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Ideas and Opinions |

Statins, Primary Prevention, and Overall MortalityStatins, Primary Prevention, and Overall Mortality

Vinay Prasad, MD
[+] Article and Author Information

From National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Disclaimer: The views and opinions of the author do not reflect those of the National Cancer Institute or National Institutes of Health.

Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-2974.

Requests for Single Reprints: Vinay Prasad, MD, National Cancer Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 12N226, Bethesda, MD 20892; e-mail, vinayak.prasad@nih.gov.

Author Contributions: Conception and design: V. Prasad.

Analysis and interpretation of the data: V. Prasad.

Drafting of the article: V. Prasad.

Critical revision of the article for important intellectual content: V. Prasad.

Final approval of the article: V. Prasad.

Collection and assembly of data: V. Prasad.


Ann Intern Med. 2014;160(12):867-869. doi:10.7326/M13-2974
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The American College of Cardiology/American Heart Association updated their cholesterol guidelines in November 2013, sparking debate about the role of statins in the primary prevention of cardiovascular disease. In response, this commentary discusses the effect of statin therapy on overall mortality and calls for a thorough review of all trials on this topic.

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Statins primary prevention and mortality – please not another meta-analysis
Posted on June 24, 2014
James McCormack professor 1, G Michael Allan associate professor 2
University of British Columbia, University of Alberta
Conflict of Interest: None Declared

What effect statins have on mortality in primary prevention is a relevant question when it comes to patients making a decision about whether or not to consider drug therapy.

Prasad in his commentary (1) suggests when it comes to the debate we need “a profession-wide commitment to reviewing all data” and that a recount of the individual-patient data is required for us to determine the answer to this question once and for all.

We would like to suggest a different take on the debate. As we have previously shown,(2) it appears the debate as to whether or not statins have an impact on mortality has to do with a “dogmatic adherence to statistical significance thresholds” that “lead authors to write dichotomized absolute conclusions while ignoring the broader interpretations of very consistent findings”

As outlined in the table (2), the point estimate in the Taylor et al meta-analysis is exactly the same as that found by Studer in 2005 and similar to that found by Brugts in 2009. In fact, the confidence intervals for these estimates overlap far more than they differ.  This should come as little surprise as they use many of the same studies.  

The findings of these 7 meta-analyses have been very consistent in their point estimates and confidence intervals. The only “real” difference being that in 2 of them the upper margin of the confidence interval squeaked above 1.00, an arbitrary cut-off for hypothesis testing. Using confidence intervals for hypothesis testing based on an arbitrary cut-off negates somewhat the value of using confidence intervals. Given this, will a recount meaningfully change the point estimate or really only subtly shift the confidence intervals which, will not change what we know?

So what do we know? It is likely that statins reduce mortality in primary prevention and the point estimate is roughly 10% but it could be as little as no effect or as great as a 20% reduction.

The baseline risk of mortality in all these meta-analyses is roughly 5%. With a 10% risk reduction this leads to a 0.5% absolute reduction but it could be as much as 1% or as little as 0% when one considers the confidence intervals – yet another meta-analysis is not going to change these findings.

TABLE – Results from meta-analyses of the effect of statins on mortality in primary prevention

Study

Year

Trials/subjects

Point estimate

95% Confidence interval

Confidence interval spread

Studer

2005

9 (26,641)

0.86

(0.76-0.99)

0.23

Thavendiranathan

2006

6 (39,937)

0.92

(0.84-1.01)

0.17

Mills

2008

19 (63,899)

0.93

(0.87-0.99)

0.14

Brugts

2009

9 (67,476)

0.88

(0.81-0.96)

0.15

Ray

2010

11 (65,229)

0.91

(0.83-1.01)

0.18

Taylor (3)

2013

13 (48,060)

0.86

(0.79-0.94)

0.15

Tonelli (4)

2011

23 (79,495)

0.90

(0.84-0.97)

0.14

AVERAGE

 

 

0.89

 

0.17

 

REFERENCES

1) Prasad V. Statins, primary prevention and overall mortality. Ann Int Med 2014;160;867-9

2) McCormack J., Vandermeer B., Allan G.M. How confidence intervals become confusion intervals. BMC Medical Research Methodology 2013;13,134

3) Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;1:CD004816. [PMID: 23440795]

4) Tonelli M, Lloyd A, Clement F, et al.  Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis.  CMAJ 2011;183(16):E1189-202

More meta-analyses that don't address the primary prevention question
Posted on July 3, 2014
Vinay Prasad
NIH
Conflict of Interest: None Declared
I thank Drs. McCormack and Allan for their comments.

The central problem with their interpretation of the data is that, with the sole exception of the meta-analysis by Ray, et al, every meta-analysis they cite includes secondary prevention patients. Secondary prevention patients comprise up to 10-20% of participants in included studies in these meta-analyses. Looking at many meta-analyses (of largely the same trials) conducted inappropriately for the question at hand does not constitute an overwhelming body of evidence.

The question my article discusses is simple: Do statins improve overall mortality among patients who have not experienced cardiovascular events? In other words, do they improve OM in a true primary prevention setting? A meta-analysis on this question must exclude all patients who already have an indication for statins. Ideally, the demographics of the remaining participants would mirror modern demographics, e.g. in the rate of smoking, and other risk factors. In other words, the patients from whom the data is derived should look like the patients we see in clinic.

For a question with profound public health importance, it is not acceptable that the largest dataset capable of addressing the question is not widely available. Drs. McCormack and Allan may not want to read another meta-analysis, but many physicians do want to see an independent analysis tackling the primary prevention question and no other. Such an analysis should be of only primary prevention patients, it should look only at statin versus placebo (not varying doses of statins), it should be based on intention to treat principles (and not weighted by ldl reduction), and it should carefully appraise harms. There is no reason not to get this important question right.
Response from Cochrane Systematic Review Authors
Posted on July 22, 2014
Mark Huffman (1,2), Fiona Taylor (2,3), Shah Ebrahim (2,3)
(1) Northwestern University Feinberg School of Medicine; (2) Cochrane Heart Group; (3) London School of Hygiene and Tropical Medicine
Conflict of Interest: Dr Huffman receives grant funding from the National Heart, Lung, and Blood Institute and AstraZeneca and Boehringer Ingelheim. Dr Ebrahim receives grant funding from Wellcome Trust and the National Institute of Health Research and royalties from Open University Press.
As co-authors of one of the two studies described in the Ideas and Opinions manuscript by Prasad,(1) we believe that Annals of Internal Medicine readers may be interested in a brief response. The author describes potential discrepancies between our 2013 update of the Cochrane systematic review of the effect of statins on cardiovascular disease prevention(2) and a systematic review by Ray et al., published in 2010.(3) The author also asks for a recount of the data to identify reasons for differences between the results of the two reviews, and we offer our perspective on these differences, the methods of review updates, and corroboration of our results.

First, as Prasad notes, we included longer-term follow-up from some trials compared with the Ray et al. review. Inclusion of longer-term data, which is important to many patients and clinicians, frequently attenuates effect sizes, yet the overall results of our update demonstrate a reduction in all-cause mortality from statins compared with placebo. Second, systematic reviews performed by the Cochrane Collaboration are updated regularly and as new data emerge, which is an important advantage of the Cochrane methodology compared with many systematic reviews performed by other groups. We plan to begin our update of this review in early 2015. Third, the effects of statins on all-cause mortality have been demonstrated by analysis of the Cholesterol Treatment Trialists’ data (pooled estimate, relative risk = 0.86 [95% CI: 0.76, 0.98]),(4) which appears to corroborate the results from our review (pooled odds ratio = 0.86 [95% CI: 0.79, 0.94]).

Regards,

Mark Huffman, MD, MPH
Northwestern University Feinberg School of Medicine
Cochrane Heart Group US Satellite

Fiona Taylor, PhD
London School of Hygiene and Tropical Medicine
Cochrane Heart Group

Shah Ebrahim, DM
London School of Hygiene and Tropical Medicine
Cochrane Heart Group


REFERENCES
1. Prasad V. Statins, primary prevention, and overall mortality. Annals of Internal Medicine. 2014; 160:867-9.
2. Taylor F, Huffman MD, Macedo AF, Moore THM, Burke M, Davey Smith G, Ward K, Ebrahim S. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews. 2013; 31:1–97.
3. Ray KK, Seshasai SRK, Erqou S, Sever P, Jukema JW, Ford I, et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Archives of Internal Medicine. 2010; 170:1024–31.
4. Huffman MD, Taylor F, Ebrahim S. Huffman and colleagues“ response to Abramson and colleagues” article on statins in low risk people. BMJ. 2014; 348:g1520.
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