What's the Story with Statins and Stroke Prevention? - A Q&A with Koto Ishida, MD

Internal Medicine World Report, December 2014,

There have been some disappointing studies and contradictory recommendations on using statins to treat stroke. HCPLive's Gale Scott interviewed Koto Ishida, MD, medical director of the NYU Langone Comprehensive Stroke Care Center, about the implications for clinicians.

There have been some disappointing studies and contradictory recommendations on using statins to treat stroke. HCPLive’s Gale Scott interviewed Koto Ishida, MD, medical director of the NYU Langone Comprehensive Stroke Care Center, about the implications for clinicians.

Has recent research changed your own thinking in what statin dose is best for stroke patients?

It has. Everything in treating stroke patients and managing these patients involves a risk/benefit analysis. When a new study comes out, people sometimes over-analyze it and blow it out of proportion. My patients are at high risk for future cardiovascular (CV) events; most have already had a stroke or a transient ischemic attack (TIA). These are the patients who are likely to benefit most from statins. The new guidelines have changed how we think about treatment and dose.

What exactly is different now?

It used to be we would really fixate on the LDL number. More recently, a lot of guidelines are focused on finding the best level of evidence—it’s more about patients’ risk of having a CV event. These newer guidelines are shifting away from numbers, and towards a patient-specific risk assessment.

How do you do that?

There is calculator from the American Heart Association (AHA) that is really helpful. It used to be we treated everyone similarly. Now we differentiate who may benefit from statins and who may not. The specific concerns with statins are muscle aches, elevated liver enzymes, and bleeding in the brain. In order to determine whether a patient will gain more benefit from treatment, the risk to the patient has to be more specifically quantified. If a patient is older, has a higher blood pressure, a history of diabetes, it is helpful to be able to incorporate those risks into one easy-to-use calculator.

Doesn’t that take a lot of time?

No, it’s a fast calculator. You can do it online or download an app, it takes about 30 seconds. You just enter high BP, the age, whether they have diabetes, etc. I tend to see patients who need secondary stroke prevention, but the calculator works even for primary prevention—for those who have never had a stroke—but have a high 10-year risk. These risk scores can help us determine in which patients the benefits of taking statins outweigh the risks.

When did your thinking about risk start to change?

The seminal trial was the SPARCL trial published in the New England Journal of Medicine that showed that in a subset of patients getting statins there was an association with bleeding in the brain. That raised some red flags and opened some new trials and discussion. We need to see how real the risk is. We really don’t know the answer. If someone has a bleed, should we stop the statin? There have been some observational studies that showed stopping a statin can lead to adverse outcomes.

My personal take on statins and bleeding risk is that if a patient has never had a bleeding event but has cardiovascular or cerebrovascular reasons to be on a statin, I will recommend one. If a patient presents with a hemorrhagic stroke and is already taking a statin, I will not stop it in the acute (hospital) setting. If they have a hemorrhagic stroke and were not taking a statin, I will weigh the risks and benefits but will probably not start a new statin in the short term.

The IMS III trial showed that following IV tPA, treatment with intra-arterial lysis did not seem to help patients. Do you agree with the findings? Did they surprise you?

There was a more recent study on this issue that came out last month, the MR CLEAN study, which changed a lot. But when IMS III came out, it caused lot of controversy. It was one of 3 trials that came out at the same time. All showed that patients who got these interventions showed no significant functional improvement over those who got IV tPA alone.

But when the IMS III trial was done it was not commonplace or practical for all patients to get vascular imaging to see if they had an occlusion. It took too long for them to get treatment and we’ve known for decades that “time is brain.” The sooner you recannalize blood vessels the better. The other thing with the earlier studies is they used first-generation devices in the interventions, which were not nearly as good as the newer devices we use now.

What changed with MR CLEAN?

Things got faster. Ninety percent of patients got IV tPA before the intervention and sooner than in other trials. Also, almost exclusively the doctors in the more recent trials used the new generation of stent retrievers as compared with only single digits in the prior trials, and the patients all got vascular imaging proving large vessel occlusion prior to enrollment.

Was it a better-designed study?

The final thing with MR CLEAN is that this trial was done in the Netherlands, where they have a unique system. The government there did not reimburse doctors for the procedure unless it was done as part of the MR CLEAN trial. In the IMS III trial it was hard to enroll patients. MR CLEAN had 600 patients and IMS II had about 500, but MR CLEAN was completed more quickly. In IMS III enrollment suffered. It was stopped out of futility. When you have to struggle to enroll patients, you have to make the criteria more broad.

But when you first saw the results of IMS III did you think they were accurate?

Like a lot of people I was disappointed with the results. But I wasn’t one of those who thought it was a poorly designed trial. We just didn’t have access to the same devices or diagnostic capabilities. It was still an important trial and ultimately provided us with information to design future trials that have now ultimately shown positive results (ie, MR CLEAN).

Did IMS III change how you practiced?

Some people just stopped doing interventions. I personally just changed the way I selected patients. If the intervention could be done quickly we would pursue doing them. We nearly always got vascular imaging to confirm there was an occlusion before putting patients through the risk involved. But we were all waiting for the next trial.

The Dutch Trial called MR RESCUE showed that there was no diffusion/perfusion therapy that helped patients more than 4.5 hours after their stroke. Did that study have any good news?

It was similar to earlier trials and done in similar fashion. The timing was slow, they used older devices. It did show that patients with a more favorable penumbra (that is, less permanent tissue damage and more at risk tissue) did better. This was not terribly surprising though, since once a stroke is completed, what’s done is done to some extent. Unfortunately, the patients with a favorable perfusion study suggesting salvageable brain tissue still did not do as well as expected after mechanical intervention. There may still be a subset of this potentially heterogeneous group of patients who may benefit with faster re-opening of blood vessels, but this study did not show that.

Was there anything encouraging, useful, or both in the new American College of Cardiology, American Heart Association, and American Stroke Association recommendations on statin therapy for stroke prevention?

It was very useful; most of us were trained to target a specific LDL goal but now we are focused more on tailoring treatment to fit specific patients. There is so much at stake. These patients are at risk for one of the most debilitating medical conditions there is.

Do you find these new guidelines contradictory when it comes to LDL goals?

Not necessarily. They purposely leave it a little vague. Guidelines are just that; they allow physicians to weigh factors to see which patients should take statins instead of just setting strict LDL goals. They purposely don’t address some issues (such as the bleeding risk of statins) since the data is still limited.

There is a fear of statins in the lay community, and it is up to the physician and patient to decide whether or not to use them. It’s a conversation I have all the time. Some patients are eager to take them and others are reticent and some will refuse altogether. Because of articles in the popular press, some people are worried about their livers—even though Tylenol can be potentially even more harmful. The big concern though is bleeding in the brain. But it would be wrong to withhold statins from a patient with proven ischemic stroke or cardiovascular risk out of fear for a potential harm of bleeding. It’s a topic that needs to be studied more.

How important are LDL goals when it comes to preventing stroke and myocardial infarction (MI)?

They used to be more important.

Do statins stabilize plaque?

We think so. The patients who have had a stroke and probably benefit most from statins are those whose strokes are presumed to be due to atherosclerosis, from “plaque.” With statin therapy, data suggest that plaque progression may be slowed. Statins may even partly contribute to regression of plaque thickness.

Should all patients with large artery disease be on high-dose statin therapy and in such cases, for how long?

That depends on what their other risks are. Are they asymptomatic? Do they have other health issues? Are there other parts of their medical history that suggest they should be on statins? As for how long, there are lifestyle changes people can make but people tend to have trouble keeping those commitments. Statins can be more effective for those who need aggressive cholesterol lowering.

What about statins for patients whose strokes are traced to atrial fibrillation (AF)? Or small-vessel disease?

Good question. People who have AF tend to be older and have higher blood pressure, elevated cholesterol, and some mild plaque in their arteries, so to me having AF doesn’t make a huge difference and doesn’t change my thinking. Small-vessel disease is traditionally not an atherosclerotic mechanism except in a small subset of patients. If they have no evidence of atherosclerosis and high BP maybe I won’t be as aggressive with statins or maybe I’ll prescribe lower doses.

Any closing thoughts on the topic you’d like to share with our readers?

The main thing is, therapy should always be individualized and based on a conversation with the patient.