adverse effect of the statins.

That cholesterol-lowering should prevent infectious diseases is also unlikely, because the lipoproteins protect against all kinds of infectious diseases.2,3 Furthermore, low cholesterol has been found associated with infectious diseases.4 Most authors assume that the low cholesterol is secondary, but this is contradicted by Iribarren et al.5 They followed more than 100,000 healthy individuals for fifteen years. At follow-up, those with the lowest cholesterol had been admitted significantly more often to hospital because of an infectious disease. Evidently low cholesterol, recorded at a time when these people were healthy, could not be caused by a disease, which they had not yet got. Another argument was presented by Sijbrand et al.6 They found that before the year 1900, when infectious diseases were the commonest cause of death, people in the Netherlands with familial hypercholesterolemia lived longer than the average Dutchman.

References

1. Sever PS, Chang CL, Gupta AK, Whitehouse A, Poulter NR on behalf of the ASCOT Investigators. The Anglo-Scandinavian Cardiac Outcomes Trial: 11-year mortality follow-up of the lipid-lowering arm in the UK. Eur Heart J doi:10.1093/eurheartj/ehr333.

2. Ravnskov U, McCully KM. Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Ann Clin Lab Sci 2009;39:3-16.

3. Han R. Plasma lipoproteins are important components of the immune system. Microbiol Immunol 2010;54:246-53.

4. Ravnskov U. High cholesterol may protect against infections and atherosclerosis. Q J Med 2003;96:927-34.

5. Iribarren C, Jacobs DR Jr, Sidney S, Claxton AJ, Feingold KR. Cohort study of serum total cholesterol and in-hospital incidence of infectious diseases. Epidemiol Infect. 1998;121:335-47.

6. Sijbrands EJ, Westendorp RG, Defesche JC, de Meier PH, Smelt AH, Kastelein JJ. Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study. Brit Med J 2001;322:1019-23.

Conflict of Interest:

None declared

I was intrigued by the recent article by Sever et al. demonstrating a reduction in non-cardiovascular deaths in atorvastatin treated patients versus placebo arm in the Anglo-Scandinavian Cardiac Outcomes Trial 11 years after randomization. The mechanism underlying this observation may be related to biofilm formation. I point to an article from the pediatric research - Liu G, et al. Pediatric Research.2009;66(6):600-4. This work, out of Dr. Margaret Hostetter's lab at Yale, demonstrated that HMG Co-A reductase inhibitors not only impair the production of sterol-ring cholesterol in humans, but that it can impair sterol production in the cell membrane of Candida albicans. They demonstrated that by increasing the in vitro dose of simvastatin from 10 uM to 25 uM, they were able to inhibit the formation of biofilms by greater than 90% and to impair the growth of C. albicans. These findings may extend to bacterial biofilms. This is a plausible explanation for why there would be reduced infections in patients who had been on atorvastatin in the past. A reduction in biofilm formation could be integral to the prevention or reduction of infections in a variety of clinical settings, from dental biofilms to biofilm formation on medical devices to biofilms in specific patient populations like those with valvular lesions or cystic fibrosis. These laboratory findings related to yeast, combined with the observational data from the statin trial, suggest that we should develop studies looking prospectively at the impact of statins on the development of infection in patients at risk for biofilm formation.

Conflict of Interest:

None declared