Journal of the American Heart Association

EDITORIAL

Lipid-­Lowering Therapy and Hemorrhagic

Stroke: A Never-­Ending Debate of Clinical
Implications. Have We Found the Answer?
David Gaist , MD, PhD; Magdy Selim , MD, PhD

N
umerous observational and epidemiological
studies have shown that cholesterol levels, in par-
ticular low-­density lipoprotein (LDL), are inversely
associated with the incidence of hemorrhagic stroke
(HS).1–6 Mendelian randomization analyses have also
shown similar associations between polygenic risk
scores determining total cholesterol and LDL levels
and risk of HS.7,8 Despite these accumulating data, the
mechanistic links between low cholesterol and HS are
not well established and a causal association between
lipid-­lowering therapies and risk of HS is debatable.
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In this issue of the Journal of the American Heart
Association (JAHA), Bétrisey et al present the results
of an updated meta-­analysis of randomized controlled
trials of lipid-­lowering therapies to examine their asso-
ciation with HS.18 This meta-­analysis includes newer
and more studies. The authors limited their meta-­
analysis to randomized controlled trials with more than
1000 participants that reported HS events within a
minimum of a 2-­year follow-­up period. Furthermore,
they expanded their meta-­ analysis to include statin
and nonstatin lipid-­lowering therapies; 33 statin trials,
2 ezetimibe trials, 2 proprotein convertase subtilisin/

kexin type 9 inhibitor trials, 2 fibrate trials, and 9 ome-

See Article by Bétrisey et al.
Statins are the most widely prescribed lipid-­lowering
drugs. Several meta-­analyses have examined the as-
sociation between statin therapy and HS with variable
conclusions.9–17 Most of these analyses were limited by
the small number of patients with history of stroke or
cerebrovascular disease included in statin trials or the
inclusion of retrospective observational studies, which
might be prone to biases related to physicians and pre-
scribing decisions. The inconsistent results from these
meta-­analyses have fueled an ongoing controversy as
to whether statins should be used or avoided in pa-
tients with HS.
ga-­3 trials were included. The authors also performed
several novel exploratory post hoc analyses to evaluate
the effect of baseline characteristics, such as age, hy-
pertension, and use of antiplatelet drugs, on HS risk.
Overall, the authors found a slight increase in HS with
LDL lowering (risk ratio [RR], 1.16 [95% CI, 1.01–1.32]);
the risk was largely driven by statins (RR, 1.17 [95% CI,
1.01–1.36]). No significant effect on HS risk was ob-
served in nonstatin trials. In statin trials of patients with
history of stroke or transient ischemic attack, the RR
was 1.46 (95% CI, 1.05–2.04). There was no evidence
of an effect modification by age, sex, comorbid history
of hypertension or diabetes, concomitant antiplatelet
use, or statin dose/intensity on HS risk. These results

Key Words: Editorials ■ cholesterol ■ hemorrhagic stroke ■ intracerebral hemorrhage ■ LDL ■ statins

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
Correspondence to: Magdy Selim, MD, PhD, Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center, 330 Brookline Avenue—
Palmer 127, Boston, MA 02215. Email: mselim@bidmc.harvard.edu
This article was sent to Neel S. Singhal, MD, PhD, Associate Editor, for editorial decision and final disposition.
For Disclosures, see page 2.
© 2024 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use
is non-commercial and no modifications or adaptations are made.
JAHA is available at: www.ahajournals.org/journal/jaha

J Am Heart Assoc. 2024;13:e034099. DOI: 10.1161/JAHA.124.0340991

 Gaist and Selim
underscore the complex interplay between choles-
terol, LDL, statins, and HS.
The authors conclude that although the RR of HS
increased by 17% with statin therapy, the absolute risk
is low and the benefit of preventing ischemic events
exceeds the risk of HS: the fear of HS risk should not
preclude statin use if clinically indicated.
Bétrisey et al must be applauded for carrying out
this comprehensive and thoughtful meta-­analysis. Is
this the end of the statins controversy? The crux of the
statins debate is about their use and potential benefit/
risk in patients with history of HS and those with per-
ceived low risk for ischemic events and not patients
with ischemic stroke. Although the SPARCL (Stroke
Prevention by Aggressive Reduction in Cholesterol
Levels) trial has clearly established that atorvastatin
is overall beneficial in patients with ischemic stroke or
transient ischemic attacks attributed to atherosclero-
sis, there are insufficient prospective randomized data
regarding risk/benefit of statin therapy in patients with
HS. The meta-­analysis by Bétrisey et al,18 like its pre-
decessors, does not address this uncertainty. Only 3
of the 48 included trials reported the number of par-
ticipants with HS as a comorbidity; 7 trials excluded
patients with HS and 38 did not report the number of
patients with HS, if any, at baseline. Overall, only 250
of the 405 285 (0.06%) participants in the included tri-
als had HS or history of HS at trial’s entry, and it is
unknown whether these cases clustered within a par-
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ticular patient subpopulation. Therefore, the results of
this meta-­analysis, its overall conclusions, and practice
implications should be interpreted with caution. One
must caution against misinterpreting the results to as-
sume that nonstatin therapies are safer alternatives to
statins in patients with HS. The authors appropriately
acknowledge that currently available data are insuffi-
cient to draw conclusions about the association be-
tween nonstatin lipid-­lowering therapies and HS risk
because of the small number of nonstatin trials and
exclusion of patients with history of HS from most of
these trials.
Several questions remain unanswered: Are lipid-­
lowering therapies associated with increased risk
for HS recurrence? What is the overall risk/benefit of
lipid-­lowering therapies in survivors of HS? Does the
risk/benefit vary based on the location/etiology of the
hemorrhage?3 A Danish cohort study showed that
survivors of HS are at high risk for subsequent major
adverse cardiovascular events and that this is primar-
ily driven in patients with lobar hemorrhage by a higher
rate of recurrent HS.19 These findings highlight the im-
portance of secondary prevention strategies for major
adverse cardiovascular events in patients with HS, and
in particular of HS in survivors of lobar hemorrhage.
Most important, they raise the question of whether a
slight increase in HS risk with statin therapy, as seen
J Am Heart Assoc. 2024;13:e034099. DOI: 10.1161/JAHA.124.0340992
Lipid-­Lowering Drugs and ICH
in the current meta-­analysis, might offset the potential
benefit/risk ratio of statin therapy in patients with lobar
versus nonlobar hemorrhage. We recently reported
that statin use was not associated with an increased
risk of recurrent HS, irrespective of hemorrhage lo-
cation, but was associated with a lower risk of any
stroke, largely due to a lower risk of ischemic stroke.20
However, our findings were based on retrospective
observational data with inherent limitations and thus
require confirmation in prospective randomized trials.
Lastly, the use of number needed to treat to cause
HS versus number needed to treat to prevent major
adverse cardiovascular events to assess the risk/ben-
efit of lipid-­lowering therapy is too simplistic and may
lead to false conclusions. It is unknown whether the
resulting disability, quality of life, morbidity, and mor-
tality are comparable between HS and major adverse
cardiovascular events including ischemic stroke. This
requires more study.
The controversy surrounding the use of lipid-­
lowering therapies, in particular statins, still goes on.
Dedicated prospective and randomized studies in pa-
tients with HS are needed to guide the best strategy
for lipid lowering in this forgotten and understudied
population.
ARTICLE INFORMATION
Received January 4, 2024; accepted January 8, 2024.
Affiliations
Research Unit for Neurology, Odense University Hospital, University of
Southern Denmark, Odense, Denmark (D.G.); and Department of Neurology,
Stroke Division (M.S.), Beth Israel Deaconess Medical Center/Harvard
Medical School, Boston, MA .
Disclosures
Dr Gaist received speakers’ honoraria from Pfizer and Bristol Myers Squibb
outside the submitted work and participated in research outside the submit-
ted work funded by Bayer with funds paid to the institution where he is em-
ployed. Dr Selim is the principal investigator for the SATURN (Statins Use in
Intracerebral Hemorrhage Patients) trial (Clini​calTr​ials.​gov ID: NCT0393636)
and receives grant support from the National Institute of Neurological
Disorders and Stroke (U01NS102289) and the National Institute of Aging
(UF1NS120871). He serves on the Advisory Board of MedRhythms Inc. and
as a consultant for Valin Technologies.
REFERENCES
1. Zhang X, Patel A, Horibe H, Wu Z, Barzi F, Rodgers A, MacMahon S,
Woodward M; Asia Pacific Cohort Studies Collaboration. Cholesterol,
coronary heart disease, and stroke in the Asia Pacific region. Int J
Epidemiol. 2003;32:563–572. doi: 10.1093/ije/dyg106
2. Rist PM, Buring JE, Ridker PM, Kase CS, Kurth T, Rexrode KM. Lipid
levels and the risk of hemorrhagic stroke among women. Neurology.
2019;92:e2286–e2294. doi: 10.1212/WNL.0000000000007454
3. Pezzini A, Grassi M, Iacoviello L, Zedde M, Marcheselli S, Silvestrelli
G, DeLodovici ML, Sessa M, Zini A, Paciaroni M, et al. Serum choles-
terol levels, HMG-­CoA reductase inhibitors and the risk of intracerebral
haemorrhage. The Multicenter Study on Cerebral Haemorrhage in Italy
(MUCH-­Italy). J Neurol Neurosurg Psychiatry. 2016;87:924–929. doi:
10.1136/jnnp-­2015-­312736
4. Ma C, Gurol ME, Huang Z, Lichtenstein AH, Wang X, Wang Y,
Neumann S, Wu S, Gao X. Low-­density lipoprotein cholesterol and
 Gaist and Selim
risk of intracerebral hemorrhage: a prospective study. Neurology.
2019;93:e445–e457. doi: 10.1212/WNL.0000000000007853
5. Sturgeon JD, Folsom AR, Longstreth WT Jr, Shahar E, Rosamond
WD, Cushman M. Risk factors for intracerebral hemorrhage in a
pooled prospective study. Stroke. 2007;38:2718–2725. doi: 10.1161/
STROKEAHA.107.487090
6. Noda H, Iso H, Irie F, Izumi Y, Doi M, Sairenchi T, Ohtaka E, Ohta
H. Low-­ density lipoprotein cholesterol concentrations and death
due to intraparenchymal hemorrhage: the Ibaraki Prefectural
Health Study. Circulation. 2009;120:2136–2145. doi: 10.1161/
CIRCULATIONAHA.108.795666
7. Falcone GJ, Kirsch E, Acosta JN, Noche RB, Leasure A, Marini S,
Chung J, Selim M, Meschia JF, Brown DL, et al. Genetically elevated
LDL associates with lower risk of intracerebral hemorrhage. Ann Neurol.
2020;88:56–66. doi: 10.1002/ana.25740
8. Sun L, Clarke R, Bennett D, Guo Y, Walters RG, Hill M, Parish S, Millwood
IY, Bian Z, Chen Y, Yu C, Lv J, Collins R, Chen J, Peto R, Li L, Chen Z;
China Kadoorie Biobank Collaborative Group; International Steering
Committee; International Co-­ordinating Centre, Oxford; National Co-­
ordinating Centre, Beijing; Regional Co-­ ordinating Centres. Causal
associations of blood lipids with risk of ischemic stroke and intrace-
rebral hemorrhage in Chinese adults. Nat Med 2019;25:569–574. doi:
10.1038/s41591-­019-­0366-­x.
9. Hackam DG, Woodward M, Newby LK, Bhatt DL, Shao M, Smith
EE, Donner A, Mamdani M, Douketis JD, Arima H, et al. Statins
and intracerebral hemorrhage: collaborative systematic review
and meta-­analysis. Circulation. 2011;124:2233–2242. doi: 10.1161/
CIRCULATIONAHA.111.055269
10. McKinney JS, Kostis WJ. Statin therapy and the risk of intracerebral
hemorrhage: a meta-­analysis of 31 randomized controlled trials. Stroke.
2012;43:2149–2156. doi: 10.1161/STROKEAHA.112.655894
11. Judge C, Ruttledge S, Costello M, Murphy R, Loughlin E, Alvarez-­Iglesias
A, Ferguson J, Gorey S, Nolan A, Canavan M, et al. Lipid lowering ther-
apy, low-­density lipoprotein level and risk of intracerebral hemorrhage
-­ a meta-­analysis. J Stroke Cerebrovasc Dis. 2019;28:1703–1709. doi:
10.1016/j.jstrokecerebrovasdis.2019.02.018
Downloaded from http://ahajournals.org by on February 11, 2024
J Am Heart Assoc. 2024;13:e034099. DOI: 10.1161/JAHA.124.0340993
Lipid-­Lowering Drugs and ICH
12. Jung JM, Choi JY, Kim HJ, Seo WK. Statin use in spontaneous intrace-
rebral hemorrhage: a systematic review and meta-­analysis. Int J Stroke.
2015;10:10–17. doi: 10.1111/ijs.12624
13. Ziff OJ, Banerjee G, Ambler G, Werring DJ. Statins and the risk of in-
tracerebral haemorrhage in patients with stroke: systematic review and
meta-­analysis. J Neurol Neurosurg Psychiatry. 2019;90:75–83. doi:
10.1136/jnnp-­2018-­318483
14. Pandit AK, Kumar P, Kumar A, Chakravarty K, Misra S, Prasad K.
High-­dose statin therapy and risk of intracerebral hemorrhage: a meta-­
analysis. Acta Neurol Scand. 2016;134:22–28. doi: 10.1111/ane.12540
15. Cheng Y, Qiao L, Jiang Z, Dong X, Feng H, Gui Q, Lu Y, Liang Y.
Significant reduction in the LDL cholesterol increases the risk of intra-
cerebral hemorrhage: a systematic review and meta-­analysis of 33 ran-
domized controlled trials. Am J Transl Res. 2020;12:463–477.
16. Teoh RJJ, Huang CJ, Chan CP, Chien LY, Chung CP, Sung SH, Chen
CH, Chiang CE, Cheng HM. Does statin increase the risk of intracere-
bral hemorrhage in stroke survivors? A meta-­analysis and trial sequen-
tial analysis. Ther Adv Neurol Disord. 2019;12:1756286419864830. doi:
10.1177/1756286419864830
17. Sanz-­Cuesta BE, Saver JL. Lipid lowering therapy and hemorrhagic
stroke risk: comparative meta-­analysis of statins and PCSK9 inhibitors.
Stroke. 2021;52:3142–3150. doi: 10.1161/STROKEAHA.121.034576
18. Bétrisey S, Haller M, Efthimiou O, Speierer A, Del Giovane C, Moutzouri
E, Blum MR, Aujesky D, Rodondi N, Gencer B. Lipid-­lowering therapy
and risk of hemorrhagic stroke: a systematic review and meta-­analysis
of randomized controlled trials. J Am Heart Assoc. 2023;12:e030714.
doi: 10.1161/JAHA.123.030714
19. Boe NJ, Hald SM, Jensen MM, Kristensen LMB, Bojsen JA, Elhakim
MT, Clausen A, Möller S, Hallas J, García Rodríguez LA, et al. Major
cardiovascular events after spontaneous intracerebral hemorrhage by
hematoma location. JAMA Netw Open. 2023;6:e235882. doi: 10.1001/
jamanetworkopen.2023.5882
20. Gaist D, García Rodríguez LA, Hallas J, Hald SM, Möller S, Høyer
BB, Selim M, Goldstein LB. Association of statin use with risk
of stroke recurrence after intracerebral hemorrhage. Neurology.
2023;101:e1793–e1806. doi: 10.1212/WNL.0000000000207792