On 2016 Sep 27, David Nunan commented:

Important methodological flaws limit the findings from the paper by Ravnskov and colleagues

We performed a post-publication critical appraisal of this paper and found a number of methodological flaws not least: 1. Lack of a published protocol 2. Searching of only one database 3. Nonuniform application of inclusion/exclusion criteria 4. A lack of critical appraisal of the methods used in the included studies 5. No indication of the quality or uncertainty of the included data 6. Issues with the accuracy of data extraction, and, 7. A lack of controlling for confounding due to the effect of lipid-lowering treatment and HDL-C levels presenting major bias and more likely underpinning the majority of the observed inverse associations.

Based on the above identified flaws in the paper by Ravnskov and colleagues we concluded: "Given that the authors failed to account for significant confounding as well as the methodological weaknesses of both the review and its included studies, the results of this review have limited validity and should be interpreted with caution. At this time it would not be responsible, or evidence-based, for policy decisions to be made based on the results of this study".

Our full appraisal can be found on our website here: http://www.cebm.net/cebm-response-lack-association-inverse-association-low-density-lipoprotein-cholesterol-mortality-elderly-systematic-review-post-publication-pee/

On 2016 Jun 16, David Keller commented:

In the elderly, statins reduce heart attacks, strokes and, probably, mortality

Ravnskov and colleagues conclude that their analysis of observational data requires "re-evaluation of guidelines recommending pharmacological reduction of LDL-C in the elderly as a component of cardiovascular disease prevention strategies." [1] I disagree, because the guidelines they challenge were based on large, randomized, placebo-controlled, double-blinded prospective interventional trials, higher-quality studies yielding more convincing data than the observational studies examined by Ravnskov. Statisticians warn us that observational data can only demonstrate associations, not causality, and should only be used for hypothesis generation, not for treatment decisions.[2]

A meta-analysis of eight high-quality controlled trials, including over 24,000 subjects with average age 73 years, was performed by Savarese and colleagues in 2013, which proved that elderly patients with CV risk factors but without established cardiovascular (CV) disease actually do benefit from statin therapy. [3] Statin therapy significantly reduced heart attacks by over 39%, and reduced strokes by over 23%, and non-significantly reduced all-cause mortality by 5.9%, and CV mortality by 9.3%. Mortality trends did not reach significance due, in part, to early termination of studies required by the significant reductions in MI and stroke, which are the #1 and #3 causes of death for the elderly. If these studies could have ethically been continued, the trends in CV and all-cause mortality could only have strengthened.

Elderly patients with CV risk factors do benefit from pharmacologic reduction of LDL-C by suffering fewer heart attacks, strokes and probably reduced mortality. Seniors should not discontinue statin therapy due to this study, which is based on lower quality data than the treatment guidelines are based on.

This comment has been published as an online letter by BMJ Open. [4]

References

1: Ravnskov U, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open. 2016 Jun 12;6(6):e010401. doi:10.1136/bmjopen-2015-010401. PubMed PMID: 27292972.

2: Hannan EL. Randomized clinical trials and observational studies: guidelines for assessing respective strengths and limitations. JACC Cardiovasc Interv. 2008 Jun;1(3):211-7. doi:0.1016/j.jcin.2008.01.008. Review. PubMed PMID: 19463302.

3: Savarese G, et al. Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis. J Am Coll Cardiol. 2013 Dec 3;62(22):2090-9.doi:10.1016/j.jacc.2013.07.069. Epub 2013 Aug 28. PubMed PMID: 23954343.

4: Keller DL, Statins do prevent heart attacks and strokes in the elderly. BMJ Open, published online on June 21, 2016 at the following URL: http://bmjopen.bmj.com/content/6/6/e010401.long/reply#bmjopen_el_9817

On 2016 Jun 15, David Keller commented:

The data in the included studies were all "corrected" under the assumption that LDL-C is a harmful risk factor

This analysis of multiple observational cohort studies reports no association, or an inverse association, between LDL-cholesterol levels and death rates, thereby challenging the widely-accepted hypothesis that high levels of LDL-C are a causal risk factor for cardiovascular atherosclerotic disease (CAD).

However, in table 2, we see that the study by Nilsson and colleagues was "corrected" for non-HDL-cholesterol, a variable which is highly correlated with LDL-C. The effect of correcting for non-HDL-C is almost the same as the effect of correcting for LDL-C itself, as we can see by using the Friedewald Equation to derive non-HDL cholesterol as LDL + Triglycerides/5 [1]

It appears that the authors of all of the analyzed cohort studies corrected their data under the assumption that higher LDL-C levels are harmful. Because Ravnskov is testing that very assumption, any "corrections" made to the original LDL-C data will actually further confound his findings. I suggest that Ravnskov reanalyze the original cohort data without any corrections or assumptions applied at all.

Reference

1: Martin SS, Blaha MJ et al, Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J Am Coll Cardiol. 2013 Aug 20;62(8):732-9. PubMed PMID: 23524048.

On 2016 Jun 15, David Keller commented:

The data in the included studies were all "corrected" under the assumption that LDL-C is a harmful risk factor

This analysis of multiple observational cohort studies reports no association, or an inverse association, between LDL-cholesterol levels and death rates, thereby challenging the widely-accepted hypothesis that high levels of LDL-C are a causal risk factor for cardiovascular atherosclerotic disease (CAD).

However, in table 2, we see that the study by Nilsson and colleagues was "corrected" for non-HDL-cholesterol, a variable which is highly correlated with LDL-C. The effect of correcting for non-HDL-C is almost the same as the effect of correcting for LDL-C itself, as we can see by using the Friedewald Equation to derive non-HDL cholesterol as LDL + Triglycerides/5 [1]

It appears that the authors of all of the analyzed cohort studies corrected their data under the assumption that higher LDL-C levels are harmful. Because Ravnskov is testing that very assumption, any "corrections" made to the original LDL-C data will actually further confound his findings. I suggest that Ravnskov reanalyze the original cohort data without any corrections or assumptions applied at all.

Reference

1: Martin SS, Blaha MJ et al, Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J Am Coll Cardiol. 2013 Aug 20;62(8):732-9. PubMed PMID: 23524048.

On 2016 Jun 16, David Keller commented:

In the elderly, statins reduce heart attacks, strokes and, probably, mortality

Ravnskov and colleagues conclude that their analysis of observational data requires "re-evaluation of guidelines recommending pharmacological reduction of LDL-C in the elderly as a component of cardiovascular disease prevention strategies." [1] I disagree, because the guidelines they challenge were based on large, randomized, placebo-controlled, double-blinded prospective interventional trials, higher-quality studies yielding more convincing data than the observational studies examined by Ravnskov. Statisticians warn us that observational data can only demonstrate associations, not causality, and should only be used for hypothesis generation, not for treatment decisions.[2]

A meta-analysis of eight high-quality controlled trials, including over 24,000 subjects with average age 73 years, was performed by Savarese and colleagues in 2013, which proved that elderly patients with CV risk factors but without established cardiovascular (CV) disease actually do benefit from statin therapy. [3] Statin therapy significantly reduced heart attacks by over 39%, and reduced strokes by over 23%, and non-significantly reduced all-cause mortality by 5.9%, and CV mortality by 9.3%. Mortality trends did not reach significance due, in part, to early termination of studies required by the significant reductions in MI and stroke, which are the #1 and #3 causes of death for the elderly. If these studies could have ethically been continued, the trends in CV and all-cause mortality could only have strengthened.

Elderly patients with CV risk factors do benefit from pharmacologic reduction of LDL-C by suffering fewer heart attacks, strokes and probably reduced mortality. Seniors should not discontinue statin therapy due to this study, which is based on lower quality data than the treatment guidelines are based on.

This comment has been published as an online letter by BMJ Open. [4]

References

1: Ravnskov U, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open. 2016 Jun 12;6(6):e010401. doi:10.1136/bmjopen-2015-010401. PubMed PMID: 27292972.

2: Hannan EL. Randomized clinical trials and observational studies: guidelines for assessing respective strengths and limitations. JACC Cardiovasc Interv. 2008 Jun;1(3):211-7. doi:0.1016/j.jcin.2008.01.008. Review. PubMed PMID: 19463302.

3: Savarese G, et al. Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis. J Am Coll Cardiol. 2013 Dec 3;62(22):2090-9.doi:10.1016/j.jacc.2013.07.069. Epub 2013 Aug 28. PubMed PMID: 23954343.

4: Keller DL, Statins do prevent heart attacks and strokes in the elderly. BMJ Open, published online on June 21, 2016 at the following URL: http://bmjopen.bmj.com/content/6/6/e010401.long/reply#bmjopen_el_9817

On 2016 Sep 27, David Nunan commented:

Important methodological flaws limit the findings from the paper by Ravnskov and colleagues

We performed a post-publication critical appraisal of this paper and found a number of methodological flaws not least: 1. Lack of a published protocol 2. Searching of only one database 3. Nonuniform application of inclusion/exclusion criteria 4. A lack of critical appraisal of the methods used in the included studies 5. No indication of the quality or uncertainty of the included data 6. Issues with the accuracy of data extraction, and, 7. A lack of controlling for confounding due to the effect of lipid-lowering treatment and HDL-C levels presenting major bias and more likely underpinning the majority of the observed inverse associations.

Based on the above identified flaws in the paper by Ravnskov and colleagues we concluded: "Given that the authors failed to account for significant confounding as well as the methodological weaknesses of both the review and its included studies, the results of this review have limited validity and should be interpreted with caution. At this time it would not be responsible, or evidence-based, for policy decisions to be made based on the results of this study".

Our full appraisal can be found on our website here: http://www.cebm.net/cebm-response-lack-association-inverse-association-low-density-lipoprotein-cholesterol-mortality-elderly-systematic-review-post-publication-pee/