Statin-Intolerant Patients Have Significantly Worse Prognosis After MI

Whether side effects from statins are real or a nocebo effect, not taking a statin after MI has a profound impact on recurrent events, say experts.

Statin-Intolerant Patients Have Significantly Worse Prognosis After MI

Myocardial infarction patients deemed intolerant to statins are more likely to have a recurrent MI or other subsequent coronary heart disease events, including a need for PCI or CABG surgery, than individuals who are highly adherent to therapy, a new analysis shows.

Statin intolerance, on the other hand, is not associated with an increased risk of all-cause mortality, investigators report.

“When we think about this debate that’s been brought forth by certain skeptics, does it really make a difference,” Robert Rosenson, MD (Icahn School of Medicine at Mount Sinai, New York, NY), asked TCTMD, whether intolerance is ‘real’ or not?

Regardless of why patients stop taking their statins, that decision appears to gravely affect clinical outcomes, said Rosenson, the study’s senior investigator. “People are having more events, and they’re costing society more money because they’re in the hospital. Regardless if someone has true statin intolerance, or they believe they have statin intolerance, [there are] more major cardiovascular events, more hospitalizations, and more costs to society—we need to find some solutions.”

In an editorial accompanying the study, Steven Nissen, MD (Cleveland Clinic, OH), observes that muscle-related statin intolerance remains a controversial topic. Some clinical researchers argue that intolerance is rare and mostly in a patient’s head while others contend it is a legitimate problem affecting as many as 20% of statin-treated patients, notes Nissen. 

“What makes this study interesting is that we’ve always suspected that if you have statin intolerance and can’t take a statin, it may have grave consequences for your cardiovascular health,” Nissen told TCTMD. “What this study shows is that yes, indeed, it does. It’s a malignant disorder.”

Current American College of Cardiology/American Heart Association guidelines recommend high-intensity statin therapy for patients who have had an acute coronary syndrome.  

Strict Definition of Statin Intolerance

The new study, published March 12, 2017, in the Journal of the American College of Cardiology, included 105,329 Medicare beneficiaries who began moderate- or high-intensity statin therapy following hospitalization for MI between 2007 and 2013. Overall, 1.65% of patients were intolerant to statins compared with 55,567 patients who had high adherence to therapy, which was defined as proportion of days covered being 80% or greater.

The researchers note that there is no widespread consensus as to how to define statin intolerance in claims-based studies. In their analysis, patients were considered statin intolerant if they stopped statin therapy and began treatment with ezetimibe (Zetia, Merck/Schering-Plough); started ezetimibe within 7 days before or after down-titrating their statin dose; had an inpatient or outpatient claim for rhabdomyolysis or other drug-related adverse effects (followed by down-titration or drug discontinuation); or filled prescriptions for three or more types of statins.

In the analysis, approximately 60% of patients defined as statin intolerant were categorized as such after filling prescriptions for three or more statins in the year. Additionally, 11.1% of patients had their dose lowered and ezetimibe initiated, while 17% were switched from a statin to ezetimibe. Just over 11% of patients had an ICD-9 code for rhabdomyolysis.   

To TCTMD, Rosenson said the claims-based assessment of statin intolerance was quite rigorous. “We didn’t want to include people who [only] discontinued therapy, because they might have stopped for multiple reasons, including pill burden, cost, or a gap in provider,” said Rosenson. “We used the most stringent definition [of statin intolerance].”

After a median follow-up of 1.9 to 2.3 years depending on the endpoint, there were 4,450 recurrent MIs, 6,250 coronary heart disease events, and 14,311 deaths.

Among those highly adherent to statin therapy, the incidence of recurrent MI and coronary heart disease events was 30.1 and 43.8 per 1,000 person-years, respectively. In the statin-intolerant patients, the incidence rates were 41.1 and 62.5 per 1,000 person-years respectively. These differences were statistically significant. There was no difference in the incidence of all-cause mortality between those adherent and intolerant to statin therapy.

In a multivariate-adjusted model, the relative risks of recurrent MI and coronary heart disease events were 50% and 51% higher in the statin-intolerant patients when compared with those with high adherence to therapy (P < 0.001 for both).

“If people are down-titrating the statin, and even down-titrating and using ezetimibe, after their myocardial infarction, they have a higher event rate,” said Rosenson. “Physicians need to make certain that patients truly have statin intolerance and to try to get them on another statin. And patients really need to understand that if they can’t tolerate a statin, there are other solutions.”

Legitimate Side Effects in Some Patients

Regarding the controversy over the legitimacy of statin intolerance, Nissen said skeptics and believers alike have valid arguments. 

“Clearly, there is the nocebo effect—adverse effects attributed to the drugs,” he said. “One of the problems we have, frankly, is that people get their information from the internet. They visit websites where there are all sorts of people telling them statins are bad, or have terrible side effects. There is no question there is a significant psychosomatic component to statin intolerance.”

That said, Nissen believes there are a group of patients who develop statin-related muscle pain and weakness even though they might not have biomarker-based evidence of the adverse effect. He noted that in the blinded GAUSS-3 study, 42.6% of patients with a history of statin intolerance had muscle-related symptoms when randomized to atorvastatin but not when they took a placebo. 

The academic argument over statin intolerance, however, is largely irrelevant for practicing physicians who must deal with a patient with high LDL cholesterol at increased risk for a recurrent event, according to Nissen. Some of these patients will adamantly refuse another therapeutic trial of a statin despite their heightened risk of recurrence.

“If in the mind of the patient they can’t take a statin, or they refuse a statin, then it doesn’t matter if it’s a nocebo effect or a real disorder,” said Nissen. “If you can’t give them a statin, they’re going to have a very bad prognosis. We have to come up with management strategies for these patients that will allow us to treat them. If we don’t treat them with a statin, they’re going to do poorly.”

At the Cleveland Clinic, the first step for a patient with claims of muscle pain or weakness is to switch statins. Following this, physicians will start patients on high-intensity statin once per week, gradually increasing the number of days the patient takes the drug, he said.

Nissen notes that despite the numerous strengths of the present study, it also has important weaknesses, including the ascertainment of statin intolerance, which was inferred rather than documented. Additionally, the study is observational and residual confounding remains an issue, particularly since patients who complain about statin-related symptoms might be less adherent to other medical therapies, he commented.

  • Serban MC, Colantonio LD, Manthripragada AD, et al. Statin intolerance and risk of coronary heart events and all-cause mortality following myocardial infarction. J Am Coll Cardiol. 2017;69:1386-1395.

  • Nissen SE. Statin intolerance: an elusive but morbid disorder. J Am Coll Cardiol. 2017;69:1396-1398.

  • Rosenson reports receiving research support from Amgen Inc., Eli Lilly, The Medicines Company, Regeneron, and Sanofi; serves on the advisory boards for Amgen, Eli Lilly, Regeneron, and Sanofi.
  • Several authors of the paper are employees of Amgen, the maker of evolocumab, a PCSK9 inhibitor for treating elevated LDL cholesterol levels.
  • Nissen reports receiving clinical trial funding through his institution from AbbVie, AstraZeneca, Amgen, Cerenis, Eli Lilly, Esperion, Pfizer, and The Medicines Company.

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