CONTINUING MEDICAL EDUCATION

“Is Low Cholesterol Linked to Higher Hemorrhagic Stroke Risk

in Women?”

Pembimbing:
dr. WahyuDjatmiko, Sp.PD (K)HOM

Disusunoleh:
Khoirunnisa 1820221073

UNIVERSITAS PEMBANGUNAN NASIONAL “VETERAN” JAKARTA

FAKULTAS KEDOKTERAN
SMF ILMU PENYAKIT DALAM
RSUD PROF. DR. MARGONO SOEKARJO
PURWOKERTO
2019
 LEMBAR PENGESAHAN

CONTINUING MEDICAL EDUCATION

“Is Low Cholesterol Linked to Higher Hemorrhagic Stroke Risk
in Women?”

DisusunOleh:
Khoirunnisa 1820221072

Diajukan untuk memenuhi syarat mengikuti Kepaniteraan Klinik di bagian

Ilmu Penyakit Dalam RSUD Prof. Dr. Margono Soekarjo

Telah disetujui dan dipresentasikan

Pada tanggal: Juni 2019

Dokter Pembimbing:

dr. Wahyu Djatmiko, Sp.PD (K)HOM

Clinical Context

The number of patients eligible to receive statins has expanded dramatically

during the last several years, but are statins effective in reducing outcomes such as
stroke among adults with a lower baseline risk for cardiovascular disease? A
previous meta-analysis by the Cholesterol Treatment Trialists' Collaborators,
published in the August 11, 2012, issue of the Lancet, addressed this issue.[1]

The researchers included individual participant data from 27 clinical trials. They
found that each 1.0 mmol/L decline in low-density lipoprotein cholesterol (LDL-
C) associated with statin use reduced the overall risk for stroke by 15%.
Surprisingly, the efficacy of statins for stroke reduction was similar regardless of
baseline calculated cardiovascular risk. Statins were also effective in reducing the
risk for major coronary events. Again, this benefit was similar regardless of
baseline cardiovascular risk.

Although hemorrhagic strokes are less common than ischemic strokes, the meta-
analysis also recorded a 15% increase in the risk for hemorrhagic stroke for each
1.0 mmol/L reduction in LDL-C. The current study uses data from the Women's
Health Study to investigate how lipid levels affect the risk for hemorrhagic stroke.

Study Synopsis and Perspective

Women with very low levels of LDL-C and triglycerides may be more than twice
as likely to have a hemorrhagic stroke than women with higher levels, a new study
suggests.

Investigators at Harvard University prospectively studied a cohort of almost

28,000 women enrolled in the Women's Health Study during a period of
approximately 20 years.

They found that compared with those patients whose LDL-C levels were from 100
to 129.9 mg/dL, women whose LDL-C levels were <70 mg/dL had more than
twice the risk of experiencing hemorrhagic stroke, after adjusting for other factors
that could affect stroke risk.

Similarly, women whose triglyceride level was in the lowest quartile had a
significantly increased risk for hemorrhagic stroke compared with women whose
level was in the top quartile, after multivariable adjustment.

"I think the main take-home message for physicians is that women with low levels
of LDL cholesterol are usually considered at low risk for heart attack and stroke,
but they might still have increased risk of hemorrhagic stroke," lead author
Pamela Rist, ScD, assistant professor, Harvard Medical School, Boston,
Massachusetts, told Medscape Medical News.

"Given the morbidity and mortality associated with hemorrhagic stroke, it is

important to monitor these women for other risk factors, such as hypertension and
smoking, to lower the risk of hemorrhagic stroke," she said.

The study was published online April 10 in Neurology.[2]

Focus on Women

High levels of LDL-C and low levels of high-density lipoprotein cholesterol

(HDL-C) are associated with increased risk for ischemic stroke or myocardial
infarction, Dr Rist observed, but some prior work has suggested that there may be
a link between very low levels of LDL-C and increased risk for hemorrhagic
stroke.

"We were interested in doing a study specifically in our cohort, which is a large
population of females, since most other studies enrolled both [males and females],
but events in females were more limited than they were in our study," she
explained.

"Since our study had almost 28,000 women, we wanted to see if the suggestion
regarding hemorrhagic stroke would be seen in our cohort as well," she said.
The cohort consisted of women participating in the Women's Health Study.
Although the trial ended in 2004, observational follow-up of participants is
ongoing.

Of 28,345 fasting blood samples obtained from participants, 27,937 were analyzed
for levels of LDL-C, HDL-C, total cholesterol, and triglycerides.

The researchers adjusted for covariates, including age, smoking status,

menopausal status, postmenopausal hormone status, body mass index, alcohol
consumption, history of diabetes and hypertension, physical activity, and
treatment with cholesterol-lowering medications.

U-Shaped Curve

Participants in the lowest LDL-C category (<70 mg/dL) were younger and were
less likely to have a history of hypertension or to use cholesterol-lowering
medications compared with those with cholesterol levels from 100 to 129.9
mg/dL.

They were also more likely to consume alcohol, be of normal weight, be

physically active, and be premenopausal

In contrast, women in the highest LDL-C category (≥160 mg/dL) were older and
were more likely to smoke, to use cholesterol-lowering medications and
postmenopausal hormone status, to have a history of hypertension or diabetes, and
to be obese.

They were also less likely to consume alcohol or be physically active than those
with cholesterol levels of from 100 to 129.9 mg/dL.

During a mean of 19.3 years of follow-up, 137 incident hemorrhagic stroke events
were confirmed.

Of these, the most common was intracerebral hemorrhage, followed by

subarachnoid hemorrhage (n=85 and n=43, respectively).
Of the 1069 women with an LDL-C level lower than 70 mg/dL, 0.8% had a
hemorrhagic stroke compared with 0.4% of 26,508 women with a cholesterol
level of at least 70 mg/dL.

A U-shaped relationship between LDL-C and hemorrhagic stroke risk was found:
After multivariable adjustment, compared with those with LDL-C levels from 100
to 129.9 mg/dL, those with an LDL-C level lower than 70 mg/dL had 2.17 times
the risk (95% confidence interval [CI], 1.05-4.48) of experiencing a hemorrhagic
stroke.

There was a suggestion of elevated risk among those with LDL-C level of at least
160 mg/dL, but the increase was not statistically significant.

Participants with LDL-C levels from 70 to 99.9 mg/dL or 130 to 159.9 mg/dL did
not have a significantly increased risk for hemorrhagic stroke (relative risk [RR],
1.25 [95% CI, 0.76-2.04]; and RR, 1.14 [95% CI, 0.72-1.80], respectively).

Results for the intracerebral hemorrhage subtype were similar to those seen for
total hemorrhagic stroke (ie, the highest risks for events were found in those with
LDL-C <70 mg/dL, followed by those with LDL-C ≥160 mg/dL).

Naturally Low Levels

Women whose triglyceride levels were the lowest quartile (≤74 mg/dL for fasting
and ≤85 mg/dL for nonfasting) had a significantly increased risk for hemorrhagic
stroke compared with those whose levels were in the top quartile, after
multivariable adjustment (RR, 2.00; 95% CI, 1.18-3.39).

The other quartiles were not associated with significantly increased risk.

Low triglyceride levels were associated with a significant risk for subarachnoid
hemorrhage, but not for intracerebral hemorrhage.

A model that included LDL-C categories as well as triglyceride quartiles found

that those whose triglyceride levels were in the lowest quartile had an increased
risk for hemorrhagic stroke (RR, 2.14; 95% CI, 1.24-3.70) compared with those
whose levels were in the highest quartile, after controlling for LDL-C.

Conversely, those with LDL-C lower than 70 mg/dL (RR, 2.04; 95% CI, 0.98-
4.23) and those with LDL-C of at least 160 mg/dL (RR, 1.75; 95% CI, 1.05-2.92)
were at increased risk for hemorrhagic stroke compared with those with LDL-C
levels from 100 to 129.9 mg/dL, after controlling for triglyceride levels.

Analyses that were restricted to women who were not taking cholesterol-lowering
medications at baseline (n=27,044) yielded results similar to those of the main
analyses, although the increased risk among those with LDL-C levels lower than
70 mg/dL was no longer statistically significant.

No significant associations were observed between HDL-C or total cholesterol

and risk for hemorrhagic stroke.

Dr Rist noted that the potential mechanism responsible for the increased risk for
hemorrhagic stroke in women with very low cholesterol levels is not clear.

"It has been suggested that the mechanism may be connected with issues of vessel
wall integrity," she speculated.

She noted that their cohort "is unique, in that our blood measurement was
performed in the early 1990s, before lipid-lowering drugs, such as statins, were as
widely used as they are today."

This is relevant because "we were looking at the long-term effects of low levels
[of cholesterol], and women with already low levels are likely different than
women who originally had high levels that were lowered through medication use,"
she said.

Flag of Long-term Safety

Commenting on the study for Medscape Medical News, Erin D. Michos, MD,
MHS, associate professor of medicine and epidemiology and associate director of
preventive cardiology, Ciccarone Center for the Prevention of Heart Disease,
Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland,
who was not involved with the research, noted that there has been "a long-
standing controversy whether low cholesterol levels place individuals at risk for
hemorrhagic stroke."

The controversy "stems from many epidemiological studies which have found an
association between low blood cholesterol and increased risk of hemorrhagic
stroke," she said.

The "key point" is expressed by the authors themselves, she pointed out:
"individuals with very low LDL-C levels may be less healthy than those with
higher LDL-C levels, making them more vulnerable to brain bleeds."

The findings therefore "do not change my practice at all, since I remain skeptical
about the residual confounding from a single lipid measurement in an
epidemiology study," she said.

However, "if this association is later to be confirmed in Mendelian randomization

genetic studies among individuals with lifetime very low LDL-C levels, or if it is
found with [randomized controlled trials] of therapies that lower LDL-C, I'd be
more convinced," she said.

In her practice, she "only treats patients with statins and lipid-lowering agents
who are anticipated to get net benefit for [atherosclerotic cardiovascular disease]
reduction, such as those at highest risk, [because] statins are not for everyone."

Raffaele De Caterina, MD, PhD, professor of cardiology and director of

cardiology at Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy, who was not
involved with the research, had a different perspective.

"I think this is an important piece of evidence because of the long follow-up of
this study, by far exceeding what is known from other ones," he told Medscape
Medical News.
 "It raises some concern about the long-term consequences of very profound LDL
lowering, as it occurs with the [proprotein convertase subtilisin-kexin type 9]
inhibitors," he said.

"We already had concerns about the cost-effectiveness of intensive LDL-lowering

treatment in persons with LDL <70 mg/dL, and this would now be even more
reinforced when a flag of long-term safety is now raised."

Dr Rist added, "The impact of low cholesterol as a result of medication on

hemorrhagic stroke risk is a different research question, and it's hard to
extrapolate from these women who already had very low levels to begin with to
people with high levels who have been treated and now have low levels."

The study was supported by the National Institutes of Health. The authors, Dr
Michos, and Dr De Caterina report no relevant financial relationships.

Neurology. Published online April 10, 2019.

Study Highlights

 The Women's Health Study was a randomized, double-blind, placebo-controlled

trial of low-dose aspirin and vitamin E for the prevention of cardiovascular
disease and cancer among female US health professionals at age 45 years or older.
 Participants submitted a single blood sample for lipid analysis at enrollment in the
study. Stroke was determined by participant self-report or death records, and all
cases of stroke were confirmed with a review of the medical record.
 The current study assesses the risk for hemorrhagic stroke based on the serum
lipid profile of participants. This result was adjusted to account for demographic
variables, body mass index, health habits, the presence of chronic disease related
to cardiovascular risk, and the use of cholesterol-lowering medication.
 27,937 women with a mean age of 55 years provided data for the study. Women
with an LDL-C of less than 70 mg/dL generally had healthier lifestyles compared
with women with higher LDL-C levels, but they were more likely to consume
alcohol.
 During a mean of 19.3 years of follow-up, there were 137 incident hemorrhagic
strokes recorded; 85 were classified as intracranial hemorrhage and 43 as
subarachnoid hemorrhage.
 The relationship between the risk for hemorrhagic stroke and LDL-C was U-
shaped. Compared with women with an LDL-C between 100 and 129.9 mg/dL,
those with an LDL-C less than 70 mg/dL had a relative risk for 2.17 (95% CI,
1.05-4.48) for hemorrhagic stroke. The respective relative risk among women
with an LDL-C of 160 mg/dL or more was 1.53 (95% CI, 0.92-2.52).
 A low LDL-C level was a significant risk factor for both intracranial hemorrhage
and subarachnoid hemorrhage.
 The relative risk for hemorrhagic stroke in comparing women with triglyceride
levels in the lowest quartile (less than 75 mg/dL fasting or less than 86 mg/dL
nonfasting) vs the highest quartile was 2.00 (95% CI, 1.18-3.39). Low triglyceride
levels were significantly associated with a higher risk for subarachnoid
hemorrhage, but not intracranial hemorrhage.
 The effects of low LDL-C and low triglycerides on the risk for hemorrhagic stroke
were independent of one another.
 Analyses limited to women who were not taking cholesterol-lowering medications
at baseline revealed similar results compared with the main study findings.
 Total cholesterol and HDL-C levels did not significantly affect the risk for
hemorrhagic stroke.
Clinical Implications

 A previous meta-analysis of clinical trials found that statins had a favorable effect
on the risk for major coronary events and stroke, regardless of baseline
cardiovascular risk. However, LDL-C reductions among adults receiving statins
were associated with a higher risk for hemorrhagic stroke specifically.
 In the current study, low LDL-C levels among women were significantly
associated with a risk for hemorrhagic stroke.
 Implications for the Healthcare Team: Although women will still benefit from
reducing LDL-C levels with statins, the healthcare team should also focus on
reducing the risk for hemorrhagic stroke related to other risks such as
hypertension and cigarette smoking.