Statins have become the most widely prescribed class of drugs in medicine. They are generally considered to be both safe and highly effective with few adverse effects. Various summaries of their benefits have been presented, as outlined in this passage from a document produced by the American College of Cardiology (ACC):
In a meta-analysis of 27 randomized trials and 174,000 participants, for every ~40 mg/dL LDL-C reduction with statin therapy, the relative risk of major adverse cardiovascular events is reduced by ~20-25%, and all-cause mortality is reduced by 10%. More intense statin regimens yield a 15% further proportional reduction in major adverse cardiovascular events compared to less intense regimens. These relative reductions are similar in primary vs. secondary prevention, lower vs. higher-risk, men vs. women, and also similar in other major subgroups. (1)
The way these data are presented strongly suggests the benefits of statins are highly significant, both statistically and clinically, in all populations, among men as well as women, and that the higher the dose of statin, the greater the benefit.
However, it could be argued that the framing of these data is misleading, presenting a significantly distorted perception of the absolute benefits. It is true that there are no agreed criteria for the way the trials are analyzed, nor for how the outcomes should be presented. Yet it is well known that the way that data are “packaged” can have significant influence over decision-making related to a drug.
Professor Michael Baum has discussed this issue, primarily with regard to cancer screening:
Each year I play a game with the senior postgraduate students at a course for specialists in cancer run by the Royal College of Surgeons of England. I tell them that there are two potentially effective screening tools for prostate cancer, one which will reduce their chances of dying from the disease by between 20 and 30 per cent, while the other will save one life after 10,000 person-years of screening. As a consumer or as a public health official, which one would you buy into? They all vote for the first, yet the two programmes are the same, they were just packaged differently. (2)
What Baum is stating in this passage is that the same health outcomes can be presented or packaged in different ways, and this can significantly impact their perceived value.
Another important issue is that certain outcomes can be included and others excluded. Again, this can alter the perception of benefit. For example, in the passage from the American College of Cardiology outlining the benefits of statins, it was stated that “with statin therapy, the relative risk of major adverse cardiovascular events is reduced by ~20-25%.”
A major adverse cardiovascular event would normally be a non-fatal heart attack or stroke (A major, or serious CV event could include fatal heart attacks and strokes, but these are normally listed separately). Reducing major cardiovascular events is clearly a benefit, but what of other major (non-cardiovascular) adverse events? Were they also reduced, did they stay the same, or did they increase?
It is important to know this information, because if statins reduce major adverse cardiovascular events but increase other major adverse events, then there may be no overall benefit. The data on serious adverse events with statins are difficult to obtain as most of the information is held by the Cholesterol Trialists Collaboration in Oxford and the group does not often extend access to independent researchers.
However, the Cochrane Collaboration at the University of British Columbia did review all the data they could access some years ago and analyzed the serious adverse event (SAE) rates, posing this question: “How can CHD [coronary heart disease] SAEs decrease, but not total SAEs?” As they stated:
All CHD events are SAEs and are counted in both categories. Therefore, a reduction in major CHD SAEs should be reflected in a reduction in total SAEs. The fact that it is not suggests that other SAEs are increased by statins negating the reduction in CHD SAEs in this population. (3)
Cochrane highlighted the fact that it could not obtain all the data:
A limitation of our analysis is that we could not get total SAE data from all the included RCTs. However, we are confident that the data from the 6 missing RCTs would not change the results, because they represent only 41.2% of the total population and include ALLHAT-LLT, where one would not expect a reduction in total SAEs; in that trial there was no effect on mortality or cardiovascular SAEs. (3)
What the Cochrane Collaboration is highlighting here is the fact that, while statins may reduce CHD-related SAEs, there is no reduction in overall SAEs.
Therefore, the statement that “with statin therapy, the relative risk of major adverse cardiovascular events is reduced by ~20-25%” is potentially misleading. It strongly implies that statins have a significant benefit on SAEs. However, if all SAE data are included, there is no overall benefit.
With regard to overall mortality, the American College of Cardiology noted that with statins, “all-cause mortality is reduced by 10%.” All-cause mortality is the risk of dying of anything. This is, potentially, the single most important outcome measure from any clinical trial.
Unfortunately, all-cause mortality is not an outcome that has much validity in preventive medicine where one cannot prevent death, only extend life expectancy. Or, to frame this in another way, an improvement in all-cause mortality does not correspond to lives saved. It simply indicates how many more people who were taking the statin were alive at the end of the clinical trials on average. There is no information on how much longer these people will live.
In contrast, in cancer trials, the outcome measure used is “increase in median survival.” Using this measure, it can be stated that if a person takes a cancer drug for, say, two years, the increase in survival time will be, say, three months. In lay terms, this could be presented to a patient in the following terms: “If you take this drug, it is likely that you will gain three months extra lifespan.”
Median survival cannot be established in (most) cardiovascular studies, because significantly more than 50 percent of participants in both arms of any RCT will still be alive when the trial is completed.
However, it is still possible to establish the mean increase in survival time. This was done in a study published in the BMJ in 2015, which included the following results and conclusions:
Results: 6 studies for primary prevention and 5 for secondary prevention with a follow-up between 2.0 and 6.1 years were identified. Death was postponed between −5 and 19 days in primary prevention trials and between −10 and 27 days in secondary prevention trials. The median postponement of death for primary and secondary prevention trials were 3.2 and 4.1 days, respectively.
Conclusions: Statin treatment results in a surprisingly small average gain in overall survival within the trials’ running time. For patients whose life expectancy is limited or who have adverse effects of treatment, withholding statin therapy should be considered. (4)
In summary, over an average of around five years of statin treatment:
- In primary prevention, life expectancy was increased by 3.2 days.
- In secondary prevention, life expectancy was increased by 4.1 days.
Therefore, packaged in a different way, a 10-percent reduction in mortality equates to approximately 0.6 to 0.75 days of additional life expectancy per year of taking a statin. Or, if a patient were to take a statin for 30 years, the mean increase in life expectancy would be 18 to 22 days.
This means that while the benefits of statins can be presented in a way that can create a perception of significant benefit, if packaged differently, it can be said that:
- Serious adverse events are not prevented by statins.
- The mean increase in life expectancy with statins is 0.6 to 0.75 days, depending on whether the patient is at low risk or high risk for CVD.
It could therefore be suggested that the ACC review of statins represents positive “spin.” The prevalence of “spin” in reporting clinical studies was reviewed in the JAMA paper “Level and Prevalence of Spin in Published Cardiovascular Randomized Clinical Trial Reports With Statistically Nonsignificant Primary Outcomes.” The study found:
[I]n reports of cardiovascular RCTs with statistically nonsignificant primary outcomes, investigators often manipulate the language of the report to detract from the neutral primary outcomes. To best apply evidence to patient care, consumers of cardiovascular research should be aware that peer review does not always preclude the use of misleading language in scientific articles. (5)
Additional Reading
Malcolm Kendrick is a family practitioner working near Manchester in England. He has a special interest in cardiovascular disease, what causes it, and what may prevent it. He has written three books: The Great Cholesterol Con, Doctoring Data, and A Statin Nation. He has authored several papers in this area and lectures on the subject around the world. He also has a blog, drmalcolmkendrick.org, which stimulates lively debate on a number of different areas of medicine, mainly heart disease.
He is a member of THINCS (The International Network of Cholesterol Sceptics), which is a network of doctors and scientists who believe that cholesterol is not the main underlying cause of heart disease. He remains a proud Scotsman, whisky drinker, and failed fitness fanatic who loves a good scientific debate — in the bar.
References
- Aronis KN, Blumenthal RS, Martin SS. Summarizing the current state and evidence on efficacy and safety of statin therapy. American College of Cardiology. 16 Nov. 2016. Available here.
- Baum M. What mammography misses. Spiked. 28 Jan. 2004. Available here.
- Do statins have a role in primary prevention? An update. Therapeutics Initiative. 18 Oct. 2010. Available here.
- Kristensen ML, Christensen PM, Hallas J. The effect of statins on average survival in randomised trials, an analysis of end point postponement. BMJ Open 5.9(2015). Available here.
- Khan MS, Lateef N, Siddiqi TJ. Level and prevalence of spin in published cardiovascular randomized clinical trial reports with statistically nonsignificant primary outcomes: A systematic review. JAMA 2.5(2019). Available here.
Statins — What Are the Benefits?