Everyone knows of the health benefits of statins, especially for those with established risk of cardiovascular disease and stroke. Statins were first prescribed as a preventative treatment for individuals with a history of a heart attack. And they have been shown to definitively reduce cholesterol levels and reduce risk of heart attack and stroke in those at-risk individuals. But the indication has been greatly broadened over the years to include people with no previous cardiovascular disease or stroke, but elevated risk factors including total cholesterol, LDL cholesterol, and/or high blood pressure (see “The Low Down on Statins: Risk Benefit Ratio Discussion”). Indeed, one study published in 2008 demonstrated a significant reduction in heart attack and stroke in individuals with no history of either elevated cholesterol nor heart disease but only elevated C-reactive protein levels indicating chronic inflammation, assumed to be of the arteries (1). Recently the Cochrane Collaboration, an independent, international team charged with reviewing evidence for effective treatments, reviewed the use of statins for primary prevention of cardiovascular disease, stroke and death (ie in people with no past history of cardiovascular abnormalities, but having more than 1 risk factor for cardiovascular disease). The data clearly demonstrated benefit: Fourteen randomised control trials including 34,272 participants were examined. Overall mortality was significantly reduced by 17% in people taking statins. Heart attacks were reduced by 28%, and strokes by 22%. They also found no evidence of adverse side effects. Because these individuals had no previous cardiovascular disease and only had risk factors predicting a potential of future cardiovascular disease, the incidence of these events was small, as expected. In these low-risk patients, 1000 patients needed to be treated in order to prevent one death per year. This type of evidence is quite convincing to me, but surprisingly, the Cochrane reviewers, while not disputing the data, concluded, “Only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.” This concluding statement was taken out of context by many in the media, but in this Health Examiner’s opinion, this latest review by the Cochrane Collaboration even more forcibly substantiates the low risk and relatively strong benefit of statins for primary prevention of cardiovascular disease in people with only one or two risk factors. The cost/benefit and risk/benefit ratio that seemed to dissuade the Cochrane group from supporting use of statins to prevent first heart attacks in at-risk individuals can be disputed depending on who that 1 person who dies of the heart attack is.
Just last week, a follow up report was published by a group that was one of the first to report results of Lipitor in preventing cardiovascular disease. In the report, published in the European Heart Journal (3), the group reported an 11 year follow up of the original group of 4,605 people with elevated blood pressure and three risk factors for cardiovascular disease. In the original study, 2288 people were treated with placebo, and 2317 were treated with 10 mg/day of Lipitor. The study was halted after 3 years because of overwhelming evidence of benefit of Lipitor in preventing fatal or non-fatal heart attacks (36% reduction in risk of heart attack), and presumably most of the people being treated with placebo went on Lipitor. But the research group continued to follow the individuals for 8 more years. There were essentially no differences between the random treatments of the 4605 people for the past 8 years between 2003 and 2011, the major difference being that half were treated with Lipitor from 2000-2003, and half were not. The researchers looked at how many people had died, and the cause of death. By 2011, 21.3% (980/4605) of the original participants had died. Surprisingly, there were significantly fewer overall deaths in the group treated with Lipitor from 2000-2003. Deaths due to cardiovascular causes were lower in the group treated with Lipitor until 2003, but not significantly lower than the group treated with placebo. Over the 11 years since the study started in 2000, the major causes of death that was reduced in the people treated with Lipitor from 2000-2003 was non-cardiovascular, in particular death due to infection and death due to respiratory disease. There was no effect on numbers of deaths due to cancer. These results are quite surprising primarily because of the fact that these patients had been treated the same for the past 8 years!
Use of any drug must have so called ‘off target’ effects. Statins are inhibitors of an enzyme called HMG-CoA reductase that is used by the liver to synthesize cholesterol. Statins therefore result in lowered cholesterol levels in the blood. Statins are beneficial in ways other than simply lowering cholesterol. There is substantial scientific evidence that statins prevent cardiovascular disease by decreasing inflammation in the blood vessels which prevent existing fatty plaque formation from becoming loose and causing strokes, and preventing new formation of plaques. The inhibition of cholesterol synthesis also decreases some intermediates important in the signaling pathways in many forms of inflammation and coagulation, and have been shown to have direct inhibitory effects on fungi, bacteria and viruses. So far, no adverse ‘off-target’ effects have raised any serious alarms in the millions of patients treated with statins.
Until 2010 Lipitor was the best selling drug in the world, racking up 12.7 billion dollars in global sales for Pfizer in 2007. Sales have dipped since likely due to competition from other statins on the market: all the statins act by the same mechanism, and there is no single drug that has demonstrated superior efficacy. Lipitor goes off patent in November 2011, and Ranbaxy Laboratories is poised to enter the market with generic Lipitor at greatly reduced prices. This will probably translate to even more accessibility of this inexpensive drug (presently Pfizer charges $3/daily dose) and more widespread use as a preventative treatment. So far, despite the unusual interpretation of the available data by the Cochrane Report, there has been little reason to avoid use of statins to prevent cardiovascular disease and stroke, and evidence is mounting suggesting that anti-inflammatory/ anti-infectious activities may be beneficial on their own.
1. Ridker PM, Danielson E, Fonseca FAH, et al. “Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein”. NEJM 359 (21): 2195–207. 2008.
2. Taylor F, Ward K, Moore THM, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD004816. DOI: 10.1002/14651858.CD004816.pub4
3. Sever, P.S., Choon L. Chang, C.L., Ajay K. Gupta, A.K., et al. The Anglo-Scandinavian Cardiac Outcomes Trial: 11-year mortality follow-up of the lipid-lowering arm in the UK. Europ Heart J. doi:10.1093/eurheartj/ehr333 Published on line August 28, 2011.