High dose versus low dose statin treatment in coronary heart disease (CHD)

A statin, in conjunction with a strict diet, is useful in a patient with coronary heart disease (CHD), or at high risk of developing CHD, because of hyperlipidaemia.

The efficacy of statins in the prevention of CHD has been shown in various randomised trials (1-5). These trials have involved a total of 30, 817 patients (817 men).

These trials revealed that daily treatment for around five years with pravastatin 40mg (2,4,5), simvastatin 10-40mg (3) or lovastatin 20-40mg (1)

• led to a reduction of developing major coronary events by 34% (95% CI 23-43%) (6) in primary prevention (1,2)
• led to a reduction of developing major coronary events by 30% (95% CI 24-35%) in secondary prevention (4,5,6)
• statin treatment was associated with a mean reduction of total serum cholesterol by 20%, LDL-cholesterol by 28% and triglycerides by 13%; also statin treatment was associated with an increase in HDL-cholesterol by 5% (6)

Notes:

• treatment with a statin is indicated in any patient with CVD with a treatment target of a serum LDL cholesterol above a threshold of <=2 mmol/l (audit standard <= 3mmol/l) (4)
• evidence from the MRC/British Heart Foundation trial supports the use of statins in high risk patients over the age of 70 years (7)
• comparing the use of high-dose versus low-dose statin therapy in patients with CHD (8):
  • a meta-analysis was undertaken
    • four trials were identified: the TNT (Treating to New Targets) and the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid-Lowering) trials involved patients with stable cardiovascular disease, and the PROVE IT-TIMI-22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction-22) and A-to-Z (Aggrastat-to-Zocor) trials involved patients with acute coronary syndromes
    • total of 27,548 patients were enrolled in the 4 large trials
      • combined analysis yielded a significant 16% odds reduction in coronary death or myocardial infarction (p < 0.00001), as well as a significant 16% odds reduction of coronary death or any cardiovascular event (p < 0.00001). No difference was observed in total or non-cardiovascular mortality, but a trend toward decreased cardiovascular mortality (odds reduction 12%, p = 0.054) was observed
    • the study authors concluded that intensive lipid lowering with high-dose statin therapy provides a significant benefit over standard-dose therapy for preventing predominantly non-fatal cardiovascular events in patients with CHD
    • an evidence based medicine commentary concerning this trial however noted that (9):
      • "..although the findings of Cannon et al show the benefits of high dose statins, achieving benefits at any dose in actual clinical practicewill require an understanding of the causes of under-treatment and systematic, system wide approaches to improving complicance with prescribing and patient adherence to therapy.."
    • a cost benefit analysis of high-dose versus low-dose statins in CHD patients has been undertaken (10):
      • the authors concluded that high-dose statin therapy was potentially highly effective and cost-effective in patients with acute coronary syndrome (ACS). In patients with stable CHD, however, the cost-effectiveness of high-dose statin therapy was highly sensitive to model assumptions about statin efficacy and cost. The authors tate that the use of high-dose statins can be supported on health economic grounds in patients with ACS, but the case is less clear for patients with stable CHD

Reference:

• (1) Downs JR et al for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA 1998; 279: 1615-22.
• (2) Shepherd J et al for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolaemia. NEJM 1995; 333: 1301-7
• (3) Scandinavian Simvastatin Survival Study Group.Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Study (4S). Lancet 1994; 344: 1383-9.
• (4) JBS2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 91 (Supp 5).
• (5) Long-term intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. NEJM 1998; 339: 1349-57.
• (6) LaRosa JC et al . Effects of statins on risk of coronary disease. A meta-analysis of randomized controlled trials. JAMA 1999; 282: 2340-6.
• (7) MRC/BHF Heart Protection Study: preliminary results.Int J Clin Pract 2002, Jan-Feb; 56(1): 53-6.
• (8) Cannon CP et al. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol. 2006 Aug 1;48(3):438-45
• (9) Newby LK. Commentary. Evidence Based Medicine 2007;12(2):42.
• (10) Chan PS et al. Incremental benefit and cost-effectiveness of high-dose statin therapy in high-risk patients with coronary artery disease.Circulation. 2007 May 8;115(18):2398-40