In its first scientific statement specifically aimed at reviewing statin harms, the American Heart Association (AHA) concludes that the benefits of these commonly used drugs greatly outweigh the risks.
"With the exception of extreme smaöö risks for hemorrhagic stroke in special cases and the possible exception of newly diagnosed diabetes mellitus and some cases of autoimmune necrotizing myositis, statin adverse effects can almost always be reversed by stopping treatment. In contrast, an MI or ischemic stroke permanently damages an individual's heart or brain and can be fatal," the committee said.
"Thus, in the patient population in whom statins are recommended by current guidelines, the benefit of reducing cardiovascular risk with statin therapy far outweighs any safety concerns."
One in four Americans older than 40 years of age are taking statins, and about 10% will discontinue statin therapy because of adverse-effect symptoms or concerns, according to the report, published online December 10 in Arteriosclerosis, Thrombosis, and Vascular Biology.
"This is one of those things that is very high on people's minds, probably because so many people are on these medications," said Larry B. Goldstein, MD, a neurologist at the University of Kentucky, Lexington, and a coauthor of the scientific statement. "It's a big deal and despite all of the studies that have been done, these issues are still out there."
On the highly controversial issue of muscle symptoms, the report states that "there is little if any difference (at most 1%) in the incidence of muscle symptoms between the statin and placebo" in double-blind randomized controlled trials (RCTs) in a broad array of patients.
It puts the risk for statin-induced myopathy, including rhabdomyolysis, at less than 0.1% of patients at maximal recommended doses. Myopathy is defined as unexplained muscle pain or weakness accompanied by increases in creatinekinase (CK) above 10 times the upper limit of normal (ULN).
"There is increasing appreciation of the role of patient expectations of harm as the cause of muscle and other symptoms in statin-treated patients," say the authors, who suggest these expectations are generated from clinician warnings about the risk for rhabdomyolysis and negative media coverage.
Commenting on the report, Professor Jane Armitage, FRCP, professor of clinical trials and epidemiology at Oxford University, United Kingdom, said, "It would be wonderful if it caused a positive upswing in people taking up statins, but I think that's unlikely. But at least it means when there is bad press coming out about statins, there's somewhere where people can go to read an authoritative, balanced account of what the data show."
Armitage, who served as a reviewer of the 44-page document, said the committee was very fair in its assessment of the evidence and included randomized and high-quality observational data.
She added, "I think the real strength of the document is that it absolutely focuses on the randomized evidence, but I think that will be cause for comment."
Armitage coauthored a 2016 meta-analysis that found a similar risk for muscle symptoms without significant CK elevations over 5 years using published data from RCTs supplemented with unpublished data from industry-sponsored statin trials. The analysis drew sharp criticisms of bias and ignited calls for disclosure of the unpublished patient-level data, held by the Cholesterol Treatment Trialists' (CTT) Collaboration.
"If you look at the trials, they do very little collection of adverse-event data; what they concentrate on is CPK rises, but most people who have muscle problems from statins don't have CPK rises, so that's not a very useful number to give," she said. "What we really need is the number of people who have actual muscle problems, which in observational data has been estimated to be 20% to 30%."
Provisional analyses will be out "as soon as possible" from the CTT, which recently published a protocol for analyses of pooled patient-level adverse events from statin RCTs, but she would not elaborate on the timing. Release of the raw data has been promised for years, observed Redberg.
Paul Thompson, MD, chief of cardiology, Hartford Hospital, and professor of medicine, University of Connecticut, said the limitation of any scientific statement is that it relies on the available evidence and that long-term follow-up is lacking.
"For example, the diabetes issue is a real side effect of statins, but it's a very low frequency, primary shown from the JUPITER trial, which was a study that only went for about 2 years," he said. "So what happens with those people who don't get treated for 2 years, but get treated for 10 and 20 years? There are a lot of things that we don't know and those limitations are present in a statement like this."
The risk for statin-induced newly diagnosed diabetes is about 0.2% per year, the AHA statement concludes, but it notes that the estimate depends on the underlying risk for diabetes in the population studied and will be greater in patients with prediabetes or clinical characteristics, such as metabolic syndrome.
The risk for statin-induced severe liver toxicity is about 0.001%, whereas dose-dependent asymptomatic elevations in transaminases above three times the ULN are more common, occurring in about one in 100 people in clinical trials. The report notes these are usually transient and typically not associated with signs or symptoms of liver disease.
Thompson said a scientific statement on statin safety is needed because many people are concerned that patients who could benefit from statins are not taking or staying on these lifesaving drugs.
Beyond Muscle Symptoms
Although the reviewers found no increased risk for hemorrhagic stroke with statin use in primary prevention patients, interpretation of data from secondary stroke prevention studies suggests an increased risk. However, "the absolute risk is very small, and the benefit in reducing overall stroke and other vascular events outweighs that risk."
There was no convincing evidence for a causal relation between statins and peripheral neuropathy, cognitive dysfunction, sleep disturbances, Alzheimer's disease, Parkinson's disease, cancer, cataracts, tendonitis, or tendon rupture.
Although statin-related muscle symptoms might garner most of the attention, Goldstein said he expects pushback on the document's stance on statins and cognitive function. The US Food and Drug Administration issued a warning in 2012 that statins might be associated with memory loss or confusion, although a subsequent review found no link between statins and cognitive decline.
Interactions, Patient Populations
The new scientific statement includes a chart on principal drug interactions that increase the risk for myopathy, usually through higher plasma concentrations of statin or active metabolites.
"The only established case in which statins affect the action of another drug is warfarin (and potentially other vitamin K antagonists), via an unknown mechanism," it says.
On the basis of randomized cardiovascular outcomes trials in patients 65 years and older treated with statins for about 3 to 5 years, the reviewers conclude there is no evidence that statins are unsafe in older patients, but caution that the risk for myopathy/rhabdomyolysis, although rare, could be about twice that in younger patients.
Because of multiple comorbidities and concomitant medications in older patients, "clinicians must carefully evaluate benefit versus risk of statin therapy, including the potential for drug interactions, priorities of care, and patient preferences," they state.
Nevertheless, he said, they performed an exhaustive review of all the available data, "such as it is," and discuss the relative issues with each particular data source.
Goldstein said that during the creation of the report, he was unaware that the AHA/American College of Cardiology (ACC) was simultaneously preparing its new lipid guidelines, but that the two documents are complementary.
"This needs to be taken into context with formal guideline recommendations, such as the recently published AHA/ACC guidelines for lipid management, which also consider risk and benefit," he said. "This is almost like an adjunct."
Arterioscler Thromb Vasc Biol. Published online December 10, 2018. Article
One in 4 Americans >40 years of age takes a statin to reduce the risk of myocardial infarction, ischemic stroke, and other complications of atherosclerotic disease. The most effective statins produce a mean reduction in low-density lipoprotein cholesterol of 55% to 60% at the maximum dosage, and 6 of the 7 marketed statins are available in generic form, which makes them affordable for most patients.
Primarily using data from randomized controlled trials, supplemented with observational data where necessary, this scientific statement provides a comprehensive review of statin safety and tolerability. The review covers the general patient population, as well as demographic subgroups, including the elderly, children, pregnant women, East Asians, and patients with specific conditions such as chronic disease of the kidney and liver, human immunodeficiency viral infection, and organ transplants. The risk of statin-induced serious muscle injury, including rhabdomyolysis, is <0.1%, and the risk of serious hepatotoxicity is ≈0.001%. The risk of statin-induced newly diagnosed diabetes mellitus is ≈0.2% per year of treatment, depending on the underlying risk of diabetes mellitus in the population studied.
In patients with cerebrovascular disease, statins possibly increase the risk of hemorrhagic stroke; however, they clearly produce a greater reduction in the risk of atherothrombotic stroke and thus total stroke, as well as other cardiovascular events. There is no convincing evidence for a causal relationship between statins and cancer, cataracts, cognitive dysfunction, peripheral neuropathy, erectile dysfunction, or tendonitis. In US clinical practices, roughly 10% of patients stop taking a statin because of subjective complaints, most commonly muscle symptoms without raised creatine kinase. In contrast, in randomized clinical trials, the difference in the incidence of muscle symptoms without significantly raised creatinine kinase in statin-treated compared with placebo-treated participants is <1%, and it is even smaller (0.1%) for patients who discontinued treatment because of such muscle symptoms. This suggests that muscle symptoms are usually not caused by pharmacological effects of the statin. Restarting statin therapy in these patients can be challenging, but it is important, especially in patients at high risk of cardiovascular events, for whom prevention of these events is a priority.
Overall, in patients for whom statin treatment is recommended by current guidelines, the benefits greatly outweigh the risks.
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