Counsel, Counsel, Counsel: EAS Stresses Statin's Benefit in Patients with Muscle Symptoms

March 25, 2015

GLASGOW, SCOTLAND — A European panel of experts has released a new consensus statement to advise physicians on how to deal with patients who develop muscle symptoms while taking statins, but they stress statins must continue to be tried in these difficult-to-manage patients[1].

"Let's start with the golden rule," said Dr Erik Stroes (Academic Medical Center, Amsterdam, the Netherlands). "Never stop using your statin."

Stroes, the lead author of the European Atherosclerosis Society (EAS) consensus statement, which was published this past February in the European Heart Journal, made the statement during a panel discussion here at EAS 2015: the European Atherosclerosis Society 2015 Congress. He said that if statins reduce the risk of major vascular events 20% with every 1-mmol/L (38.6 mg/mL) reduction in LDL cholesterol, that risk returns if the lipid-lowering drugs are stopped. He pointed to a recent paper showing that MI patients who stopped their statin had a four- to sevenfold increased risk of cardiac death over a 4-year follow-up period.

"Stopping a statin is not just an important [decision], but pivotally important," said Stroes. "I can quote at least seven studies where discontinuing a statin has direct and imperative consequences."

So when we start talking about taking a patient off a statin, we're talking about doing them harm.

Dr Colin Baigent (University of Oxford, UK), who was not part of consensus panel but who provided an overview on the relative risks and benefits of statin therapy during the EAS meeting, was equally adamant about the risks of needlessly stopping statin therapy. Before abandoning a statin because of muscle symptoms, physicians need to be absolutely certain the muscle-related events are attributable to the drug.

"What we're talking about are a class of drugs that are extremely effective at reducing the risk of major vascular events, which are very often fatal," said Baigent. "So when we start talking about taking a patient off a statin, we're talking about doing them harm. We need to be very clear about this."

Based on data from randomized, controlled clinical trials, the rate of myopathy is 0.5 events per 1000 patients over a 5-year period, said Baigent. The risk of rhabdomyolysis is even lower, with data suggesting an event rate of 0.1 events per 1000 patients over a 5-year period. That said, some of these trials excluded patients during the run-in phase if symptoms were detected, while other trials did not document such cases as well as they could have with detailed questionnaires.

In observational studies, though, the rate of muscle-related side effects can be as high as 18% with simvastatin and 14% with atorvastatin, noted Stroes. In the STOMP trial, which was reported by heartwire from Medscape, there was an increase in creatine kinase (CK) levels and muscle pain with high-dose atorvastatin, with 19 patients diagnosed with myalgia with statin therapy vs 10 in the control arm (P=0.05).

The Role of the Media

Speaking at the EAS Congress, Stroes said that when experts began preparing the consensus statement, a number of the contributors blamed the media for sensational headlines trumpeting a risk with statins. He said some believed the media were responsible for blowing the potential side effects out of proportion, which in turn led to patients needlessly stopping the drugs.

For Baigent, he too found fault with the media, but also with research universities or institutions that trumpet data from observational studies where data "have been tortured until they confess." He said observational studies highlighting risks with statins have sowed confusion among patients taking the drugs. Last year, in a survey by the British Cardiovascular Society, 60% of cardiologists reported that at least one of their patients stopped a cardiac medication because of concerns they read in the media. Approximately one-third of cardiologists had five or more of their patients stop cardiac medications because of such concerns.

"But I think it's a little bit more complicated than this," said Stroes in reference to the media's culpability. "If you actually take a look at the literature, there are some good journalists. There are a lot of positive stories about statin use. Obviously, there are negative stories, but there's also some good literature around."

The Consensus Statement

One of their first tasks with the consensus statement was to develop a definition for statin-associated muscle symptoms (SAMS). The definition of SAMS are classified by symptoms and elevations in CK.

According to the EAS, myalgia, which has normal CK levels or minor increases, might be related to statin therapy, but cause and effect is not definite. Moderate elevations in CK with muscle symptoms are frequently due to physical exercise but might also be attributable to the statin. Rhabdomyolysis is defined as the presence of muscle symptoms, CK levels 40 times the upper limit of normal, underlying renal impairment, and/or myoglobinuria.

If a patient is identified with SAMS, Stroes said the first task is to rechallenge the patient with another statin at usual dose after stopping the first drug for 2 to 4 weeks. He noted one Cleveland Clinic study showed that more than 70% of patients who stopped their statin because of side effects could be successfully restarted with a different statin. A Boston-based study showed that 92% of patients who stopped their statin were successfully rechallenged with statin therapy and were still taking the drug 12 months later.

Baigent also noted that in a recent study of "statin-intolerant" patients in the ODYSSEY ALTERNATIVE trial with alirocumab (Sanofi/Regeneron Pharmaceuticals), a study that included a low-dose atorvastatin arm as a comparator, more than 75% of patients were able to tolerate atorvastatin 20 mg.

These results imply that such "intolerance" is not a true pharmacologic reaction "but due to other factors," said Stroes.

Try and Try Again

In their treatment algorithm, if the rechallenged patient is still unable to tolerate a statin, Stroes said physicians should try again, aiming for a lower dose with an particularly potent statin such as atorvastatin or rosuvastatin (Crestor, AstraZeneca) or advising the patient to take a statin every other day or twice weekly. If still unsuccessful, the remaining step might involve trying again with the highest maximally tolerated dose of statin and then adding additional lipid-lowering agents, specifically ezetimibe (Zetia, Merck/Schering-Plough), to reduce LDL-cholesterol levels to goal.

If there is still no success with the statin, the physician can consider fibrates, but not gemfibrozil, or bile-acid sequestrants, as add-ons to ezetimibe.

"We need to counsel, counsel, and counsel for statins and to emphasize there is a strong cardiovascular benefit," he said. "We need to explain the long-term safety of statins and explain to them that if they have muscle aches, it doesn't mean they have myonecrosis and it doesn't mean they fall into the high-risk category they read in the package insert."

Additional tasks for the physician include checking for potential drug-drug interactions, such as with antibiotic or antifungal medications. Physicians should never prescribe supplements to help reduce the muscle pain, said Stroes. He said there is no evidence to support the use of vitamin D or coenzyme Q10.

We need to explain to them that if they have muscle aches, it doesn't mean they have myonecrosis.

For Baigent, he said the Clinical Trialists Collaboration (CTT) was designed to initially examine vascular events, mortality, and cancer, but they are planning to return to each individual trial within the CTT to obtain patient-level data on all adverse events, including SAMS. They hope to publish these data later this year.

"The known hazards of statins, and I do mean known hazards, are far outweighed by the known benefits, even in low-risk patients but certainly in high-risk patients," said Baigent. "Statin intolerance is mostly not related to statins, and we need to be careful we're not creating a category of patients just by sloppy thinking."

This EAS statement was supported by unrestricted educational grants from Amgen, AstraZeneca, Eli Lilly, Esperion, Merck, Pfizer, and Sanofi-Regeneron. Stroes has previously reported receiving research grant support from Sanofi, Merck, and Novartis. Disclosures for the coauthors are listed in the article. Baigent, who was not part of the EAS writing committee for statin intolerance, reports research grants to his institution for trials in which he is the principal investigator from Novartis, Pfizer, and Merck but accepts no personal money from pharmaceutical companies.


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