ARTICLE IN BRIEF
A retrospective, observational cohort study from Israel does not provide definitive proof that statins lower intracerebral hemorrhage risk, but its findings suggest that physicians shouldn't be overly worried about the possibility of brain bleeds when prescribing statins for the primary or secondary prevention of heart attack and ischemic stroke.
Amid a nagging concern that the use of statins could increase the risk for intracerebral hemorrhagic stroke comes a new study suggesting that the cholesterol-lowering drug may in fact offer some protection against intracerebral hemorrhage (ICH).
The retrospective, observational cohort study from Israel does not provide definitive proof that statins lower ICH risk, but its findings suggest that perhaps doctors shouldn't be overly worried about the possibility of brain bleeds when prescribing statins for the primary or secondary prevention of heart attack and ischemic stroke. The picture has been somewhat confusing because low cholesterol levels have been associated with an increased risk for ICH, making it tricky to decide whether someone who's already had ICH should continue with a statin or be put on one.
“Our large population-based study confirms the previous notion that the risk of intracerebral hemorrhage, the most devastating type of stroke, decreases with increasing cholesterol levels,” said the study's co-lead investigator, Eitan Auriel, MD, MSc, chairman of neurology at Carmel Medical Center in Haifa, Israel. “However, we found that statin use is associated with a dose-dependent decrease in the risk of intracerebral hemorrhage.”
Dr. Auriel told Neurology Today that while a large randomized, controlled trial would be needed to conclusively settle the questions surrounding statin use and ICH, “we believe, based on our results, that fear of ICH should not discourage prescription of statins for primary and secondary prevention in most patients.” The results appear in the July 3 online edition of Neurology.
Concerns about the downside to statins in regards to ICH stem mainly from the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, which found more ICH in patients randomized for statin therapy, according to the study authors. A similar finding emerged among a subgroup of patients with history of cerebrovascular disease in the Heart Protection Study, a large, multicenter randomized trial.
“In addition, some epidemiological and case report studies have indicated that patients with lower lipid levels are at increased risk for ICH,” the study authors noted. “As low lipid levels weaken endothelial cells it has been hypothesized that fragile endothelium promote vessels rupture and ICH in patients with low cholesterol. The mechanism, however, remains poorly understood.”
To further explore the issue, the researchers drew on the computerized database of Clalit Health Services (CHS), which provides inclusive health care for more than half of the Israeli population. Health care coverage is mandatory in Israel and care is provided by four HMO-style groups. The CHS database includes patient information from multiple sources including records of primary care physicians, community specialty clinics, hospitalizations, laboratories, and pharmacies.
The researchers identified all adults age 50 or older who were new users of statins, starting between January 1, 2005 and December 31, 2010. That amounted to 345,531individuals. Of those, 1,304 were diagnosed with ICH during a median follow-up of 9.5 years. (The study cut-off was June 30, 2017.) The strongest risk factors for ICH were prior ICH, prior stroke/transient ischemic attack, alcohol abuse, use of anticoagulants, diabetes, hypertension, male sex, and older age.
To assess a dose-response relationship between ICH and statins, regardless of what particular type of statin was taken, the researchers used a uniform measurement called the average atorvastatin equivalent daily dose (AAEDD). They found that the incidence of ICH decreased in a dose-response manner with increased statin use: 46.1 per 100,000 person years in those with AAEDD less than 10 mg a day; 31.1 per 100,000 person years in those with AAEDD of 10 to 19.9 mg/day; and 27.3 per 100,000 person years in those with AAEDD of 20 mg or more.
After adjusting for various factors, including cholesterol levels, there was a 38 Percent lower risk of ICH in those getting the highest statin dose compared to those at the lower dose range, said Dr. Auriel.
“It is indeed puzzling that despite promoting reduction in cholesterol levels, a known risk factor for ICH, we found that statins still protect from ICH,” said Dr. Auriel, who led the study with Walid Saliba, MD, MPH. But he noted that the “clinical effect of statins is not limited to a lipid-lowering effect but are also derived from pleotropic effects such as attenuation from inflammation, neuroprotective effects and improving blood flow.”
“Inconsistency across previous trials has led to uncertainty in decision making, such as balancing the risk of hemorrhagic versus ischemic consequences when prescribing statins,” he said. “We believe, based on our results, that fear of ICH should not discourage prescription of statins for primary and secondary prevention in most patients. However, in patients with previous ICH many factors should be taken into account such as location of the bleed, other comorbidities and medications.”
The researchers noted that the study had some limitations in addition to the fact that it was retrospective in design. The administrative computerized database used for the analysis was not specifically designed for the study. Also, the researchers looked at location of ICH only among highly persistent statin users.
Dr. Auriel said his team is planning to study the issue of statins and ICH further, including looking at possible differences across statin types, interaction with other drugs and radiological markers of cerebral small vessels that may indicate higher ICH risk.
Daniel Woo, MD, FAAN, vice chair of clinical research and professor of neurology at University of Cincinnati, said the new study suggests that lowering cholesterol with statins “does not remove the protective effect” that naturally high cholesterol seems to have against ICH. He agreed the other effects of statins, such as an anti-inflammatory action, may be at work, perhaps serving as a counter-balance.
“This study would suggest it is perfectly safe to have people on statins” to lower cardiovascular risk post-stroke, Dr. Woo said, but he thinks that the drugs may be unwarranted for certain subgroups, such as those with amyloid angiopathy.
“There is some evidence that suggests that in that group statins might increase the risk of hemorrhage,” he said.
Daniel F. Hanley, MD, FAAN, professor of acute care neurology at Johns Hopkins University, said he welcomed the added insight from the new study but cautioned that “it doesn't fully answer the questions about safety issues of statins” when it comes to ICH risk, in part because it wasn't a prospective randomized, controlled trial. He said the study cohort, while large, may not represent the general population at risk for ICH because everyone included in the retrospective study had started on statins.
“That's why I don't get too excited about epidemiological studies,” he said. He added that the reduced risk of ICH associated with higher doses of statins in the study was “not much different” than at lower doses, and said it was possible that cholesterol wasn't lowered enough for any negative consequences to emerge.
Still, despite some unresolved questions, Dr. Hanley said he generally supports the use of statins in overall stroke prevention strategies, including post ICH, though he tries to avoid “too low” of cholesterol in his patients.
Steven M. Greenberg, MD, PhD, FAAN, professor of neurology at Harvard Medical School, said the question of whether to keep a patient on a statin following a hemorrhagic stroke “is something I've worried about a lot.” Dr. Greenberg said the new study, while not definitive proof, provides a rationale for using statins if warranted for high cholesterol or cardiovascular risk.
“If they have a good reason to be on a statin, then continue them on it,” he said.
Dr. Greenberg said among the pros and cons that need to be weighed in making a decision on prescribing is the fact that ischemic stroke is far more common than hemorrhagic stroke, though it is associated with lower mortality and morbidity. Also, the two types of stroke may not exist in isolation. Some people who have ICH might show evidence of a previous stroke or TIA that may have gone unrecognized.
“People at risk for hemorrhagic stroke can also be at risk for non-hemorrhagic stroke,” he said, “a fact that can't be overlooked amid concern about a recurrent brain bleed.”
Drs. Auriel, Woo, Hanley, and Greenberg reported no disclosures related to this study.