Volume 211 - Issue 6
Intensive lipid‐lowering therapy in the 12 months after an acute coronary syndrome in Australia: an observational analysis
Authors: Simon B Dimmitt and Jennifer H Martin
Med J Aust 2019; 211 (6): 284-284.e1. || doi: 10.5694/mja2.50324
Published online: 16 September 2019
Published online: 16 September 2019
To the Editor: The efficacy of evidence‐based doses of statins is well established. The poor compliance with high intensity lipid‐lowering pharmacotherapy reported by Brieger and colleagues1 in the CONCORDANCE study has been noted in many studies.2 Compliance is related to several factors, including patients’ perspectives and concerns about quality of life and possible adverse effects3 compared with potential benefits.
Adverse effects of statins are extensively documented, are dose‐related, and contribute to suboptimal compliance.2 Outcomes with high intensity lipid‐lowering doses are predominantly extrapolated from trials and epidemiological endpoints. Treatment to specific target cholesterol levels is not supported by any direct trial evidence, acknowledged in the United States lipid guidelines since 2013.4 Further, a Cochrane meta‐analysis has failed to show any reduction in hard clinical endpoints such as myocardial infarction, stroke or mortality when receiving statin treatment in the first 3–6 months after acute coronary syndrome.5 The maximum reduction in total mortality reported on statins, around 15% by 3 years, is seen with about 40 mg of simvastatin, equivalent to about 5 mg of atorvastatin, associated with over a 25% reduction in myocardial infarction6 — impressive for a single coronary preventive intervention.
The safety and efficacy of only a 10 mg dose of simvastatin led to its approval for over‐the‐counter sale in the United Kingdom in 2005.7 Being competitive enzyme inhibitors, as approved statin doses are increased, plateauing efficacy is overtaken by increases in a variety of adverse effects and potential harms. For example, high dose compared with conventional dose statin (2.5–10 mg of atorvastatin) has no impact on survival (Box) but increases myopathy by up to 29‐fold and liver dysfunction by up to ninefold.6
Higher intensity statin may achieve a small reduction in coronary events (only statistically significant in the Treating to New Targets [TNT] trial10) but at a price with respect to safety, tolerability, overall survival and compliance, particularly in older patients with multiple comorbidities. Instead of increasing statin dose, a greater reduction in cardiovascular risk may be achieved by combining smoking cessation, antithrombotic therapies, control of blood pressure and diabetes, weight loss and other lifestyle measures, each of which can reduce coronary events by 10–20%.
Box – Trials comparing conventional versus high intensity statin dose
Trials
|
Number of patients |
Statin |
Doses*
|
Major CHD events†
|
Mortality†
| ||||||||||
Total |
CHD | ||||||||||||||
SEARCH8 |
12 064 |
Simvastatin |
2.5 |
20% |
16% |
7% |
|||||||||
7 years (mean) |
Simvastatin |
10 |
20% |
16% |
7% |
||||||||||
A to Z9 |
4497 |
Simvastatin |
2.5 |
12% |
7% |
5% |
|||||||||
2 years (median) |
Simvastatin |
10 |
12% |
6% |
4% |
||||||||||
TNT10 |
10 001 |
Atorvastatin |
10 |
8% |
6% |
2% |
|||||||||
5 years (median) |
Atorvastatin |
80 |
7% |
6% |
2% |
||||||||||
IDEAL11 |
8888 |
Simvastatin |
2 |
10% |
8% |
4% |
|||||||||
5 years (median) |
Atorvastatin |
80 |
9% |
8% |
4% |
||||||||||
PROVE‐IT TIMI12 |
4162 |
Pravastatin |
2 |
9% |
3% |
1% |
|||||||||
2 years (mean) |
Atorvastatin |
80 |
8% |
2% |
1% |
||||||||||
A to Z = Aggrastat to Zocor; CHD = coronary heart disease; IDEAL = Incremental Decrease in Endpoints through Aggressive Lipid Lowering; PROVE‐IT TIMI = Pravastatin or Atorvastatin in Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction; SD = standard deviation; SEARCH = Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine; TNT = Treating to New Targets. * Statin doses expressed as equivalent atorvastatin dose, based on mean low‐density lipoprotein‐lowering in a meta‐analysis (Law et al13). †None of the differences in major CHD events and mortality (total and CHD) were significantly different, except major CHD events in TNT (P = 0.002). | |||||||||||||||
Competing interests
No relevant disclosures.
References
- Brieger D, D'Souza M, Huyn K, et al. Intensive lipid‐lowering therapy in the 12 months after an acute coronary syndrome in Australia: an observational analysis. Med J Aust 2019; 210: 80–85. https://www.mja.com.au/journal/2019/210/2/intensive-lipid-lowering-therapy-12-months-after-acute-coronary-syndrome
- Maningat P, Gordon BR, Breslow JL. How do we improve patient compliance and adherence to long‐term statin therapy? Curr Atheroscler Rep 2013; 15: 291–301.
- Roose SP. Compliance: the impact of adverse events and tolerability on the physician's treatment decisions. Eur Neuropsychoparmacol 2003; 13 (Suppl): S85–S92.
- Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129 (Suppl): S1–S45.
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- Dimmitt SB, Stampfer HG, Warren JB. The pharmacodynamic and clinical trial evidence for statin dose. Br J Clin Pharmacol 2018; 84: 1128–1135.
- Simvastatin over the counter. Drug Ther Bull 2005; 43: 25–28.
- Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12 064 survivors of myocardial infarction: a double‐blind randomised trial. Lancet 2010; 376: 1658–1669.
- de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004; 292: 1307–1316.
- LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352: 1425–1435.
- Pedersen TR, Faergeman O, Kastelein JJ, et al. High‐dose atorvastatin vs usual‐dose simvastatin for secondary prevention after myocardial infarction the IDEAL study: a randomized controlled trial. JAMA 2005; 294: 2437–2445.
- Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350: 1495–1504.
- Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta‐analysis. BMJ 2003; 326: 1423.