Primary prevention with statin therapy meta-analysis (Thavendiranthan et al, 2006)

• Thavendiranthan et al have undertaken a study to examine the role of statins in primary prevention of cardiovascular disease (1)
  • Cochrane Collaboration, and American College of Physicians Journal Club databases were searched for RCTs published between 1966 and June 2005. The authors included RCTs with follow-up of 1 year or longer, more than 100 major CV events, and 80% or more of the population without CV disease. From each trial, demographic data, lipid profile, CV outcomes, mortality, and adverse outcomes were recorded. Summary relative risk (RR) ratios with 95% confidence intervals (CIs) were calculated using a random effects model
    • seven trials with 42,848 patients were included. Note that the analysis also included primary prevention patients from the HPS trial (more than 80% were in secondary prevention) and the patients from the CARDS trial
    • mean follow-up was 4.3 years
    • statin therapy reduced the RR of major coronary events, major cerebrovascular events, and revascularizations by 29.2% (95% CI, 16.7%-39.8%) (P<.001), 14.4% (95% CI, 2.8%-24.6%) (P = 0.02), and 33.8% (95% CI, 19.6%-45.5%) (P<.001), respectively
    • statins produced a nonsignificant 22.6% RR reduction in coronary heart disease mortality (95% CI, 0.56-1.08) (P = 0.13)
    • no significant reduction in overall mortality (RR, 0.92 [95% CI, 0.84-1.01]) (P = .09) or increases in cancer or levels of liver enzymes or creatine kinase were observed
  • the authors affirm that statin therapy could reduce the absolute risk of coronary events during the next 4.3 years by 0.75% in low-risk patients (NNT= 133), by 1.63% (NNT=61) in moderate-risk patients and by 2.51% (NNT=40) in high-risk patients. They also conclude that it could be cost-effective in patients with an absolute risk over 20% of having a coronary event in the following 10 years. It would not be cost-effective in patients with a risk <10%, and its use would be controversial in the risk-group of 10-20%
  • the study authors concluded that, in patients without CV disease, statin therapy decreases the incidence of major coronary and cerebrovascular events and revascularizations but not coronary heart disease or overall mortality
    
    
• Mills et al have undertaken a more recent meta-analysis study that aimed to evaluate the effectiveness of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) in primary prevention of cardiovascular events
  • this study revealed a reduction in all-cause mortality - although only just significant based on the confidence interval of the relative risk (a relative risk (RR) of 0.93 (95% confidence interval [CI]: 0.87 to 0.99, p = 0.03)) - which was not seen in the study by Thavendiranthan et al (1)
    • this meta-analysis included 20 randomized clinical trials (more than 65,000 patient) compared to the 7 studies included by Thavendiranthan et al (n = 63,899 patients)(1)
      • all-cause mortality
        • pooled 19 trials (n = 63,899) for all-cause mortality and found a relative risk (RR) of 0.93 (95% confidence interval [CI]: 0.87 to 0.99, p = 0.03)
      • cardiovascular deaths
        • eighteen trials (n = 59,469) assessed cardiovascular deaths (RR: 0.89, 95% CI: 0.81 to 0.98, p = 0.01)
      • major cardiovascular events
        • seventeen trials (n = 53,371) found an RR of 0.85 (95% CI: 0.77 to 0.95, p = 0.004 for major cardiovascular events
      • myocardial infarctions
        • 17 trials (n = 52,976) assessed myocardial infarctions (RR: 0.77, 95% CI: 0.63 to 0.95, p = 0.01)
      • incidence of cancer was not elevated in 10 trials (n = 45,469) (RR: 1.02, 95% CI: 0.94 to 1.11, p = 0.59, nor was rhabdomyolysis (RR: 0.97, 95% CI: 0.25 to 3.83, p = 0.96)
  • notes:
    • analysis did not show an association between a reduction in LDL cholesterol and mortality or morbidity
      • lack of statistical significance in the trend of reduced morbidity and mortality with a reduction in LDL may be a reflection of the restricted variance in the meta-regression technique, or it may genuinely indicate that the major benefit of statins is not in LDL reduction
    • "..treating all patients at risk of cardiovascular events would mean treating a very large number of people and could have important implications for public health costs, insurability.." (2)
    • unlike Thavendiranthan et al, the study by Mills et al did not include absolute risk reductions and hence numbers needed to treat (NNTs) for different risk groups - this information would have been a valuable addition to the paper and helpful in evaluating the use of the data from this study in a clinical setting
      
      
• a Cochrane review was undertaken to assess the effects, both harms and benefits, of statins in people with no history of CVD (3)
  • fourteen randomised control trials (16 trial arms; 34,272 participants) were included
    • observed outcomes ranging from 1-5.3 years, amounting to approximately 113,000 patient years. The size of the population recruited ranged from 47- 8,009. The mean age of the participants was 57 years (range 28-80 years), 65.9% were male and of the five trials which reported on ethnicity; 91.4 % were Caucasian
    • eleven trials recruited patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria)
    • all-cause mortality was reduced by statins (RR 0.83, 95% CI 0.73 to 0.95) as was combined fatal and non-fatal CVD endpoints (RR 0.70, 95% CI 0.61 to 0.79). Benefits were also seen in the reduction of revascularisation rates (RR 0.66, 95% CI 0.53 to 0.83). Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects. There was no clear evidence of any significant harm caused by statin prescription or of effects on patient quality of life
  • the study authors concluded that the".. current systematic review highlights the shortcomings in the published trials of statins for primary prevention. Selective reporting and inclusion of people with cardiovascular disease in many of the trials included in previous reviews of their role in primary prevention make the evidence impossible to disentangle without individual patient data. In people at high risk of cardiovascular events due to their risk factor profile (i.e. >=20% 10-year risk), it is likely that the benefits of statins are greater than potential short term harms although long-term effects (over decades) remain unknown. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk..."
    
    
• benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors (4)
  • a more recent meta-analysis revealed reduction in mortality associated with statin use in patients without CVD but with CV risk factors
    • 10 trials enrolled a total of 70 388 people, of whom 23 681 (34%) were women and 16 078 (23%) had diabetes mellitus. Mean follow-up was 4.1 years
      • treatment with statins significantly reduced the risk of all cause mortality (odds ratio 0.88, 95% confidence interval 0.81 to 0.96), major coronary events (0.70, 0.61 to 0.81), and major cerebrovascular events (0.81, 0.71 to 0.93)
    • the authors concluded that in patients without established cardiovascular disease but with cardiovascular risk factors, statin use was associated with significantly improved survival and large reductions in the risk of major cardiovascular events

Reference:

• 1. Thavendiranathan P et al. Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials. Arch Intern Med. 2006 Nov 27;166(21):2307-13.
• 2. Mills EJ et al. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. J Am Coll Cardiol. 2008 Nov 25;52(22):1769-81.
• 3. Taylor F et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2011 Jan 19;1:CD004816.
• 4. Piccini JP et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. Eur Heart J. 2009 May;30(10):1245-53