COMMENTARY

Statins After Stroke: Don't Take as Gospel

John Mandrola, MD

Disclosures

August 14, 2017

At my hospital, and perhaps yours too, statin use after stroke has become sacrosanct. Nearly everyone with a diagnosis of stroke gets high-dose atorvastatin. The stroke-order sets extract thinking from care delivery.

When I asked medical leadership about this policy, the mantra, the talking point, was that high-dose statins after stroke is evidence-based and it's a quality measure. The unsaid message was clear: get with the program!

And this month, publication of two methodologically weak observational studies bolstered the sanctity of statin use after stroke.

The first study used an administrative database in Taiwan and found a higher incidence of recurrent stroke when poststroke patients stopped using a statin.[1] The second was a retrospective medical-record review of participants in the REGARDS trial that found that less than half of patients who had a stroke were prescribed a statin—and statin use was worse in states from the Stroke Belt.[2]

These prostatin papers pushed me to look more closely at the evidence behind the statin-for-all-after-stroke policy. I discovered there is room for nuance. And thought.

The statin-after-stroke quality measure mostly began after publication of the Pfizer-sponsored SPARCL trial,[3] which also included Pfizer employees as authors.

This multicenter randomized controlled trial (RCT) tested the hypothesis that treatment with 80 mg of atorvastatin per day would reduce the risk of fatal or nonfatal stroke in patients with a history of stroke or TIA. About 4700 patients were randomized at 205 centers.

The top-line results were positive. During a median follow-up of nearly 5 years, 11.2% of patients on atorvastatin had a fatal or nonfatal stroke vs 13.1% of those on placebo. This approximate 2% absolute difference (NNT=50) barely met statistical significance (P=0.03). In secondary outcomes, statin use significantly reduced the risk of recurrent cardiac events. Post hoc analyses, however, suggested a heterogeneous treatment effect based on the type of stroke: atorvastatin use associated with a reduced the risk of ischemic stroke (HR 0.78, 95% CI 0.66–0.94) but an increased risk of hemorrhagic stroke (HR 1.66, 95% CI 1.08–2.55).

Six other facts from SPARCL dampen enthusiasm for a statins-for-all-after-stroke policy:

  • Patients with atrial fibrillation were excluded.

  • Patients had to be ambulatory to get in the trial.

  • The mean baseline LDL-C was 133 mg/dL (it had to be 100–190 mg/dL [2.9-4.9 mmol/L] to get in the trial).

  • The mean age of participants was 63.

  • There was no difference in mortality between treatment groups.

  • Subjects were randomly assigned within 30 days of being screened—not immediately after stroke.

These limitations suggest we can at least stop and think about high-dose statin use in poststroke patients. To wit:

AF-related stroke is common. I regularly see patients with AF-related stroke—many without a whiff of atherosclerotic disease—on high-dose statins. This non–evidence-based therapy is fallout from algorithmic medicine run amok.

Similarly, I also see nonambulatory frail elders burdened with high-dose statins. My wife Staci, a hospice and palliative-care specialist, says frail elders should eat food, not pills. Her commonsense advice is backed up by the evidence—these patients are excluded from trials like SPARCL because trialists know these patients will not benefit from preventive therapies.

SPARCL, like so many cardiovascular RCTs, included younger patients. How do these results translate to 80- to 90-year-olds? The answer is we don't know.

In SPARCL, the small differences in primary outcome argue for shared decision making. Stroke patients are usually hospitalized for a few days and then seen shortly after discharge. There is time to discuss the NNT and how it applies to their situation to see if statin use aligns with their goals.

On the matter of timing of statin use after stroke, SPARCL investigators randomized patients weeks—not minutes—after the stroke event. The average time from stroke event to study entry was 84 to 87 days. What's more, the Kaplan-Meier curves for the primary outcome took a year to separate. This makes sense as the beneficial statin effects on atherosclerosis take time.

The data in support of immediate high-dose statin therapy are weak. A Japanese RCT presented as an abstract[4] at the International Stroke Conference in March found no improvement in neurologic function with early (within 24 hours) statin use compared with delaying statin therapy to 7 days. Proponents of early statin use criticized these results on the grounds that the study included patients with low stroke severity who would be unlikely to benefit.

That's reasonable criticism, but the existing evidence for early statin use after stroke is not strong. The often-cited THRAST study[5], which is touted as showing benefit for statins in the acute phase of stroke, was a noncontrolled observational study—hardly high-level evidence. And although a systematic review of 70 relevant studies of immediate poststroke statin use reported positive results, the authors note in their conclusions that "the findings were mostly driven by observational studies at risk of bias."[6]

Conclusion

I strongly support the notion that younger ambulatory patients with stroke who have diffuse atherosclerosis and elevated LDL-C stand to benefit from statin therapy. The benefits in these patients is not only in the prevention of recurrent stroke but also recurrent cardiac events.

The problem is that stroke presents in many different ways and often in patients who bear little resemblance to those selected for inclusion in SPARCL. These patients deserve thoughtful care rather than obedience to algorithms.

The obvious benefit of thoughtful evidenced-based poststroke care is avoidance of possible statin side effects. The less obvious but, in my opinion, bigger problem with prescribing nonhelpful therapies is that it distracts from other types of care—things like attention to rehab, diet, exercise, blood-pressure control, and anticoagulation regimens.[7]

Recovering from a stroke is hard enough; making it harder with nonbeneficial therapies should be avoided. All it requires is some thought and evidence review.

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