The Lancet published a meta-analysis of 27 statin trials

Data, Drugs, and Deception: a True Story

 

Wednesday, May 23, 2012

      

Last week The Lancet published a meta-analysis of 27 statin trials, an attempt to determine whether patients with no history of heart problems benefit from the drugs—true story. The topic is controversial, and no less than six conflicting meta-analyses have been performed—also a true story. But last week’s study claims to show, once and for all, that for these very low risk patients, statins save lives—true story.

Actual true story: the conclusions of this study are neither novel nor valid.

The Lancet meta-analysis, authored by the Cholesterol Treatment Trialists group, examines individual patient data from 27 statin studies. Their findings disagree with an analysis published in 2010 in the Archives of Internal Medicine, and with analyses from two equally respected publications, the Therapeutics Letter and the Cochrane Collaboration.* Despite this history of dueling data the authors of last week’s meta-analysis, in a remarkable break from scientific decorum, conclude their report with a directive for the writers of statin guidelines: the drugs should be broadly recommended based on the new analysis.

As an editorialist points out, if implemented, the CTT group recommendations in the United States would lead to 64 million people, more than half of the population over the age of 35, being started on statin therapy—true story.

Where is the magic, you ask, in this latest effort? What is different? In some ways, nothing. Indeed just a year and a half earlier The Lancet published a meta-analysis of 26 of the same 27 studies, with the same results, by the same authors (true story, and an odd choice on the part of the journal). So the findings aren’t new. They are, however, at odds with other meta-analyses. Why? It is the way they calculated their numbers. This meta-analysis, like the earlier one from the same group, reports outcomes per-cholesterol-reduction. The unit they use is a “1 mmol/L reduction in low density lipoprotein (LDL)”, in common U.S. terms, a roughly 40-point drop in LDL.

That’s the magic: each of the benefits reported in the paper refers to patients with a 40-point cholesterol drop. Voilá. One can immediately see why these numbers would look different than numbers from reviews that asked a more basic question: did people who took statins die less often than people taking a placebo? (The only important question.) Instead, they shifted the data so that their numbers corresponded precisely to patients whose cholesterol responded perfectly.
Patients whose cholesterol drops 40 points are different than others, and not just because their body had an ideal response to the drug. They may also be taking the drug more regularly, and more motivated. Or they may be exercising more, or eating right, and more health conscious than other patients. So it should be no surprise that this analysis comes up with different numbers than a simple comparison of statins versus placebo pills. Ultimately, then, this new information tells us little or nothing about the benefits someone might expect if they take a statin. Instead it tells us the average benefits among those who had a 40-point drop in LDL.

But LDL drop cannot be predicted. Some won’t drop at all, some will drop just a bit, and some may drop more. Therefore the numbers here tell an interesting story about certain patients who took statins, but they have no relevance to patients and doctors considering statins. And yet, the latter group is the target of the study's concusions.

True story: in prior meta-analyses that found no mortality benefit the investigators simply looked at studies of patients without heart disease and compared mortality between the statin groups and the placebo groups. No machinations, no acrobatics, no per-unit-cholesterol. They took a Joe Friday approach (just the facts, ma’am), and found no mortality benefit.

Perhaps never has a statistical deception been so cleverly buried, in plain sight. The study answers this question: how much did the people who responded well to the drug benefit? This is, by definition, a circular and retrospective question: revisiting old data and re-tailoring the question to arrive at a conclusion. And to be fair they may have answered an interesting, and in some ways contributory, question. However the authors’ conclusions imply that they answered a different, much bigger question. And that is not a true story.

Guideline writers, doctors, patients, journalists, and policy makers will all have to pay close attention to avoid the trappings of deceptive data, dressed up as a true story.

*The Cochrane Collaboration analysis reports an overall mortality benefit with statins (RR=0.86), however their summary suggests that statins should be used for primary prevention “with caution.” In particular on p.12, after a discussion of the biases in many of the trials that led to their numerical finding, they clearly state that using statins for patients with anything less than a 2% per year risk of coronary events “is not supported by existing evidence.” This cutoff encompasses virtually all people that would be considered candidates for primary prevention.
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BMJ exposes ways we have been misled over the ‘benefits’ of statins - Briffa

BMJ articles exposes the ways we have been misled over the ‘benefits’ of statins

By Dr John Briffa on 1 November 2013   

 

The ‘Cochrane Collaboration’ is an international collective of researchers whose self-proclaimed role is to provide accurate and robust assessments of health interventions. The group specialises in ‘meta-analyses’: the grouping together of several similar studies on interventions including drug therapies.
In 2011, Cochrane researchers assessed the evidence relating to statin use in individuals at low risk of cardiovascular disease (defined as a less than 20 per cent risk over 10 years), and concluded that there was limited evidence of overall benefit [1]. I appeared on Channel 4 news to discuss this publication and the issues surrounding it, and you can see the discussion here.

Earlier this year, the same Cochrane group updated their data and concluded that overall risk of death and cardiovascular events (e.g. heart attack or stroke) were reduced by statins in low risk individuals, without increasing the risk of adverse events (including muscle, liver and kidney damage) [2]. It seems the Cochrane reviewers had had quite some change of heart. A paper published in the BMJ on 22 October questions the evidence on which this U-turn appears to have been made [3].

The authors of the BMJ piece note that although the 2013 meta-analysis included four additional trials, these trials did not substantially change the findings. The change in advice was actually based on another meta-analysis, published in 2012, conducted by a group known as the Cholesterol Treatment Trialists’ (CTT) collaboration [4].

Among other things, the CTT authors concluded that, in low risk individuals, for each 1.0 mmol/l (39 mg/dl) reduction in LDL-cholesterol, statins reduce overall risk of death and heart attack by about 9 per cent and 20 per cent respectively. The conclusion was that statins have significant benefits in low risk individuals that greatly exceeded known risks of treatment.

However, the CTT authors took the odd step of calculating the benefits of statins according to a theoretical reduction in LDL-cholesterol levels. A much more realistic appraisal would be simply to calculate if, compared to placebo, statins actually reduce the risk of health outcomes.
The BMJ authors use the data from the CTT meta-analysis and found that risk of death was not reduced by statins at all. So, the CTT authors had used had extrapolated the data in a way that showed a benefit that actually does not exist in reality.

And what of the claim that statins reduce the risk of cardiovascular events such as heart attack or stroke? The data shows that about 150 low-risk individuals would need to be treated for five years to prevent one such event (i.e. only about one in 750 individuals will benefit per year).

They also draw our attention to the impact of statin treatment on ‘serious adverse events’. This outcome can be improved by statins as a result of, say, a reduced number of heart attacks, but worsened through side effects such as muscle or liver damage. The BMJ authors note that the CTT review did not consider serious adverse events (a major omission). Without knowing more about this, though, we simply cannot make a judgement regarding the overall effect of statins, and whether the net effect is beneficial or not. Interestingly, of three major trials that were included in the CTT review that assessed overall serious adverse effects, none found overall benefits from statin treatment.
So, while the CTT authors seem to have over-hyped the benefits of statins, they seem at the same time to have been quite keen to steer clear of talk of their very real risks and the absence of evidence foroverall benefit.

The BMJ authors draw our attention to the fact that every single trial included in the CTT was industry funded. Such trials are well known to report results more favourably and perhaps downplay risks than independently funded research. The BMJ authors cite specific ways in which the adverse effects of drugs seen in clinical trials can be ‘minimised’. These include:

• The exclusion of individuals from trials with known health issues likely to be exacerbated by statins or signal susceptibility to statin side effects (such as liver, kidney and muscle disease).
• The use of a ‘run-in’ period before the study starts which detects and then excludes individuals who do not tolerate statins.
• The possibility that individuals ‘drop out’ from the study because of side effects, meaning that the incidence of some side effects can be ‘lost’ from the data.
• Failure of the study investigators to assess and monitor adverse events such as muscle damage and changes in brain function.
• Failure to properly ascertain or report adverse events.

It is noted that the Cochrane authors admit the reporting of adverse effects in studies is generally poor, but also state that it’s unlikely statins have major life-threatening hazards. The authors of the BMJ piece are not convinced, though, writing: “[The] large discrepancies between the frequency of adverse events reported in commercially funded randomised controlled trials included in the CTT meta-analysesand non-commercially funded studies show that determination of harms cannot be left to industry alone.”

The BMJ piece is accompanied by an editorial from the journal’s editor, Fiona Godlee [5]. Her comment on this issue starts:

None of this does much to bolster confidence in the published literature.

Godlee goes on to write:

Nor am I reassured by discussions at two recent meetings co-hosted by the European Federation of Pharmaceutical Industry Associations (EFPIA). Drug company AbbVie is suing the European Medicines Agency to stop summary reports of its clinical trials becoming publicly available. AbbVie’s lawyer made clear that the company considers even the data on adverse events to be commercially confidential. Despite industry’s claims to be in favour of greater transparency, EFPIA and its American counterpart PhRMA are supporting Abbvie. The BMJ and BMA have joined forces to intervene on behalf of the EMA.

If I were to summarise, I’d say that, at best, there seems to be a degree of complacency regarding the veracity of statin data on the part of both the CTT and the Cochrane researchers. There is a sense that they are happy to present the ‘positive’ findings in the best possible light, and at the same time seem relaxed about the clear gaps we have in our knowledge about potential harms. The fact that statins appear to have no overall benefit in those at low risk of cardiovascular disease should not go unacknowledged, either.

Worse still, we have evidence that drug trials can be designed, conducted and reported in ways that obscure the truth. And sometimes, even when we have data that can help us make informed decisions about the appropriateness of a treatment, some drug companies will fight tooth and nail to prevent that data seeing the light of day.

This sort of subterfuge may be good for sales and share price, but it is almost certainly bad for our collective health. On this point, the BMJ authors state than instead of doctors following guidelines and prescribing statins for individuals at low risk of cardiovascular disease, they should explain the magnitude of benefits and uncertainties regarding harm. In addition, they might also discuss the fact that the vast majority of cardiovascular disease risk is linked with lifestyle factors such as smoking, diet and physical activity. Fiona Godlee backs this approach, but states that the benefits of lifestyle change are: “something that the dominance of industry sponsored clinical trials too often obscures.”
Personally, I am delighted that the misdeeds of drug companies and some researchers can now be exposed in this way, and in a high-profile medical journal at that. In the past, I think there was much more opportunity for the industry and its hired hands to mislead us. Greater transparency means that the industry as a whole is getting more of what I believe it deserves: our contempt.
References:
1. Taylor F, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2011;1:CD004816.
Medline
2. Taylor F, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev2013;1:CD004816.
3. Abramson JD, et al. Should people at low risk of cardiovascular disease take a statin?
BMJ 2013;347:f6123
4. Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. The Lancet 2012;380(9841):581–90.
5. Godlee F. Statins for all over 50? No BMJ 2013;347:f6412.
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Do statins have a role in primary prevention? An update.

Do statins have a role in primary prevention? An update.

Therapeutics Letter Issue 77 / Mar - Apr 2010

 

Therapeutics Letter #48 (April-June 2003)¹ concluded that “statins have not been shown to provide an overall health benefit in primary prevention trials” based on the 5 RCTs^8-12 available at that time. More RCTs are now available and 5 systematic reviews^2-6 designed to answer this question have been published since 2003. Unfortunately, these reviews do not answer the question “Do the benefits of statins outweigh the harms in people without proven occlusive vascular disease?” This question is critically important to patients, physicians and health care resource utilization.

The Cochrane Collaboration is regarded as the gold standard of systematic reviews. One of its guiding principles is avoiding unnecessary duplication: any independent reviewer following the proper methodology would include the same trials, extract the same data and come to the same interpretation and conclusions. The review is then updated as new trials are published.

 

The 5 published systematic reviews^2-6 (none of which are Cochrane reviews) vary in the RCTs included, summary effect estimates, conclusions and declared conflicts of interest of the authors (Table 1).

Table 1. Published systematic reviews

Two of these reviews report a decrease in total mortality while 3, including the latest, conclude that mortality is not decreased by statins in this setting.

 

What is the explanation for the different relative risk estimates? In part, it is due to the timing of the review and the trials that were available for inclusion. The 2006 review² did not have access to 3 RCTs^17-19.  The 2007 review³ did not have access to 2 RCTs^18,19.  The 2008 review⁴ did not include 2 RCTs^13,19 and included 10 RCTs^20-29 not included in any of the other reviews. The 2009 and 2010 reviews^5,6 had access to the same RCTs and had very small differences in the RCTs included (Table 1). The reason for the variation in the overall mortality estimate between the 2009 and 2010 reviews is that the 2010 review requested and obtained additional details from authors, allowing exclusion of 3659 secondary prevention patients from 4 large RCTs^8,10,11,12.

Why is a new systematic review necessary?

The differences in the interpretation and conclusions of these non-Cochrane reviews are confusing for clinicians. They can be resolved by using Cochrane methodology, including the Cochrane Risk of Bias Tool. Therefore we performed a new systematic review starting with the 22 RCTs included in at least one of these 5 systematic reviews. We excluded 10 of the RCTs^20-29 included in the 2008 review because the population studied was largely or entirely people with occlusive vascular disease at baseline. We included the remaining 12 RCTs^8-19, which provided data for at least one of 3 outcomes that we judged least subject to bias and most meaningful to patients: total all-cause mortality, total people with at least one serious adverse event (SAE) and total people with at least one major coronary heart disease (CHD) serious adverse event. All-cause mortality is an important outcome, for which we used the more accurate data from the 2010 review. Total SAEs capture overall mortality and all serious morbidity. Major CHD (non-fatal MI and death from coronary heart disease) is the outcome specifically reduced by statins, and less subject to bias than other cardiovascular outcomes such as revascularizations and strokes.

 

Results. All 12 RCTs report major CHD data, 11 report mortality data and 6 report SAE data. Our meta-analysis demonstrates that the reduction in mortality and major CHD, both SAE outcomes, is not reflected in a reduction in total SAEs (Table 2). The results are similar if they are limited to the 6 RCTs^{8,9,11,14,16,19} that reported SAEs:  mortality RR 0.90 [0.79-0.98], ARR 0.4%; Major CHD RR 0.70 [0.62-0.79], ARR 1.0%.

 However, getting accurate data entered and analysed is insufficient on its own. Cochrane reviews require assessing the risk of bias for each included RCT using the Risk of Bias Tool. Using this tool we found some risk of bias for each of the 12 included RCTs. Table 2.

 

Table 2. Statins for primary prevention meta-analysis

*Click here to see the forest plots.

 

Loss of blinding to treatment allocation probably occurred in all 12 RCTs, because statins predictably lower LDL cholesterol and the physicians managing the patients knew the lipid parameters. This loss of blinding likely biased clinical decisions regarding revascularization procedures and how outcomes were categorized (e.g. transient ischemic attack or reversible ischemic neurological deficit). Fewer revascularization procedures in the statin group as a result of loss of blinding would result in fewer complications secondary to the procedures, e.g. myocardial infarctions.

 

Other risks of bias affected only some RCTs. Of highest risk are the biases due to stopping RCTs early for benefit, affecting 3 RCTs^12,14,19, and incomplete outcome reporting bias (not an intention to treat analysis), affecting 1 RCT¹⁸. A recent research study demonstrated that the magnitude of the bias effect from stopping RCTs early for benefit is surprisingly large and robust, RR 0.71 [0.66-0.77].⁷ Testing the effect of this bias estimate on the early terminated JUPITER trial changes the RR for major CHD from 0.54 to 0.76 and completely negates the mortality benefit.

 

In order to test the effect of the bias from these 4 RCTs we removed them; analysis of the remaining 7 RCTs (Table 2, second row) shows no reduction in mortality. This suggests that the claimed mortality benefit with statins for primary prevention is more likely due to bias than being a true effect. Removing the 4 potentially biased trials also diminished the magnitude of the major CHD relative risk reduction from 26% to 21%.

How can CHD SAEs decrease, but not total SAEs?

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. 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-LLT¹⁰, where one would not expect a reduction in total SAEs; in that trial there was no effect on mortality or cardiovascular SAEs. 

Conclusions

• Systematic reviews and meta-analyses are challenging and require much more than locating RCTs and plugging in the numbers.
• The claimed mortality benefit of statins for primary prevention is more likely a measure of bias than a real effect.
• The reduction in major CHD serious adverse events with statins as compared to placebo is not reflected in a reduction in total serious adverse events.
• Statins do not have a proven net health benefit in primary prevention populations and thus when used in that setting do not represent good use of scarce health care resources.

The draft of this Therapeutics Letter was submitted for review to 45 experts and primary care physicians in order to correct any inaccuracies and to ensure that the information is concise and relevant to clinicians.

References

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