Drs Eng-Frost and Chew address the diagnosis and management of acute coronary syndromes in their helpful review.1 However, we question the need for the maximum tolerated statin dose in secondary prevention.

Significant toxicities are not always symptomatic and can be difficult to ascertain particularly in older patients or patients with comorbidities. Higher statin doses have not been shown to improve overall survival nor coronary mortality.2,3 Safety and quality of life are important and toxicities increase with increasing drug doses.4

The greatest absolute risk reductions in mortality in randomised placebo-controlled clinical trials were seen with 40 mg of simvastatin or pravastatin in the 4S, HPS and LIPID studies.3 Although some reductions in coronary events have been reported with higher statin doses, there is plateauing efficacy, as seen with all drugs at the top of their dose-response curves. This makes it likely that a greater reduction in coronary events will be achieved with statins in combination with other therapies such as antithrombotics, antihypertensive drugs, weight reduction and smoking cessation.

Specific target cholesterol concentrations have never been established in any appropriately designed randomised clinical trial. Epidemiology shows that reductions in coronary event rates plateau with lower cholesterol concentrations. There is no reduction, and in several analyses an increase, in mortality with total cholesterol concentrations below 5 mmol/L5,6 (low-density lipoprotein cholesterols below 3.5 mmol/L).

In addition to plateauing efficacy, the failure of higher doses of statins to reduce mortality is likely to be related to the often non-plateauing increases in potentially serious toxicities, such as liver dysfunction,3,7,8 diabetes,9 cerebral haemorrhage10 and renal impairment.7,8 We suggest that for many patients it may be neither necessary nor prudent to increase doses, especially if the statin is used with other therapies known to reduce mortality.

Simon B Dimmitt
Clinical Professor, School of Medicine and Pharmacology, University of Western Australia, WA

Jennifer H Martin
Professor, School of Medicine and Public Health, University of Newcastle, NSW


Authors' response

Joanne Eng-Frost and Derek Chew, the authors of the article, comment:

The recommendation that statins should be up-titrated to the highest tolerated doses is not solely intended to reduce mortality. It also aims to reduce the broader array of future coronary events, specifically recurrent myocardial infarction and revascularisation. There is a significant burden of recurrent events in patients who have symptomatic coronary artery disease..

The practice of encouraging the use of higher statin doses, to achieve lower concentrations of low-density lipoprotein in patients with symptomatic coronary artery disease to reduce recurrent cardiac events, is recommended in several guidelines. This provides greater benefit than the other therapies mentioned in the letter. However, clinical judgement and individualisation of therapy for each patient should always prevail when selecting statin doses.



  1. Eng-Frost J, Chew D. Diagnosis and management of acute coronary syndromes. Aust Prescr 2021;44:180-4.
  2. Dimmitt SB, Martin JH. Intensive lipid-lowering in the 12 months after acute coronary syndrome in Australia: an observational analysis. Med J Aust 2019;211:284.
  3. Dimmitt SB, Stampfer HG, Warren JB. The pharmacodynamic and clinical trial evidence for statin dose. Br J Clin Pharmacol 2018;84:1128-35.
  4. Ferner R, Aronson J. Susceptibility to adverse drug reactions. Br J Clin Pharm 2019;85:2205-12.
  5. Yi SW, Yi JJ, Ohrr H. Total cholesterol and all-cause mortality by sex and age: a prospective cohort study among 12.8 million adults. Sci Rep 2019;9:1596.
  6. He G, Liu X, Liu L, Yu Y, Chen C, Huang J, et al. A nonlinear association of total cholesterol with all-cause and cause-specific mortality. Nutr Metab (Lond) 2021;18:25.
  7. Cai T, Abel L, Langford O, Monaghan G, Aronson JK, Stevens RJ, et al. Associations between statins and adverse events in primary prevention of cardiovascular disease: systematic review with pairwise, network, and dose-response meta-analyses. BMJ 2021;374:
  8. Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: a population based cohort study using the QResearch database. BMJ 2010;340:c2197.
  9. Ridker P, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207.
  10. Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, Rudolph AE, et al.; The Stroke Prevention by Aggressive Reduction in cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:549-59.

Simon B Dimmitt

Clinical Professor, School of Medicine and Pharmacology, University of Western Australia, WA

Jennifer H Martin

Professor, School of Medicine and Public Health, University of Newcastle, NSW

Joanne Eng-Frost

Cardiology advanced trainee, Flinders Medical Centre, Southern Adelaide Local Health Network

Derek Chew

Matthew Flinders fellow and Professor in Cardiology, Flinders Medical Centre, Southern Adelaide Local Health Network