Tackling Intolerance: What to Do When Patients Pull the Plug on Statins

Despite their well-documented benefits, statins are often discontinued by patients because of their equally acknowledged side effects. This has continued to fuel heated debate over how widespread—or even legitimate—these adverse events are, whether physicians give up too easily on patients who are statin intolerant and what other options exist for patients who could gain by taking their cholesterol-lowering medicine? 

Familiar frustration

It’s an all-too-familiar—and frustrating—tableaux for cardiologists today. A patient comes into the office and announces he’s taken himself off his statin medicine. The reason: persistent muscle aches and pains. After weighing the evidence, the physician looks the high-risk patient in the eye and assures him continued use of the statin could reduce by 25 to 35 percent the risk of a future heart attack or stroke. It’s no use. The patient refuses to budge, and the physician glumly makes the entry in the patient’s record. “Part of it is just fatigue from patient after patient coming in and saying this medication is making me feel terrible,” acknowledges Michael Miedema, MD, a cardiologist at Minneapolis Heart Institute who has conducted research on statin intolerance. “Physicians feel it’s much easier to just stop the statin.” 

[[{"fid":"22765","view_mode":"media_original","type":"media","attributes":{"height":309,"width":600,"alt":" - reasons-forstatin-discontinuation-routine-care","class":"media-element file-media-original"}}]]

One of the biggest mysteries around statins is how many patients are intolerant. “Statin intolerance”—generally defined as the inability to tolerate a dose of statin required to sufficiently reduce cardiovascular risk—has been linked primarily to muscle discomfort, though patients have also complained of fatigue, gastrointestinal issues, headaches, poor vision, cognitive dysfunction and much more. Studies suggest that statin intolerance afflicts between 15 to 20 percent of patients, though some cardiologists claim as many as half their patients report adverse events. Curiously, the recent GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3) randomized clinical trial to investigate an alternative treatment to statins found that 26.5 percent of patients who had failed three or more statins in phase A of the trial reported symptoms while taking a placebo, compared to 42.6 percent while taking atorvastatin (JAMA 2016;315[15]:1580-90). “There are clearly people who have a real disorder, but there are also a lot of people who have perceived harms from their [statin] therapy,” says Steven Nissen, MD, chair of Cardiovascular Medicine at the Cleveland Clinic and lead investigator of GAUSS-3. “It’s called the ‘nocebo effect,’ and what makes it so vexing for doctors is trying to tell the difference.”

[[{"fid":"22766","view_mode":"media_original","type":"media","attributes":{"height":512,"width":600,"style":"font-size: 13.008px; width: 180px; height: 154px; margin: 5px; float: left;","alt":" - s-nissen","class":"media-element file-media-original"}}]]

Not all patients who report a problem with their statin abandon it, of course, but the number is high enough to concern physicians. Researchers who analyzed information from a national Danish registry found that between 1995 and 2010, statin use among 675,000 individuals who were 40 years and older grew from 1 percent to 11 percent (Eur Heart J 2016;37[11]:908-16). During that same period, the number of patients who discontinued their statins within the first six months tripled. Just as intriguing was the connection the study drew between that discontinuance and negative stories about statins in the press. Specifically, it found that patients were 9 percent more likely to stop their medicine when the news coverage was bad, and 8 percent less likely when the news coverage was positive. As for the all-important impact of their decisions on health outcomes, the Danish study found that patients halting their statins within the first six months had a 26 percent greater risk of heart attack and 18 percent greater risk of death than those who remained on the medication. In the U.S., a study of 79,240 Medicare patients who began moderate- or high-potency statins after suffering a myocardial infarction also raised red flags. It found that for statin-intolerant patients, the incidence of recurrent myocardial infarction was 41 percent vs. 32 percent for patients who adhered to their treatment (J Am Coll Cardiol 2016;67[13_S]:1838).

“Try & try again” 

Given the stakes, do too many physicians prematurely throw in the towel when confronted with statin-intolerant patients? “I think so,” responds Salim Virani, MD, PhD, associate professor at Baylor College of Medicine and head of its lipid clinic. “Statins are a full class with lots of medications and options available, and physicians should be trying at least two or three medicines before labeling a patient statin intolerant.  It could be life-saving for the patient.”

[[{"fid":"22767","view_mode":"media_original","type":"media","attributes":{"height":512,"width":600,"style":"font-size: 13.008px; width: 180px; height: 154px; margin: 5px; float: left;","alt":" - s-virani","class":"media-element file-media-original"}}]]

Indeed, there is growing clinical evidence that most patients who decide to end their statin regimens can be successfully rechallenged. One large retrospective study from Brigham and Women’s Hospital and Massachusetts General Hospital documented statin-related events in 17.4 percent of the patients it investigated. Of these, over 92 percent who were rechallenged with a statin were still taking the medicine 12 months after the event, leading the researchers to conclude: “Most patients who are rechallenged can tolerate statins long-term. This suggests that many of the statin-related events may have other causes, are tolerable, or may be specific to individual statins rather than the entire drug class” (Ann Intern Med 2013;158[7]; 526-34).

Miedema with Minneapolis Heart Institute cites patients who failed four and five statins who now are successfully taking low doses of other statin medicines. “Literature suggests that a statin is better than no statin, and while it’s not a perfect solution, we’ve found that at 5 mg our patients typically tolerate a new statin well,” he says.

Adds Nissen with Cleveland Clinic, “Good physicians will try and try again a different drug with low or intermittent dosing.” The GAUSS-3 trial looked at a member of the emerging class of PCSK9 inhibitors (evolocumab) as a statin alternative and found it effective in reducing low-density lipoprotein cholesterol compared to another non-statin (ezetimibe). But persistent muscle symptoms in 20.7 percent of evolocumab-treated patients (and the drug’s $14,000 a year price tag) suggest it will have a hard time achieving mass market appeal.

[[{"fid":"22768","view_mode":"media_original","type":"media","attributes":{"height":512,"width":600,"style":"font-size: 13.008px; width: 180px; height: 154px; margin: 5px; float: left;","alt":" - m-miedema","class":"media-element file-media-original"}}]]

In the end, what may prove the most effective strategy for alleviating statin intolerance is open and honest communication between doctor and patient. As Virani with Baylor College of Medicine puts it: “Too often patients on statins don’t know why they’re taking them. It’s not just to lower their cholesterol, but to prevent the future risk of a heart attack or stroke. Once that risk–reward discussion has taken place with the patient, I think they’re much more likely to take their medicine.”