Statins: The Good, the Bad, and the Unknown

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Statins: The Good, the Bad, and the Unknown

Post by freckles1880 » October 15th, 2014, 5:19 pm ... c=168565HJ

Medscape Family Medicine

Statins: The Good, the Bad, and the Unknown
Clinicians Are Talking About Statins
Gordon H. Sun, MD, MS October 10, 2014

Talking About Statins and Drug-Lifestyle Interaction

In July, Medscape posted "Growing Doubt on Statin Drugs: The Problem of Drug-Lifestyle Interaction," a perspective by cardiac electrophysiologist Dr John Mandrola about the value of statin medications in primary prevention for cardiovascular disease (CVD). The driver for his article was a recent experience in which he treated a patient's myalgia and arthralgia bydiscontinuing her statin. Dr Mandrola had no qualms about stopping the statin, citing a lack of data supporting a significant benefit for these drugs in primary prevention.
The commentary generated more than 600 responses from Medscape readers, a substantial majority of whom agreed with his viewpoint. This is a particularly interesting observation in light of the American College of Cardiology (ACC)/American Heart Association (AHA) "Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults," published in November 2013, which eliminated treating to target lipid-level goals based on patient risk for CVD and instead identified four subgroups of patients for whom high-, moderate-, or low-intensity statin therapy would be recommended.

The stakes are high. Estimates of the number of US adults who would be newly eligible for statin use under the new guideline range from 12.8 million to 45 million. Put another way, about 1 in 3 American adults overall, and perhaps as many as 1 billion worldwide, would be potential candidates for statin treatment. In an editorial in the Journal of the American Medical Association (JAMA), Dr John Ioannidis estimated that the total sales of statins may approach $1 trillion worldwide by 2020; the most commercially successful drug in history, atorvastatin (Lipitor®), had sales exceeding $120 billion between 1996 and 2011.
Comments from our readers about this contentious issue clustered in four major themes.

Statin Use in Women, the Elderly, and People Without CVD

The 2013 ACC/AHA guideline and two subsequent meta-analyses concluded that statins, as primary prevention, reduce overall and CV-related mortality and CV events in people at low risk for CVD. In light of this, a substantial number of readers were concerned that the ACC/AHA guideline would lead to indiscriminate use of statins as primary prevention in populations that might not substantially benefit from them. Readers who commented on this focused on women and the elderly (generally those in their 70s-90s).
Is it true that "no study has shown any benefit in women," as a family physician commented on Medscape? There has been substantial debate over this issue. In a letter to the editor published inAmerican Family Physician in 2006, Michael Allen, MD, writing on behalf of the Canadian Academic Detailing Collaboration, noted that the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP-III) report published in 2002, until now the previous authoritative guideline on statin use as primary prevention, based their rationale for therapy in women on extrapolation of benefit in men. However, since then, other studies have shown a more conclusive benefit in women. In 2012, Kostis and colleagues published a meta-analysis of 18 randomized trials of 141,235 participants, 40,275 of whom were women, demonstrating a significant reduction in all-cause mortality and cardiovascular (CV) events in both men and women who were taking statins compared with those taking placebo or receiving usual care.

Another Medscape reader, a geriatrician, commented that he "did not find reliable data for the benefit of statin use in the elderly." As with women, recent research has shed new light on this growing population. A 2013 meta-analysis of eight randomized trials that included 24,674 patients aged 65 years or older without known CVD concluded that statins significantly reduced the risk for myocardial infarction and stroke compared with placebo. However, statins did not lower the risk for all-cause or CV-related mortality. A meta-analysis[11] of randomized trials and observational cohort studies involving 13,622 elderly participants, over a quarter of whom were 80 years old or older, found insufficient data to make any recommendation regarding statin treatment in this population.

The new ACC/AHA guidelines describe four subgroups of patients in whom the benefits of statins outweigh the risks:
• Patients with clinically evident atherosclerotic CVD (ASCVD);

• Patients with primary low-density lipoprotein (LDL) cholesterol levels of 190 mg/dL or higher;

• Patients with type 1 or type 2 diabetes and an LDL cholesterol level of 70 mg/dL or higher in patients aged 40-75 years; and

• Patients with a 10-year risk of ASCVD of 7.5% or higher and an LDL cholesterol level of 70 mg/dL or higher, also in patients aged 40-75 years.
In addition to changes in the LDL threshold
s used to determine eligibility for statin intervention, the new guideline changed the CV risk formula from the Framingham risk calculator used in the 2002 NCEP ATP-III report[12] to a newer algorithm incorporating community-based pooled cohorts and development of the initial hard ASCVD event (defined as first occurrence of nonfatal myocardial infarction, coronary heart disease death, or fatal or nonfatal stroke).

Most of the increase in the number of American adults theoretically eligible for statins under the new guideline would be observed among those without CVD—the fourth subgroup— or about 10.4 million new people.[4] To a lesser degree, the guidelines would potentially contribute to an increase in the number of eligible diabetic patients—the third subgroup—because the LDL threshold for statin eligibility was lowered from 100 to 70 mg/dL.

It is worth noting that the ACC/AHA guideline, like its predecessor, does acknowledge the limited data available in the elderly, specifically those older than 75 years old:
Few data were available for individuals >75 years of age. Additionally, in individuals 40 to 75 years of age with < 5% estimated 10-year ASCVD risk, the net benefit from statin therapy over a 10-year period may be small.

The guideline continues by stating that in patients in whom risk-based treatment decisions are uncertain despite quantitative risk assessment, shared decision-making is critical. As Dr Neil Stone, lead author of the new ACC/AHA guideline, told Medscape in an interview published on August 27, 2014, the discussion of CV risk is a four-step process that includes determination of a risk factor profile, discussion of optimal lifestyle choices, examination of benefits and risks associated with statins, and finally an "informed patient preference."

Statin-Related Myopathy

Harms from taking statins were a major concern of Medscape readers, and commenters reported numerous anecdotal experiences with potentially statin-related side effects, ranging from decreased cognitive ability and fatigue to diabetes and liver and kidney damage. However, the vast majority described myalgia and rhabdomyolysis thought to be related to statin use. Of note, the 2014 Statin Intolerance Panel also suggested that "[m]ost statin intolerance is related to myalgia." Below is a sampling of comments from across the spectrum of familiarity with statins:

• From a clinician treating patients with statins: "In my almost 18 years of prescribing statins, most of the muscle and joint pain complaints come from the elderly patients, both males and females."

• From a general practitioner with a relative on a statin: "My elderly father: in his late 80s with a significant dementia: was on a statin [...] He began to develop troublesome leg pains: had DVT [deep vein thrombosis] scans (negative); but they persisted. I suggested to his family physician stopping his statin for which there was no clear indication. His leg pains have gone. More interestingly: he can once again write his signature; remember what he used to do for a living; and in a fractured way remember some events from earlier in the day or yesterday."

• From a family medicine physician personally taking a statin: "80 years old, HDL 10 [high density lipoprotein level 10 mg/dL]. Was bullied into statins – lasted 1 week. Main gainers [are the] drug companies."
The actual rate of statin-related myopathy has been debated at length. This is likely owing in part to variability in the clinical definition of myopathy and how it is reported in peer-reviewed literature.[15]Clinical reviews[16,17] of observational cohort studies report the incidence of statin-related myopathy at 0.44 to 5.34 per 10,000 person-years and the incidence of fatal rhabdomyolysis at 0.15 deaths per 1 million prescriptions.
Of interest, complaints of myalgia are more common in observational cohorts (11%-29%) than in randomized clinical trials (1%-5%).[15] The substantially lower rate seen in clinical trials of statin use probably reflects specific exclusion of patients with musculoskeletal complaints prior to randomization; thus, clinical trial results are unlikely to accurately characterize the prevalence of myopathy, Among observational studies, in the Prediction of Muscular Risk in Observational Conditions (PRIMO) project, a cohort of 7924 unselected hyperlipidemic patients received high-dose statin therapy in ambulatory settings in France, and 10.5% of patients reported muscular symptoms, with a median time to onset of 1 month after statin initiation. Understanding Statin Use in America and Gaps in Patient Education (USAGE), an Internet-based survey of 10,138 current and former statin users, found that 29% of survey respondents reported a muscle-related side effect while taking a statin; while 25% of current users reported muscle-related side effects, 60% of former users reported that they had experienced this side effect. Given that randomized trials are often insufficiently powered to detect adverse events, some scientists have stated that real-world observational data are needed to truly appreciate the potential for adverse outcomes related to statin use. A recent meta-analysis of 90 observational cohort and case-control studies, which identified an increased risk for myopathy among statin users relative to controls (odds ratio, 2.63; 95% confidence interval, 1.50-4.61), illustrates how such data can better inform the public about the quantitative impact of adverse events potentially related to statin use.

The "Statin-Lifestyle Interaction"

The benefits of lifestyle modifications to prevent CVD are well known, and several Cochrane reviews have demonstrated the value of dietary advice and increased consumption of fruits and vegetables for primary prevention. The ACC/AHA guideline authors explicitly state that "a healthy lifestyle is the foundation for cardiovascular health." Moreover, no randomized trial has compared statins with beneficial lifestyle changes and found that statins had a superior or additive effect on clinical outcomes.[24] A 2003 randomized trial comparing the effects of a cholesterol-lowering diet with lovastatin (Mevacor®, Altoprev®) on serum lipid profiles found that both interventions were equally effective in reducing cholesterol.
That being said, Dr Mandrola worried that any benefit of statin use might be attenuated by the impact of an unhealthy lifestyle, a concern echoed by many Medscape readers. Typical responses included one by a dietitian, who remarked, "I see so many patients who think taking a statin is an insurance policy against disease, and this gives them license to not make any lifestyle changes." Another physician wondered how long lifestyle modification should be attempted, asking whether doctors should "have exercise equipment in their offices and a nutritionist on site instead of a statin and prescription pad."
The evidence on whether patients taking statins adhere to healthier lifestyles is conflicting. Population-based studies indicate that patients initiating statins were more likely to receive other preventive services (eg, influenza vaccinations) and participate in health-promoting behaviors compared with non-users. However, another population-based study, this one conducted in central Denmark, found that the average current statin user was more likely to have a healthy diet but also less likely to exercise regularly and to have never smoked compared with non-users.

To that end, one of Dr Mandrola's cited references warrants further explanation. Lee and colleagues published a multicenter community-based prospective cohort study of 5995 elderly men participating in the Osteoporotic Fractures in Men Study. The study found that after controlling for medical history and other potential confounders, statin use was associated with modestly lower physical activity. The study authors speculated that statin- or exercise-related myopathy, or general muscular fatigue, were possible explanations. This brings up another unique point: A statin user may be less inclined toward physical activity not because of lack of patient (or provider) motivation but because the patient's ability to exercise might be compromised by statin-induced muscle damage.

Personal Beliefs Regarding Statins
One physician astutely observed that "what is most remarkable here [at Medscape] is that so few physicians have commented favorably on the use of statins." The reader then postulated that the overwhelming number of comments against broad use of statins as primary prevention of CVD perhaps reflected a biased sample.

This is certainly a reasonable possibility. The international From the Heart study interviewed 750 physicians from Europe, Asia, and Central America, examining opinions about the relative importance of causes and treatments for high cholesterol in 2007 (before the ACC/AHA guideline). This survey found that 56% of physicians prescribed statins with or without lifestyle changes as first-line therapy for dyslipidemia, compared with 43% who prescribed lifestyle changes alone. Most physicians also reported that they believed that lifestyle changes were ineffective alone, difficult to maintain over a long period of time, and patients would become discouraged if they saw no improvements with diet and exercise regimens. This philosophy was reflected in another Medscape reader comment that "many docs use statins as first choice as many patients are noncompliant when it comes to diet, etc."
However, several other studies have suggested that both providers and patients may be more in favor of lifestyle modification over statins in prevention of CVD. Vamvakopoulos and colleagues published a three-part survey conducted during February-May 2005 of 99 general practitioners, 79 pharmacists, and 121 potential consumers in the United Kingdom on issues related to the over-the-counter availability of simvastatin (Zocor®) 10 mg. All three groups of participants reported that improving lifestyle habits such as smoking cessation, proper diet, and regular exercise were more effective than statins in preventing CVD (pharmacists 54.4%, physicians 72.6%, and consumers 95.0%).

A 2010 survey of 98 Kaiser Permanente Southern California members examined reasons for nonadherence to prescribed statin therapy. Among 73 people who did not fill the prescription at any pharmacy, the most commonly cited reasons included general concerns about taking the medication (63.0%), a decision to attempt lifestyle modifications (63.0%), and fear of side effects (53.4%).

JAMA has been no stranger to the statin debate. In fact, the "Dueling Viewpoints" section of JAMA, intended to encourage a vigorous discussion of controversial medical topics, used the question of whether a healthy middle-aged man with elevated cholesterol should begin statin therapy as its inaugural topic.[33-35] Since the publication of the ACC/AHA guideline, the New England Journal of Medicine (NEJM)[36] weighed in on the statin controversy with an interactive clinical vignette of a 52-year-old white man with an estimated 10-year ASCVD risk of 10.9%. The journal subsequently published the results from the responses of 1641 readers from 97 countries who weighed in on the issue.[37] Most NEJM respondents (57%) favored no initiation of statin therapy; 50% of respondents in the United States and Puerto Rico chose not to start statin therapy compared with 60% of respondents in other countries. The poll results showed that most respondents were strongly in favor of lifestyle modifications, particularly smoking cessation (the patient in the case vignette was a smoker). Many respondents expressed concerns about statin-related side effects, whereas others discussed the importance of shared decision making. The minority of NEJM respondents who recommended starting statin treatment believed that lifestyle modifications were desirable in theory but difficult to achieve in practice.

These themes were echoed in comments made by Medscape readers. Lifestyle modifications were commonly suggested as first-line therapies, although several readers also mentioned use of niacin and omega-3 fatty acid supplements. The ACC/AHA guidelines discuss safety precautions and contraindications associated with the use of these compounds, but the guidelines otherwise provide little direction in terms of populations who potentially might benefit from these therapies. Of note, the United Kingdom's National Institute for Health and Care Excellence (NICE) clinical guideline 181,[38] released in July 2014, states that niacin or omega-3 supplements should not be offered to patients being treated for primary prevention of CVD. Clinicians also warned against becoming "[statin] prescription pad scientists," urged avoidance of "cookie cutter medicine," and expressed concerns about colleagues treating "numbers" and not people. Ultimately, regardless of whether the Medscape and NEJM respondents supported or opposed statins as primary preventive therapy, all believed that a detailed discussion with the patient was the most appropriate decision.

In summary, several important issues were broached in comments by Medscape readers, reflecting the notable controversy generated by the latest ACC/AHA guidelines, nearly a year after publication:

• Up-to-date meta-analyses of statin use as primary prevention in women and the elderly have provided further evidence of their usefulness in these populations, although some of the literature was inconclusive and many Medscape readers remain skeptical.

• Myopathy potentially related to statin use was the most commonly reported adverse event by Medscape readers.

• Medscape readers were concerned that the guidelines did not sufficiently emphasize the benefits of positive lifestyle habits on prevention of CVD. A randomized trial comparing statins with beneficial lifestyle changes and examining clinical outcomes has yet to be conducted.

• Studies contrasting statin use and healthy lifestyle adherence—the "statin-lifestyle interaction"—demonstrate conflicting results. Recent research hypothesized that statin-related myopathy might actually compromise the ability to exercise, thus complicating patients' ability to adhere to good lifestyle habits.
It would be fair to say that this debate is far from settled.

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