In-Hospital Statins Linked to Better Outcome in ICH

Pauline Anderson

September 22, 2014

Patients with hemorrhagic stroke who received a statin while in the hospital had better survival rates and were more likely to be discharged home or to a rehabilitation center than those who don't get a statin while an inpatient, a new study suggests.

Importantly, patients with hemorrhagic stroke in the study who had been receiving a statin and were taken off the drug while in the hospital did worse than those who continued taking the drug as inpatients.

The study should affect in-hospital practices, said lead author, Alexander Flint, MD, PhD, medical director, Neuroscience Quality, Kaiser Permanente, Redwood City, California.

"I think that in the wake of our findings, the way our practice in Kaiser Permanente, in terms of how we treat intracerebral hemorrhage, is going to certainly be to not stop someone taking statins acutely in hospital."

Statin continuation or discontinuation as an outpatient in the ensuing months is an issue to be discussed between clinicians and patients, he said.

Dr. Alexander Flint

The study is published online September 22 in JAMA Neurology.

Array of Pathways

Statins affect an array of molecular pathways that can play a role in stroke, the authors note. They may modulate the immune system, inhibit the inflammatory process, and improve cerebral blood flow, promoting neuroprotection and tissue recovery. However, statins may decrease the level of platelet aggregation and thrombogenesis and thus worsen outcomes in intracerebral hemorrhage (ICH).

While it's clear from randomized controlled trials that statins can prevent recurrent ischemic stroke, the situation has not been as clear for hemorrhagic stroke prevention. One study, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, published in 2006, showed that patients taking a statin who had a history of hemorrhagic stroke had a higher rate of another hemorrhagic stroke.

"The question becomes, if you think it's important to take those patients off their statin eventually, should you do that right away, or should you wait, or is this really not as an important a step as we thought?" said Dr. Flint.

In the past, doctors have shied away from prescribing statins in patients with brain hemorrhage, he said.

The current study cohort included 3481 patients older than 50 years who were admitted to 1 of the 20 hospitals in Kaiser Permanente Northern California (KPNC) during a 10-year period (January 2002 to December 2011) and who received a primary discharge diagnosis of ICH. The KPNC healthcare system is broadly representative of the overall population of northern California.

Researchers obtained details of statin use before and during hospitalization from electronic pharmacy records and medical records. Nonusers of statins had not been prescribed this medication in the preceding year.

Of the 2321 patients not receiving a statin as an outpatient before ICH, 18.3% received a statin as an inpatient, and of the 1160 patients receiving a statin as an outpatient, 33.7% did not receive a statin as an inpatient.

The statins used by 1194 inpatients included lovastatin (58.3%), simvastatin (37.9%), atorvastatin (3.2%), and pravastatin sodium (0.6%).

Mortality Rate

Patients treated with a statin while in the hospital had an unadjusted 30-day mortality rate of 18.4% compared with 38.7% for those who were not treated with a statin during admission for ICH.

After adjustment for age, sex, race/ethnicity, comorbidities, number of ICH cases by hospital, and dysphagia, inpatient statin users were more likely than nonusers to be alive at 30 days (odds ratio [OR], 4.25; 95% confidence interval [CI], 3.46 - 5.23). This association remained after adjustment for severity of the initial bleeding and for do-not-resuscitate status within 24 hours.

Dr. Flint noted that statin users had significantly more severe illness and more comorbidities, such as diabetes and atrial fibrillation, than nonusers, "which should have pulled in the other direction" or resulted in worse outcomes. "But despite that, we see this improved outcome in statin users."

Patients who received statin therapy during hospitalization were discharged home or to an inpatient rehabilitation facility 51.1% of the time compared with 35.0% of those not receiving statin therapy during admission. Discharge home or to rehab is considered a favorable outcome compared with discharge to a hospice, skilled nursing facility, or death while in hospital.

Patients whose statin therapy was discontinued after hospital admission had an unadjusted mortality rate of 57.8% compared with a mortality rate of 18.9% for those using a statin before and during hospitalization. They were less likely to be alive at 30 days (OR, 0.16; 95% CI, 0.12 - 0.21; P < .001).

Discontinuation of statin therapy was associated with an unadjusted rate of discharge to home or inpatient rehabilitation facility of 22.3% compared with a rate of 49.9% for patients taking a statin before and during hospitalization (P < .001).

The authors controlled for timing of statin administration, reasons why patients may not have been given a statin (eg, swallowing difficulties), and dying before receiving a statin, "and we still see a robust effect," noted Dr. Flint.

A small proportion of study patients (3.3%) were taking high-dose statins. When researchers looked at a possible dose response, they found "a signal that the higher dose is better" in terms of survival and discharge status, but the differences weren't statistically significant, said Dr. Flint.

Dr. Flint doesn't think that the benefit of statin therapy was through lowering low-density lipoprotein cholesterol because the in-hospital effects were "just too fast." Instead, he believes statins affect different signaling pathways, including one involved in the production of nitric oxide. This more rapid effect may better explain the relatively rapid statin effect, he said.

The study doesn't settle the issue of long-term outpatient use of statins in this population, said Dr. Flint.

"An important conversation for patients who have suffered an intracerebral hemorrhage to have with their primary care doctor and neurologist is whether it makes sense for them to be on a statin in the long run to prevent endpoints like heart attack and ischemic stroke," he said.

While with ischemic stroke it would be "ethically problematic" to randomly assign patients to placebo because the evidence is so strong that a statin can prevent recurrent stroke, that may not be the case for hemorrhagic stroke, said Dr. Flint. He thinks there's "absolutely" room for a randomized controlled trial "to look at the appropriateness of long-term statin use in patients with a personal history of intracerebral hemorrhage."

Amyloid Angiopathy

In an accompanying editorial, Marco Gonzalez-Castellon, MD, and Randolph Marshall, MD, Division of Stroke, Department of Neurology, Columbia University Medical Center, New York, New York, agreed that the controversy surrounding statin use in patients with ICH "is far from settled."

Although the study authors provide compelling evidence that treatment with statins after acute ICH is safe and improves outcomes, at least in the short term, "It may still be that certain pathologies, such as amyloid angiopathy, pose an increased risk with statin use, and, therefore, should be avoided," Dr. Gonzalez-Castellon and Dr. Marshall write.

And despite its positive findings, the study has limitations, they note. It has a retrospective design, lacks data on the volumes of ICH cases, and doesn't include reporting on other medications that might influence outcomes.

For these reasons, they said, the study needs to be validated in a prospective cohort.

"For now, however, it provides sufficient evidence to recommend at least the continuation of statin therapy after nonamyloid ICH for at least 30 days after the initial event."

The study was supported by a Community Benefit grant from the Kaiser Foundation Research Institute. Sanofi provides drug and placebo to a National Institutes of Health–sponsored trial led by coauthor Claiborne Johnston, MD, PhD. Dr. Johnston receives research support from AstraZeneca. No other disclosures are reported.

JAMA Neurol. Published online September 22, 2014. Abstract Editorial

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