Greater Adherence to Statin Therapy, Even When Already High, Boosts Survival

February 13, 2019

The more patients adhered to their prescribed statin regimen, the lower their mortality, even though they had been selected for the retrospective study for not being novices to statin therapy. The entry criteria were also designed to minimize the outcomes effects of poor statin adherence due mostly to perceived adverse effects.

The more than 340,000 patients with atherosclerotic cardiovascular disease (ASCVD) in a Veterans Affairs cohort were selected for having ongoing, refilled statin prescriptions without any changes to treatment intensity.

That helped produce a cohort in which average adherence to statin therapy was about 87%, which clinical practice considers high, and yet they still showed a dose–response relationship between adherence and mortality over about 3 years, Fatima Rodriguez, MD, MPH, Stanford University, California, told | Medscape Cardiology.

"We were surprised at how strong an effect adherence had, even at this high level of adherence. There was still this graded relationship."

That was especially true for patients who had been prescribed high-intensity statins, compared to moderate- or low-intensity statin therapy, said Rodriguez, who is lead author on the analysis published February 13 in JAMA Cardiology.

"Even in patients who seem moderately adherent, there's still a benefit to being in the highest-adherence category, to be taking all your medications all the time."

Such inverse relationships between statin adherence and clinical outcomes have been long observed, but "a lot of the work that has been done in this area has focused on people who get a prescription right away after an event," Rodriguez said.

"And we know that their adherence is very low, less than 50%, usually, at 1 year, even though they're very high-risk."

The current patients, who were receiving regular outpatient care, including continued statins at stable dosages, she noted, were thought perhaps less likely than statin recipients in overall practice to avoid taking their prescribed statins because of perceived muscle pain or discomfort or other adverse effects.

Confounding Effects?

Still, the inverse relationship between statin adherence and mortality "is not unexpected," writes Ann Marie Navar, MD, PhD, Duke Clinical Research Institute, Durham, North Carolina, in an accompanying editorial.

"What is novel about this study is the comprehensive attempt by the authors to understand whether the association between statins and mortality was due to the drug itself vs 'healthy adherer' bias, in which adherence is a marker for improved self-care and healthy behaviors," the editorial states.

Indeed, a high level of adherence even to placebo "has been associated with improved outcomes after myocardial infarction and lower cardiovascular mortality. It is possible that patients with low adherence are also likely to engage in detrimental health behaviors, such as smoking, or have poor psychosocial support," the report acknowledges.

"We tried to account for the fact that patients who adhere to medications are different from those who do not adhere to medications," Rodriguez said. The mortality analysis was adjusted for baseline features, including blood pressure, but also adherence to ACE inhibitors, beta blockers, and other cardiovascular meds.

"It attenuated the findings, but didn't change them," she said; statin adherence was still significantly related to survival in a dose–response fashion.

Secondly, the editorial notes, the researchers found no significant relationship between hospitalizations for pneumonia or gastrointestinal bleeding, which served as controls for mortality.

Also, "the adherence–mortality association was strongest in those who were prescribed high-intensity statins and lowest in those prescribed low-intensity statins," Navar writes.

"These three findings provide evidence that the mortality benefit in this study was not purely due to a healthy-adherer effect."

"Look for Signs of Nonadherence"

The analysis confirms an effect observed in other studies with varying populations, agreed Neil J. Stone, MD, Northwestern University, Chicago, in an interview.

He lauded the effort to focus on patients who tended already to be tolerating statins, and to minimize the healthy-adherer influence.

But, "at the end of the day, it's just an observational study that supports a number of other observational studies," said Stone, a coauthor of the American Heart Association and American College of Cardiology 2018 Guideline on the Management of Blood Cholesterol. "Here, you have corroboration in the VA population."

There is evidence that about two-thirds of physicians are unaware of whether their patients are taking their prescribed meds, Stone observed. "I would say, number one, look for signs of nonadherence, because it may be more common than you think. Asking the question, 'how many pills have you missed in the last 30 days' is much better than 'do you take your medicines.'"

Also, he said, guidelines have long recommended lipid-panel follow-ups after a patient starts statin therapy, "for adherence as well as adequacy of effect."

When adherence isn't good, "it's worthwhile for the patient and the doctor to figure out what's going on, and see if they can get the patient on if not the same statin, a different statin."

Adherence can also wane over time, suggesting the need to track continually. "Sometimes when you have a medication that's been on board for a while, we just assume they're taking them," Rodriguez observed.

High Adherence Overall

The study involved 347,104 adults up to 85 years of age with ASCVD on at least two evaluations within the previous 2 years who were prescribed statin therapy without any adjustment in intensity. They were treated within the Veterans Affairs Health System over a 16-month period in 2013 and 2014.

The researchers defined statin use as a filled prescription for one of the drugs in the previous 6 months; patients with new statin prescriptions had been excluded.

Statin adherence, defined in accordance with the medication possession ratio (MPR), was the ratio of outpatient days supplied with a prescribed daily statin dose to alive out-of-hospital days over 12 months.

With adherence defined in absolute terms as an MPR of at least 80%, 87.7% of the cohort was adherent to their prescribed statin therapy. But about 85% of the cohort had an MPR of at least 70%, and more than 63% had an MPR of at least 90%.

Not surprisingly, low-density-lipoprotein cholesterol (LDL-C) levels went down further with greater statin adherence, to means of 92.1 mg/dL for patients with MPR less than 50% and 77.2 mg/dL for those with MPR at least 90% (P < .001 for trend).

A similar relationship was seen for adjusted all-cause mortality, the primary end point. Absolute mortality averaged 24.8% over a mean follow-up of 2.9 years.

Outcomes by MPR Tier, Compared With MPR ≥90%
MPR Mortality Hazard Ratio (95% CI) IHD or Ischemic Stroke Odds Ratio (95% CI)
<50% 1.30 (1.27–1.34) 1.08 (1.03–1.14)
50% to 69% 1.21 (1.18–1.24) 1.02 (0.99–1.07)
70% to 89% 1.08 (1.06–1.09) 1.09 (1.06–1.12)
IHD=ischemic heart disease.
Adjusted for baseline characteristics, including adherence to ACE inhibitors and beta blockers, age, statin intensity, sex, race or ethnicity, ASCVD diagnosis, comorbidities, teaching hospital or not, creatinine, vital signs, pulse oximetry, and weight.

"This effect is most prominent for patients on high-intensity statins. Especially in the VA, probably the highest-risk patients are being placed on high-intensity statins, which is appropriate, so I think we are seeing the effect magnified for these patients," Rodriguez said.

"You not only want your patients to be adherent, but you want them to be adherent to the highest-intensity statin that they can possibly tolerate, because there's just a greater magnitude of benefit when you're on a high-intensity statin compared with a low-intensity statin. But a low-intensity statin is better than being on zero statins."

Mortality Hazard Ratio for Statin Intensity* by MPR Tier, Compared With MPR ≥90%
MPR High, 25% (95% CI) Moderate, 63% (95% CI) Low, 12% (95% CI)
<50% 1.35 (1.27–1.43) 1.32 (1.27–1.36) 1.21 (1.13–1.29)
50% to 69% 1.23 (1.17–1.30) 1.21 (1.17–1.24) 1.18 (1.11–1.25)
70% to 89% 1.10 (1.06–1.14) 1.07 (1.05–1.10) 1.04 (1.00–1.09)
Adjusted for baseline characteristics, including adherence to other cardiac medications, age, statin intensity, sex, race or ethnicity, ASCVD diagnosis, comorbidities, hospital teaching status, creatinine, vital signs, pulse oximetry, and weight.
*Statin intensity: High = atorvastatin 40 to 80 mg, or rosuvastatin 20 to 40 mg. Moderate = atorvastatin 10 to 20 mg; fluvastatin 40 mg twice daily or extended-release 80 mg once daily; lovastatin 40 mg; pitavastatin 2 to 4 mg; pravastatin 40 to 80 mg; rosuvastatin 5 to 10 mg; simvastatin 20 to 40 mg. Low = fluvastatin 20 to 40 mg; lovastatin 20 mg; simvastatin 10 mg; pitavastatin 1 mg; pravastatin 10 to 20 mg.

Rodriguez reported no conflicts. Disclosures for the other authors are in the report. Navar discloses receiving grants and personal fees from Amarin, Amgen, Regeneron, and Sanofi; fees from NovoNordisk and AstraZeneca; and grants from Janssen. Stone reported no conflicts.

JAMA Cardiology. Published February 13, 2019. Report, Editorial

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