Newer cholesterol-lowering drugs appear safer than statins for some patients

Statins increased the risk of bleeding in the brain for some patients while PCSK9 inhibitors did not.

For patients at increased risk of hemorrhagic stroke, a class of cholesterol-lowering drugs known as PCSK9 inhibitors may be a safer choice for cholesterol management than statins, according to a new study by UCLA researchers.

Some 40 million people in the United States currently take statins, which are powerful cholesterol-lowering medications that also reduce the risk of heart disease.

Statins also reduce the risk of the most common type of stroke – ischemic stroke due to plaque buildup in blood vessels. But some studies have suggested they may increase the risk of less-common hemorrhagic strokes – bleeding in the brain due to blood vessel rupture.

Because statins have been extensively tested over the last two decades, the UCLA researchers were able to pool data from 36 completed randomized trials to evaluate even rare side effects.

One such side effect appears to be an increase in the risk of hemorrhagic strokes.

“In the past, we were limited in what we could do about the possible increased risk of hemorrhagic stroke, because we didn’t have great alternative agents to statins,” says Jeffrey Saver, professor of neurology and director of the Comprehensive Stroke and Vascular Neurology Program at the David Geffen School of Medicine at UCLA.

In the last few years, however, a new class of drugs called PCSK9 inhibitors have come on the market. “They lower cholesterol as strongly or even more than the statins do, and they appear to have fewer off-target effects,” Saver says.

Statins work by blocking the chemical reaction in the liver that produces cholesterol. Doctors prescribe statins to people to lower blood cholesterol levels and reduce the build up of cholesterol plaques on blood vessel walls, which helps prevent heart attacks and ischemic strokes.

“Statins have been a mainstay of cholesterol-lowering therapy for 20 years,” Saver says. “They have in general been a tremendous benefit to patients with vascular disease worldwide.”

They also have other effects in the body, including mildly reducing the ability of the blood to form clots. This is good for preventing ischemic strokes, which occur when clots block the flow of blood in the brain.

It’s not good, however, for hemorrhagic strokes, which are caused by bleeding that accumulates in the brain and compresses tissue.

PCSK9 inhibitors “work through an entirely different mechanism,” Saver says. The enzyme PCSK9 causes liver cells to remove more LDL (the “bad” cholesterol) from the bloodstream.

Importantly, PCSK9 inhibitors don’t have the mild anti-clotting effects that statins seem to have. It’s this anti-clotting effect that could lead to a higher risk of bleeding in the brain.

Calculating risk

To compare the risk of hemorrhagic stroke between statins and PCSK9 inhibitors, Saver and his colleague Borja Sanz Cuesta analyzed hemorrhagic stroke rates across 41 different clinical trial reports – 36 trials of statins and five trials of PCSK9 inhibitors. Their results were published online June 22 in the journal Stroke.

They found that statins increased the risk of hemorrhagic stroke very slightly in all patients. The risk was higher in patients taking high doses of statins and in patients who had some baseline injury to the brain from a prior ischemic stroke. And the risk was highest in patients who had already had a prior hemorrhagic stroke.

“Patients with a past ischemic stroke went from a 1.1% chance of hemorrhagic stroke to a 1.6% chance,” says Saver. For these patients, he says, “the benefit of statins in terms of reducing ischemic stroke greatly outweighs this slight risk of hemorrhagic stroke.”

But in the small subset of patients who had previously suffered a hemorrhagic stroke, taking statins increased their risk of a future brain bleed by about four-fold. Having a prior hemorrhagic stroke already increases the risk of a second one to about 4.7%. Add in statins, and that risk jumps to 16%.

“In contrast, the PCSK9 inhibitors did not show any increase in risk of hemorrhagic stroke,” Saver says.

The findings suggest that in those patients who have had prior hemorrhagic stroke, PCSK9 inhibitors may be a safer choice for cholesterol management than statins, the authors say.

“In certain types of patients, who have this damage to the brain, a high dose of statins can put them at risk,” says Sanz Cuesta, who is now at Lenox Hill Hospital in New York. “It’s important that for these patients, we can propose alternative therapeutics. The PCSK9 inhibitors reduce cholesterol and are not associated with hemorrhagic stroke risk.”

The authors emphasize that statins pose very little risk to patients who have not had prior bleeding in the brain. “Statins remain the first-line agent for these patients,” Saver says.

Learn more about stroke research at UCLA Health.

Jeffrey Saver reports receiving consulting fees from Amgen and Boehringer Ingelheim for clinical trial design.

Caroline Seydel is the author of this article.