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Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis

BMJ 2003; 326 doi: https://doi.org/10.1136/bmj.326.7404.1423 (Published 26 June 2003) Cite this as: BMJ 2003;326:1423

Rapid Response:

Statins and vascular risk: the gender dilemma

Statins are a key element of vascular prevention. Some RCTs suggest
that they are effective in reducing coronary event rates and overall
mortality also in high–risk patients with average cholesterol levels,
regardless of sex. Prescription data show that this conclusion has already
been adopted in clinical practice, since statins are commonly (and evenly)
prescribed to people of both sexes: in our area (Province of Modena, in
Northern Italy, 630,000 inhabitants and 520 General Practitioners) 9,164
and 9,045 Defined Daily Doses (DDD) of the drugs have been prescribed in
2002 to female and male patients, respectively.

We believe, however, that statins’ efficacy in females is still to be
convincingly demonstrated. A previous meta-analysis (1999) on 5 studies
showed that statins are beneficial in both sexes (1) , but a cost-
effectiveness analysis (including 2 out of 5 studies considered in the
former meta-analysis) raised doubts on their use in females in primary
prevention (2). Newly published RCTs add further uncertainty on this
issue. In their meta-analysis, Law et al (3) included data from three
large RCTs (4-6)(of either primary or secondary prevention) showing lower
efficacy in females who may not even get a statistically significant
benefit (table).

Indeed low statistical power may hinder gender-related differences in
treatment effect and prevent trialists in highlighting these “by sex”
differences: the vascular event rate in females is lower than males and
trialists tend to prefer the inclusion of male subjects to increase power.
In absence of a convincing empirical demonstration, however, this is not a
good reason to conclude that statins work equally well in both sexes. Meta
-analyses might in fact help overcoming the “low power” issue. The meta-
analysis from Law et al3, including data from new RCTs, could help in this
regard. We invite trialists to provide results stratified by gender so
that readers can evaluate whether females benefit from statins and a
relevant public health benefit could be expected for this subgroup.
Waiting for this a generalisation of statins’ effects on female does not
seem warranted.


Table 1: Effects of statins ( overall and in gender
subgroups) on primary end-points in large placebo controlled RCTs

Study Acronym


Total n.


Males

n.


Females

n.


Male/

Female ratio


 

Relative Risk (95% CI)


All subjects


Only males


Only females

Patients enrolled without known vascular disease
on entry

ASCOT - LLA


10305


8347


1958


4,26


0,64 (0,50-0,83)


0,59 (0,44-0,77)


1,10 (0,57-2,12)

AFCAPS/

TexCAPS


6605


5746


859


6,69


0,63 (0,50-0,79)


0,64 (0,51-0,81)


0,54(0,22-1,34)

Patients enrolled with or without known vascular disease on entry

ALLHAT – LLT


10355


5281


5074


1,05


0,91 (0,79-1,04)


0,84 (0,71-1,00)


1,02 (0,81-1,28)

Patients enrolled with known vascular disease on entry

HPS


20536


15402


5134


3,04


0,76 (0,72-0,81)


0,78 (0,74-0,83)


0,81 (0,72-0,92)

PROSPER


5804


2804


3000


0,93


0,85 (0,74-0,97)


0,77 (0,65-0,92)


0.96 (0,79-1,18)

LIPID


9014


7482


1532


4,88


0,78 (0,70-0,86)


0,76 (0,68-0,85)


0,87( 0,67-1,13)

MIRACL


3086


2006


1080


1,86


0,92 (0,75-1,13)


NOT REPORTED


NOT REPORTED

4S


4444


3617


827


4,38


0,70 (0,62-0,80)


0,70 (0,62-0,78)


0,67 (0,50-0,90)

CARE


4159


3577


582


6,14


0,77 (0,65-0,91)


0,82 (0,72-0,92)


0,60 (0,37-0,97)

REFERENCES

(1) LaRosa JC, Jiang He, Vupputuri S. Effect of Statins on Risk of
Coronary Disease. A Meta-analysis of Randomized Controlled Trials JAMA
1999; 282: 2340-6

(2) Prosser LA, Stinnett AA, Goldman PA, et al. Cost-effectiveness of
cholesterol-lowering therapies according to selected patient
characteristics. Ann Intern Med. 2000; 132: 769-79

(3) Law MR, Wald NJ, Rudnicka AR Quantifying effect of statins on low
density lipoprotein cholesterol, ischaemic heart disease, and stroke:
systematic review and meta-analysis BMJ 2003; 326: 1423-1427

(4) Shepherd J, Blauw GJ, Murphy MB, et al. Prospective Study of
Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at
risk of vascular disease (PROSPER): a randomised controlled trial. Lancet.
2002; 360:1623-30

(5) ALLHAT Officers and Coordinators for the ALLHAT Collaborative
Research Group. The Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial. Major outcomes in moderately
hypercholesterolemic, hypertensive patients randomized to pravastatin vs
usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT-LLT). JAMA. 2002; 288: 2998-3007

(6) Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and
stroke events with atorvastatin in hypertensive patients who have average
or lower-than-average cholesterol concentrations, in the Anglo-
Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a
multicentre randomised controlled trial Lancet. 2003; 361:1149-58

Competing interests:
None declared

Competing interests: No competing interests

23 July 2003
Oreste Capelli
General Practitioner and consultant, CeVEAS
Emilio Maestri, Giulio Formoso, Anna Maria Marata, Annalisa Campomori, Anna Vitoria Ciardullo, Nicola Magrini, and Alessandro Liberati
CeVEAS (Centre for the Evaluation of the Effectiveness of Health Care). 41100 Modena