Taken together, the studies hint at the need for risk calculators—or at least risk reduction strategies—to be better applied at the population level and potentially tailored to different groups.
The 2012 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines recommended statin therapy based on LDL cholesterol levels in combination with a risk-estimate tool to predict 10-year risk of CVD mortality for adults aged 40 to 65. By contrast, the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines abandoned specific cholesterol levels and instead recommend statin therapy for all adults aged 40 to 75 who have a 10-year risk of atherosclerotic CVD amounting to 7.5% or more. While both sets of guidelines recommend statin therapy to adults with existing atherosclerotic CVD, diabetes, and possible familial hyperlipidemia, the European guidelines also single out adults with severe hypertension and chronic kidney disease as candidates for treatment.
Polish and American Cohorts Analyzed
In one of the two studies, Jerry C. Lee, MS, MPhil (Duke University Medical Center, Durham, NC), and colleagues examined the population effect of the two sets of guidelines in two nationally representative samples: the 3,136 US adults in the 2007-2012 National Health and Nutrition Examination Survey (NHANES) and 1,060 adults in similar Polish survey called NATPOL. In both cohorts, the adults studied were aged 40 to 65.
In the analysis that applied the US guidelines to the US sample, 43.8% of the NHANES cohort could be recommended for statin therapy, a number that dipped to 39.1% if the ESC/EAS guidelines were applied. In the Polish cohort, however, the US guidelines would lead to statin therapy in 49.9% of patients, compared with 47.6% under the ESC/EAS guidelines. That means that roughly one in 10 subjects with no cardiovascular disease in both countries would have been eligible for statin therapy according to one set of guidelines but not the other. Those differences were driven largely by patients with chronic kidney disease (more likely to be recommended under the European guidelines) and by patients with lower HDL cholesterol or with a higher predicted risk of cardiovascular disease within 10 years (more likely to be recommended for therapy in the US guidelines).
“Although the guidelines appear somewhat different in their approach, when you look at who gets recommended or not recommended for statins under each guideline, in general those guidelines lead to remarkably concordant conclusions for the vast majority of adults,” senior author Ann Marie Navar, MD (Duke Clinical Research Institute, Durham, NC), told TCTMD. “There is some discordance between the two guidelines, but for the most part the guidelines actually agree. . . . When we look under the hood of the guidelines, there is potentially a lot more overlap than maybe the controversy would suggest. No guideline is going to get it 100% right, so we may be able to learn from the discordance analysis who we might be overlooking.”
Guidelines Applied to Rotterdam Study
In the second study, Jelena Pavlović, MD (Erasmus Medical Center, Rotterdam, the Netherlands), and colleagues applied criteria from both the US and European guidelines to 7,279 participants in the Rotterdam Study between the ages of 45 and 75 years. They also looked at how many of these community-based subjects would have been eligible for one of the 10 major randomized controlled trials for primary CVD prevention—the studies that form the backbone of the lipid-lowering guidelines.
The investigators found that 4,284 subjects, or 58.9%, would have been eligible for statin therapy based on the ACC/AHA guidelines. That’s considerably more than the 2,399 participants eligible (33%) according to the ESC/EAS guidelines. A full 95.8% of subjects eligible for statin therapy in the European guidelines would also have been identified by the American guidelines. In all, 53% of subjects in the Rotterdam study would have been eligible for enrollment in at least one of the primary prevention trials.
Of note, just one in five subjects met the recommendations for statin therapy according to both sets of guidelines and clinical trial criteria. An additional 23.4% of participants would have been eligible for a statin according to the guidelines but were not candidates according to the clinical trial enrollment criteria. Almost an identical number would not be eligible for treatment by either set of guidelines or the pivotal trials.
Speaking with TCTMD, senior author Maarten Leening, MD, PhD (Erasmus Medical Center), acknowledged that one of the criticisms of the ACC/AHA guidelines has been that it is not “evidence-based”—the patients recommended for therapy aren’t necessarily the same ones that were studied in the randomized trials. “That was the starting point for us to say, let’s look at how these trial criteria overlap with the recommendations from the guidelines,” he explained. “And then we used the Rotterdam study data just to see how many people would be recommended for treatment based on the US or European guidelines.”
Leening believes this led to one of the analysis’ most important findings.
“One of the things that surprised us the most was that more than half of the general population free of cardiovascular disease would have been eligible to participate in one of the statin versus placebo trials with hard cardiovascular endpoints—basically indicating that in more than half of the population of middle-aged to older-aged adults, there is actually hard randomized clinical trial evidence that statins are beneficial.”
Leening also points to the roughly one in five subjects in whom the benefits of statins appear indisputable. “It’s 21.2% of the population where both sets of guidelines as well as the trial evidence converges—which indicates that in one-fifth of the general population on both sides of the Atlantic, people should be treated, and in each and every individual, there is randomized controlled trial evidence to support this.” There has been a lot of debate about which primary prevention tool should be applied, but in these high-risk patients, he continued, “there should be no discussion on people where the guidelines and trial evidence converge.”
Of note, the Navar paper found a high degree of agreement between the proportion of patients eligible for treatment between the two guidance documents in both the US and Poland, whereas the difference was much larger between the two guidelines when applied to the Rotterdam participants in the Leening paper. Navar speculated that this might be due to the different age windows studied or, potentially, to the fact that the general Polish population may have a higher burden of risk factors than participants in the Netherlands and thus be more similar to US subjects. This possibility opens the door to the question of whether risk prediction tools need to be tailored for different populations.
For her part, Navar notes that this is something already being considered in Europe and might be worth considering in the United States, where certain risk factors may be more prevalent than others in specific subpopulations. In fact, the newest European cardiovascular disease prevention guidelines, released in May, put new emphasis on factors unique to specific groups, including women and minorities. Leening, meanwhile, noted that statin benefits have been shown to work across different risk factor profiles—in both obese and normal weight subjects, in smokers and nonsmokers, and so on. Thus, while the guidance itself can be standardized, he said, it may be that the emphasis of different population-based efforts for reducing risk factors should be tailored to different regions or groups.
Both Navar and Leening agree, however, that the key point of both papers is the large proportion of older adults who could benefit from treatment. “Rather than focusing on the differences in the guidelines, it’s probably more important to focus on the number of adults in both countries who are recommended for therapy under both guidelines but aren’t on treatment,” Navar said. “There’s a big gap in recommendations and implementation of treatment, and it’s not driven by differences between the two guidelines. It’s undertreatment across the board.”
Treatment Gaps and the Art of Medicine
Both studies point to treatment gaps—patients identified as at-risk by one guideline but not another, or who were deemed eligible for inclusion in one of the pivotal trials analyzed in the Leening paper but weren’t covered in either set of guidelines—more than 16% in the Leening paper. Leening believes many of these patients are likely younger and female, who have some risk factors but whose risk-prediction scores may have not met the threshold for treatment.
In interviews, both Navar and Leening spoke to the fact that guidelines can only offer guidance—outliers in their analyses, be they patients with chronic kidney disease, or younger women, allow physicians to use their judgement.
“In the end we cannot do trials in each and every subgroup of the general population,” Leening said. “There will always be people who would not have qualified for any of the trials we’ve done so far, or that are still ongoing. But even if we have evidence from these trials, there will always be individuals for whom we have never tested whether statins work. And does that mean statins don’t work? We don’t know.”
Navar agreed, noting: “Fortunately there is still some room for the art of medicine in this, where we can look at what trial data are available and then make reasonable extrapolations as to what might benefit without waiting for clinical trials to show each and every individual that would need to be treated.”
- Lee JC, Zdrojewski T, Pencina MJ, et al. Comparison of ACC/AHA and ESC guideline recommendations following trial evidence for statin use in primary prevention of cardiovascular disease: results from the population-based Rotterdam Study. JAMA Cardiol. 2016;Epub ahead of print.
- Pavlović J, Greenland P, Deckers JW, et al. Population effect of differences in cholesterol guidelines in Eastern Europe and the United States. JAMA Cardiol. 2016;Epub ahead of print.
- Lee reports support from an American Heart Association training grant. Other authors had no disclosures.
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