Risk-Based Tops 'Trial-Based' Primary Statin Therapy in Study

Marlene Busko

January 13, 2016

AARHUS, DENMARK — The decision to prescribe statins for primary prevention of atherosclerotic cardiovascular disease (CVD) should be founded on the risk-based 2013 American College of Cardiology/ American Heart Association (ACC/AHA) cholesterol treatment guidelines rather than on a clinical-trial–based approach or a hybrid approach, concludes a study published in the December 22, 2015 issue of the Journal of the American College of Cardiology[1]. However, it is still not clear how best to identify patients who would benefit from statin therapy, and moreover, clinicians should not forget other risk factors, experts say.

Dr Martin B Mortensen (Aarhus University Hospital, Denmark) and colleagues looked at statin eligibility and 5-year CVD outcomes in close to 40,000 people in the Copenhagen General Population Study. "Our results indicate that the ACC/AHA guidelines will prevent more [atherosclerotic] CVD events than the trial-based and hybrid [statin-eligibility] approaches, while treating fewer people compared with the trial-based approach," they conclude.

But "as in every external validation study done to date, the ACC/AHA risk-prediction tool overestimated risk, so clinicians will continue to wonder why this discrepancy has yet to be resolved," Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA), a coauthor of the articles describing the trial-based and hybrid approaches, commented to heartwire from Medscape.

This approach only slightly overestimated risk in very high-risk individuals, the current study's senior coauthor, Dr Børge G Nordestgaard (Copenhagen University Hospital, Herlev, Denmark) countered. At the cut point (a 7.5% 10-year atherosclerotic CVD risk), "the ACC/AHA risk prediction tool worked fine in our population; overtreatment was more pronounced in the trial-based approach."

"Among the three options, the 2013 ACC/AHA guidelines approach seemed to be best for identifying subjects destined to have a future event," Dr Vera Bittner (University of Alabama at Birmingham) agrees in an accompanying editorial[2]. "However, is this approach necessarily best at identifying subjects at risk who will benefit from treatment?" she wonders. The study suggests that lipoprotein a [Lp(a)] levels might help identify the 8% of individuals who had an event despite being ineligible for statins, she noted.

Head-to-Head Comparison of Three Statin Strategies

Mortensen and colleagues performed a head-to-head comparison of three strategies to determine statin eligibility (to examine who would qualify and what hard outcomes would occur by 5 years) in 37,892 individuals (57% women) who were aged 40 to 75 years and free of atherosclerotic CVD, diabetes, or statin use when they enrolled in the Copenhagen General Population Study.

To be eligible for statin therapy, in the ACC/AHA risk-based approach, participants had to have a >7.5% 10-year risk of atherosclerotic CVD[3].

In the trial-based approach, participants had to meet entry criteria (including different levels of LDL, HDL, and total cholesterol) in one of five primary-prevention trials: the West of Scotland Coronary Prevention Study (WOSCOPS), the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA), the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) trial, and the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial[4].

In the hybrid approach, patients had to have a >7.5% 10-year risk of atherosclerotic CVD and lipid levels corresponding to those of trial patients who benefited from statins[5].

During 182,641 person-years of follow-up, 834 people developed atherosclerotic CVD, of which 323 had an MI.

Ridker pointed out that the current study uses a slightly different interpretation of the hybrid approach. Nordestgaard and colleagues recalculated this and noted that the results were similar and the conclusions were the same.

The study showed that 42% of subjects were eligible for statin therapy using the ACC/AHA risk-based approach; 56% qualified using the trial-based approach; and only 28% (revised from 21%) were eligible with the hybrid approach.

Furthermore, there were 9.8 atherosclerotic CVD events rate per 1000 person-years with the ACC/AHA risk-based approach, 6.8 such events with the trial-based approach, and 10 events (revised from 11.2) in the hybrid approach.

Compared with the ACC/AHA risk-based approach for statin eligibility, the net reclassification index was -0.21 for the trial-based approach and -0.09 (revised from -0.13) for the hybrid approach.

It was not unexpected that compared with the guidelines approach, more people would qualify for statins in the trial-based approach (which aims to find out what works and in whom), according to the authors. "The ACC/AHA guidelines aim to offer statins to those who will likely benefit the most, whereas enrollment criteria in [randomized controlled trials] are decided by many other criteria," they note. It is also not surprising that the hybrid approach, which selects only those with evidence of benefit from clinical trials, would find fewer patients who were eligible for primary prevention with statins.

Study limitations include that it looked only at white subjects and only had 5-year follow-up data. Nevertheless, "The hybrid approach substantially decreased the number of subjects eligible for statin therapy in the general population, but the balance between sensitivity and specificity still favored the ACC/AHA risk-based approach," Mortensen and colleagues conclude.

Control Other Risk Factors, Watch Lp(a) Levels

"Future research should be directed toward developing more accurate risk-prediction tools," a perspective accompanying the article notes.

In the meantime, Bittner notes that in clinical trials of lipid-lowering therapy, risk reductions are about 30%, so clinicians need to use a broader approach. "Atherosclerosis is a multifactorial disease and requires a multifactorial approach, with smoking cessation, dietary modification and weight management, regular physical activity, attention to psychosocial risk factors, and pharmacological therapy of lipid and nonlipid risk factors," she notes. "Comprehensive risk-factor control is associated with improved prognosis, and our challenge is to develop care models that will allow us to achieve such control."

In an audio commentary, JACC editor in chief Dr Valentin Fuster (Icahn School of Medicine at Mount Sinai, New York) summarizes: "This paper . . . is a good exercise for all of us to [contemplate] and perhaps not to disregard the 2013 ACC/AHA guidelines in part based on the risk calculator, which appears to be not so bad. In addition, let's begin to pay attention to Lp(a), since it may explain coronary artery disease events in patients who otherwise do not have a significant risk-factor profile."

The research was supported by Herlev and Gentofte Hospital, Copenhagen University Hospital, the Copenhagen County Foundation, and Aarhus University. The authors have no relevant financial relationships. Bittner has received research support from Amgen, AstraZeneca, Bayer Health-Care, Janssen, Pfizer, and Sanofi and has served on advisory panels for Amgen and Eli Lilly.

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