Debate Ensues As USPSTF Finalizes Statin Primary Prevention Guideline

–Broad disagreement about how, when, and if to use statins.

The U.S. Preventive Services Task Force (USPSTF) has issued final recommendations regarding the use of statins for primary prevention of cardiovascular disease in adults. The recommendations, first proposed last December, are broadly consistent with the 2013 American College of Cardiology/American Heart Association guidelines.

But accompanying the guideline, published in the Journal of the American Medical Association, came a slew of editorials and viewpoints, most expressing disagreements with many key details of the recommendation. No common theme emerged in the articles, suggesting that there is little consensus on how to implement or even think about primary prevention. Most— but not all— the experts expressed strong support for the concept of primary prevention with statins. but with different underlying philosophies and widely varying ideas about how it should best be implemented.

The Recommendations

The USPSTF gave a B recommendation— indicting high certainty that the benefit is moderate or moderate certainty that the benefit is moderate to substantial— for starting low- to moderate-dose statins in adults ages 40 to 75 years without a history of cardiovascular disease (CVD) who have one or more CVD risk factors and a 10-year CVD risk of 10% or greater.

The USPSTF dropped its level of endorsement to C for adults with a lower 1-year risk (7.5%-10%) and made no recommendations for adults 76 years of age and older, explaining that there was insufficient evidence for this age group.

“USPSTF should be commended for focusing on use of statins rather than particular targets – and the alignment of treatment with risk,” said Harlan Krumholz, MD, (Yale), an early advocate of the risk-based approach. “I don’t believe it is useful, however, to create risk thresholds for treatment since that should properly depend on an individual’s preferences – and cannot be derived directly from any trial.”

Like Goldilocks, the various experts found the USPSTF guideline either too cold (not aggressive enough), too hot (far too aggressive), or just about right.

The Porridge Is Too Cold (USPSTF Not Aggressive Enough)

Ann Marie Navar, MD, PhD, and Eric Peterson, MD, (both Duke University) pointed out logical inconsistencies and other weaknesses in the USPSTF and AHA/ACC guidelines, arguing for a more flexible and more aggressive primary prevention approach that will result in greater long term benefits.

In particular, they took aim at the central role of cardiovascular risk to guide treatment and they decried the diminishing role of cholesterol levels as a critical factor in both risk assessment and as a treatment guide. They cited examples of patients inappropriately treated or not treated based on the current guidelines. These patients, they argued, are representative of many real-world patients who would be better treated if cholesterol levels played a more central role.

They also questioned the use of a 10-year horizon for the assessment of risk. They noted that 10-year risk was not the basis for patient enrollment in any of the trials. More importantly, “for younger adults, a decade-wide time window ignores the pathobiology of atherosclerosis, a progressive lifetime process of cholesterol-rich plaque development in arteries that begins in the teenage years.”

Navar and Peterson agreed with the USPSTF that the evidence for older patients is insufficient. “There may be a point at which it is too late for statin therapy.” They called for trials to develop evidence in this important group.

By contrast, despite the absence of evidence, they argued in favor of statins in younger patients. “The absence of evidence does not equate to the evidence of absence, a failure to recommend treatment usually will result in a failure to treat. As an alternative, it may be reasonable to consider offering therapy to younger populations even before the benefits are fully confirmed.”

The Porridge Is Too Hot (USPSTF Too Aggressive)

The case against primary prevention was put forth by Rita Redberg, MD, (University of California San Francisco) and Mitchell Katz (Los Angeles Department of Health). They focused on the weak evidence base and the underappreciated role of side effects. They wrote that the benefits of statins are small at best. They put a spotlight on the small absolute benefit from the drugs, compared with the seemingly more impressive reduction in relative risk highlighted by primary prevention advocates.

Key to their case was that the USPSTF has likely underestimated the true risk of the drugs, since, they claimed, this data was not systematically or rigorously collected in the trials. They estimated that the rate of muscle pain may be as high as 20% in the real world. “Although reported rates of adverse events in clinical trials are low, this does not reflect the experience of clinicians who see patients who are taking statins,” they wrote.

The risk-benefit equation is particularly troublesome in people at lower risk. “Persons at low risk have little chance of benefit but equal chance of harms and thus are more likely to have a net harm,” they wrote. They cited a decision aid showing that for every 100 people who take a statin for 5 years, two will avoid an MI but 98 will derive no benefit, while five to 20 will experience side effects and “will have a take a pill every day.”

Further, they pointed out “there are unintended consequences of the widespread statin use in healthy persons. For example, people taking statins are more likely to become obese and more sedentary over time than nonstatin users, likely because these people mistakenly think they do not need to eat a healthy diet and exercise as they can just take a pill to give them the same benefit.”

Paul Thompson, MD, (Hartford Hospital) focused entirely on the problem of side effects in his viewpoint article. He agreed with Redberg and Katz that statin trials did not rigorously assess this issue. “How could the statin RCTs miss detecting mild statin-related muscle adverse effects such as myalgia?” he asked. His terse response: “By not asking.”

But he also concluded, after a careful review of the data, that the true incidence of side effects is likely far smaller than some have feared. But, it may be “a moot point, he argued. “If patients are convinced that the statins are responsible, it is difficult to convince them otherwise or to ignore their symptoms. So, how should these symptoms be managed?” The solution to managing these symptoms “is not evidence based but requires reassuring the patient, reassessing the need for statin therapy, determining if statins may be responsible for the symptoms, eliminating possible contributors to the process, and developing alternative treatment plans.”

The Porridge Is About Right

More supportive of the USPSTF guideline were Philip Greenland, MD, and Robert Bonow, MD, (both of Northwestern University). Although clinical trials have not established any definitive cutoff point or subgroup for benefit, they defended the risk-based approach, writing that “the likelihood that patients will benefit from statin treatment is directly associated with their absolute baseline risk of experiencing a CVD event.” The primary prevention guidelines “do not pertain to adults with very high CVD risk, such as those with familial hypercholesterolemia” or very high LDL levels, since these patients were excluded from primary prevention trials. However, these patients should of course be treated appropriately for their hyperlipidemia.

Greenland and Bonow also stated that there is no agreement on specific LDL targets or treatment initiation thresholds. Given the absence of data to guide these decisions, “disagreement is inevitable,” they wrote.


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