Abstract
Background
New American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines emphasize 10-year risk of cardiovascular disease (CVD) to identify adults eligible for statin therapy for primary prevention. Whether these CVD risk thresholds should be individualized by age and sex has not been explored.
Objectives
To determine the potential impact of incorporating age- and sex-specific CVD risk thresholds into current cholesterol guidelines.
Methods
Using data from the Framingham Offspring Study, we evaluated current treatment recommendations among age- and sex-specific groups in 3685 participants free of CVD. Then, we evaluated how varying age- and sex-specific 10-year CVD risk thresholds for statin treatment affect the sensitivity and specificity for incident 10-year CVD events.
Results
Basing statin therapy recommendations on a 10-year fixed risk threshold of 7.5% results in lower statin consideration among women than men (63% vs. 33% <0.0001), yet the vast majority of those aged 66–75 years were recommended for treatment (90.3%). The fixed 7.5% threshold also had relatively low sensitivity for capturing 10-year events in younger women and men (aged 40-55 years). Sensitivity of the recommendations were substantially improved when the treatment threshold was reduced to 5% in those aged 40-55 years (changing sensitivity from 36% to 61% in women, and 49% to 71% in men). Among older adults (aged 66– 75) specificity was poor (18% in women, 3% in men), but when the treatment threshold was raised to 10% in women and 15% in men, specificity significantly improved (to 34% in women, 14% in men), with only small to no loss in sensitivity (95% to 87% in women, and 96% at both thresholds in men).
Conclusions
Cholesterol treatment recommendations could be improved by utilizing individualized age- and sex-specific CVD risk thresholds.
Keywords: cholesterol treatment, cardiovascular disease, age-specific risk threshold, sex-specific threshold
The new American College of Cardiology/American Heart Association (ACC/AHA) blood cholesterol guidelines strongly recommend statin therapy consideration in adults with elevated 10-year risk of atherosclerotic cardiovascular disease (CVD), which is defined as a 7.5% or higher risk of experiencing a cardiovascular event over the next decade with an option to also treat those with a risk between 5% and 7.5%.
These new guidelines increase the number of adults in the United States recommended for statin therapy by nearly 13 million (1,2), with the majority of the increase being among older adults ≥60 years where statin therapy is now recommended in 80% or more of patients (3). The new guidelines base their primary prevention treatment recommendations on the 10-year predicted CVD risk model using the Pooled Cohort Equations. The thresholds for therapeutic consideration were selected based on three statin primary prevention trials: 1) the Primary Prevention of Cardiovascular Disease with Pravastatin in Japan (MEGA Study); 2) the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS); and 3) the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER). This selection of treatment thresholds has been a point of controversy (4). Ideally, one would want to treat a majority of those who will subsequently develop an event (high sensitivity), while avoiding unnecessary treatment among those not who will not develop a CVD event (high specificity). Yet to date, it is unclear whether the guideline-recommended thresholds achieve this goal among certain subgroups, such as younger and older adults, and women and men. Furthermore, it is possible that the performance of the guidelines could be improved if treatment thresholds were age- and sex-specific.
Using data on adults from the Framingham Offspring Study, we estimated the sensitivity and specificity of current ACC/AHA cholesterol treatment guidelines for identifying adults at risk for CVD. We also estimated the impact of varying the 10-year risk thresholds that are used to identify adults for statin therapy across age and sex groupings in order to determine how sensitivity and specificity may be impacted by using different risk thresholds.
Methods
Our study population included adults from the Framingham Offspring Study aged 40–75 who were free of CVD at exam 3 or 6. Baseline characteristics (at exam 3 or 6) including blood pressure, blood pressure treatment, diabetes status, smoking status, sex, and lipid levels were used to calculate a patient's estimated 10-year estimated risk based on the Pooled Cohort Equations. We excluded those adults with missing data for variables in the Pooled Cohort Equations (n=43). Statin treatment recommendations were based on the 2014 ACC/AHA cholesterol guidelines (5). The number and percentage of adults recommended for statin therapy was first calculated based on the 2014 ACC/AHA cholesterol guideline for all patients, and then by age-specific (40-55 years, 56-65 years, and >65 years) and sex-specific (women and men) subgroups.
Adults were followed prospectively for new onset CVD events over the subsequent 10 years, defined as a nonfatal myocardial infarction, coronary heart disease death, fatal or nonfatal stroke, peripheral arterial disease, or heart failure. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the guideline statin treatment recommendations were calculated based on a patient's predicted likelihood for subsequent CVD events, taking into account the time-to-event nature of the data (6). Analyses were stratified by age (40-55 years, 56–65 years, and 66–75 years) and sex. Next, we varied the treatment threshold for statin therapy from 3% to 20% and determined the effect these changes had on guideline performance characteristics (e.g., sensitivity, specificity, PPV, NPV).
Framingham participants provided written informed consent for participation. This analysis was approved by the Duke University Institutional Review Board. All analyses were performed using SAS software version 9.3 (SAS Institute, Inc., Cary, NC).
Results
Our study population included 3685 adults; the average age was 57.2 years. Table 1 shows the baseline characteristics of the study population at the “baseline” visit (nearest to age 55 years). Overall, 46.8% of adults met criteria for statin therapy based on the current guidelines 10-year risk threshold of 7.5%. Treatment recommendations varied substantially by age and sex. Among adults 40–55 years, 21.0% met criteria for statin therapy, compared with 55.2% of adults 56–65 years and 90.3% of adults 66–75 years. The 10-year CVD event rate also increased across age groups (12.5%, 17.5%, and 23.0%, respectively), but not as sharply as the rate at which statin therapy was recommended. In women, the 10-year CVD rate was 11% versus 22.6% in men.
Table 1. Characteristics of the Study Population.
| All Adults | Men | Women | Age 46-55 |
Age 56-65 |
Age 66-75 |
|
|---|---|---|---|---|---|---|
| n | 3685 | 1715 | 1970 | 1663 | 1280 | 742 |
| Age (IQR) | 57.2 | 57.2 | 57.3 | 49.2 | 60.4 | 69.6 |
| Male (%) | 46.5% | 46.5% | 47.3% | 45.3 | ||
| Hypertension (%) | 40.0% | 44.1% | 36.4% | 26.6% | 45.3% | 60.8 |
| SBP (mmHg) | 128.4 | 130.5 | 126.7 | 121.8 | 131.5 | 137.9 |
| DBP (mmHg) | 76.9 | 70.2 | 74.8 | 77.0 | 77.6 | 75.5 |
| BP treatment (%) | 24.4% | 26.1 | 22.9 | 14.9% | 28.0% | 39.4% |
| Non–HDL-C (mg/dL) | 159.2 | 161.4 | 157.2 | 156.0 | 162.3 | 161.1 |
| Total cholesterol (mg/dL) | 210.5 | 205.5 | 214.9 | 206.8 | 214.1 | 212.4 |
| LDL-C (mg/dL) | 131.7 | 132.5 | 130.9 | 129.6 | 133.6 | 132.9 |
| Cholesterol treatment (%) | 51.3 | 8.9% | 7.1% | 3.5% | 9.3% | 15.4% |
| Diabetes (%) | 7.9% | 10.5% | 7.3% | 5.6% | 9.9% | 13.9% |
| Smoking (%) | 8.8% | 19.0% | 18.8% | 24.7% | 16.5% | 10.0% |
| BMI (kg/m2) | 27.6 | 28.3 | 27.1 | 27.5 | 27.8 | 27.6 |
| 10-year CVD observed rate | 16.3% | 22.6% | 11.0% | 12.5% | 17.5% | 23.0% |
| Statin recommended* | 46.8% | 63.1% | 32.6% | 21.0% | 55.2% | 90.3% |
Statin recommended based on current guidelines
BMI = body mass index; BP = blood pressure; CVD = cardiovascular disease; DBP = diastolic blood pressure; HDL-C = high-density lipoprotein cholesterol; IQR = interquartile range; LDL-C = low-density lipoprotein cholesterol; SBP = systolic blood pressure
Table 2 and Table 3 display the proportion of women and men adults recommended for statin therapy, along with sensitivity, specificity, PPV, and NPV of the guidelines based on varying thresholds ranging from 3% to 20%, stratified by age group. Differences in sensitivity and specificity by age group in women and by age group in men are illustrated in Figures 1 and 2, respectively.
Table 2. Percent of Women Recommended for Statin Therapy and Guideline Performance Based on Varying Risk Cutoffs.
| 10-year Threshold |
% Meeting Treatment Threshold |
Sensitivity | Specificity | PPV | NPV | |||
|---|---|---|---|---|---|---|---|---|
| All ages | ||||||||
| 3% | 15 | 35 | 88 | 26 | 92 | |||
| 4% | 18 | 41 | 85 | 25 | 92 | |||
| 5% | 26 | 53 | 77 | 23 | 93 | |||
| 7.5% | 33 | 61 | 71 | 21 | 94 | |||
| 10% | 43 | 72 | 60 | 18 | 94 | |||
| 15% | 49 | 78 | 54 | 17 | 95 | |||
| 20% | 57 | 85 | 47 | 16 | 96 | |||
| Age 40-55 | ||||||||
| 3% | 9 | 23 | 92 | 18 | 94 | |||
| 4% | 9 | 23 | 92 | 18 | 94 | |||
| 5% | 10 | 27 | 91 | 19 | 94 | |||
| 7.5% | 12 | 36 | 90 | 23 | 95 | |||
| 10% | 25 | 61 | 78 | 18 | 96 | |||
| 15% | 25 | 61 | 78 | 18 | 96 | |||
| 20% | 25 | 61 | 77.9 | 18 | 96 | |||
| Age 56-65 | ||||||||
| 3% | 15 | 31 | 88 | 24 | 91 | |||
| 4% | 15 | 31 | 87 | 23 | 91 | |||
| 5% | 20 | 41 | 82 | 23 | 92 | |||
| 7.5% | 29 | 49 | 73 | 19 | 92 | |||
| 10% | 47 | 65 | 55 | 16 | 92 | |||
| 15% | 59 | 78 | 43 | 15 | 94 | |||
| 20% | 74 | 91 | 29 | 14 | 96 | |||
| Age 66-75 | ||||||||
| 3% | 27 | 47 | 77 | 32 | 87 | |||
| 4% | 43 | 67 | 63 | 29 | 89 | |||
| 5% | 70 | 87 | 34 | 23 | 92 | |||
| 7.5% | 85 | 95 | 18 | 21 | 93 | |||
| 10% | 98 | 99 | 3 | 19 | 89 | |||
| 15% | 99 | 99 | 1 | 18 | 67 | |||
| 20% | 99 | 99 | 1 | 18 | 67 | |||
Table 3. Percent of Men Recommended for Statin Therapy and Guideline Performance Based on Varying Risk Cutoffs.
| 10-year Threshold |
% Meeting Treatment Threshold |
Sensitivity | Specificity | PPV | NPV |
|---|---|---|---|---|---|
| All ages | |||||
| 3% | 27 | 43 | 77 | 35 | 82 |
| 4% | 38 | 54 | 67 | 32 | 83 |
| 5% | 52 | 66 | 51 | 28 | 84 |
| 7.5% | 63 | 77 | 41 | 27 | 85 |
| 10% | 75 | 88 | 29 | 27 | 89 |
| 15% | 81 | 92 | 23 | 26 | 90 |
| 20% | 87 | 95 | 16 | 25 | 92 |
| Age 40-55 | |||||
| 3% | 12 | 18 | 89 | 28 | 83 |
| 4% | 14 | 23 | 88 | 30 | 83 |
| 5% | 21 | 34 | 82 | 31 | 85 |
| 7.5% | 32 | 49 | 72 | 28 | 86 |
| 10% | 49 | 71 | 56 | 27 | 89 |
| 15% | 60 | 80 | 44 | 25 | 91 |
| 20% | 73 | 90 | 30 | 23 | 93 |
| Age 56-65 | |||||
| 3% | 24 | 37 | 80 | 38 | 80 |
| 4% | 40 | 55 | 65 | 34 | 82 |
| 5% | 68 | 76 | 35 | 27 | 82 |
| 7.5% | 84 | 90 | 18 | 26 | 85 |
| 10% | 96 | 99 | 5 | 25 | 92 |
| 15% | 98 | 99 | 3 | 25 | 93 |
| 20% | 98 | 99 | 2 | 25 | 92 |
| Age 66-75 | |||||
| 3% | 68 | 87 | 40 | 37 | 89 |
| 4% | 89 | 96 | 14 | 31 | 91 |
| 5% | 97 | 96 | 3 | 29 | 63 |
| 7.5% | 97 | 96 | 3 | 29 | 63 |
| 10% | 97 | 96 | 3 | 29 | 63 |
| 15% | 97 | 96 | 3 | 29 | 63 |
| 20% | 97 | 96 | 3 | 29 | 63 |
Figure 1. Varying CVD Risk Thresholds in Women.
Sensitivity and specificity analysis of ACC/AHA guideline performance using varying 10-year CVD risk thresholds in women
ACC = American College of Cardiology; AHA = American Heart Association; ASCVD = atherosclerotic cardiovascular disease; CVD = cardiovascular disease
Figure 2. Varying CVD Risk Thresholds in Men.
Sensitivity and specificity analysis of ACC/AHA guideline performance using varying 10-year CVD risk thresholds in men
ACC = American College of Cardiology; AHA = American Heart Association; ASCVD = atherosclerotic cardiovascular disease; CVD = cardiovascular disease
In younger women and younger men (aged 40–55), the guideline sensitivity for identifying adults who would develop CVD over the next 10 years using a cutoff of 7.5% was relatively low, with only 36% of future cases identified as treatment candidates in women and 49% of future cases identified in men. Reducing the 10-year risk threshold to 5% in women and men aged 40-55 markedly improved sensitivity (from 35% to 61% in women, 49% to 71% in men), with only a modest reduction in specificity (90% to 78% in women, 71% to 56% in men).
More marked differences were seen in guideline performance between men and women aged 56–65; since 84% of men were recommended for statins in this age group at a cutoff of 7.5%, compared with only 29% of women, sensitivity was markedly higher in men compared with women (90 % vs. 49%, respectively). Using a risk threshold of 7.5%, the guidelines were able to identify nine in ten men who would develop CVD over the next 10 years, but less than one in two women. When the optional cutoff for statin use was extended of 5% was extended to women aged 56–65, sensitivity improved to 65%.
In men aged 66–75, guideline sensitivity and specificity varied little across treatment thresholds since nearly all men in this age group were recommended for statin therapy—even at a risk threshold of 10% (97% recommended). Consequently, specificity for a threshold of 10% or less was extremely low (2.6%). Raising the 10-year risk cutoff in older men to 15% led to a reduction in the number of men recommended for statin therapy (97% to 89%), with no change in sensitivity (96% to 96%) and improved specificity (3% to 14%). Even when the threshold was increased to 20% (thereby reducing the number treated with a statin to 67%) the sensitivity was only reduced to 87%, while specificity improved to 40%. Similarly, among older women, increasing the threshold from 7.5% to 10% only slight reduced the sensitivity from 5% to 87%, but nearly doubled the specificity from 18% to 35%.
Discussion
The new ACC/AHA cholesterol guidelines substantially increase the number of individuals recommended for statin therapy, particularly among older women and men, and among adult men of all ages. Our study evaluated the treatment thresholds used by the new guidelines to determine the number treated who are likely to develop actual events over the next decade. We found that guideline treatment performance varied in clinically significant ways across age- and sex-specific groups. Existing thresholds had decreased sensitivity for predicting future CVD events in women and younger adults, and had poor specificity for predicting such events in men and older individuals. Most importantly, we found that guideline treatment performance could be improved by selecting age- and sex-specific thresholds for statin initiation.
Previous work has questioned the accuracy of the Pooled Cohort Equations in predicting 10-year atherosclerotic CVD risk, with criticism focusing on the calibration and discrimination of the risk estimates (7,8). However, applied in the new AHA/ACC cholesterol guidelines, the Pooled Cohort Equations are used not to predict precise risk, but rather to stratify adults into “high” (≥7.5% 10-year risk) or “low” risk categories using binary risk categories. Therefore, the continuous precision of the Pooled Cohort Equations may actually be less important than its ability to appropriately divide patients into those above and below a particular risk threshold. Our objective was not to examine the calibration of the Pooled Cohort Equations, but to focus on the practical issue of altering statin treatment thresholds by age- and sex-specific groups in order to determine the performance characteristics of these treatment recommendations.
Our study highlights two key concerns regarding the use of a fixed risk threshold in any type of treatment guideline. First, the 7.5% threshold adopted by the current cholesterol guidelines may not be optimal for identifying young adults in need of statin therapy. Using the “optional” 5% threshold, we observed an improvement in guideline performance sensitivity in identifying young adults (aged 40–55) who are at risk for premature CVD. This sensitivity improvement supports the use of the optional 5% threshold proposed in the current ACC/AHA guidelines. Furthermore, our results underscore the importance of efforts aimed at increasing our ability to detect younger adults who are at increased risk for CVD, beyond what is offered by current 10-year risk estimation methods. Similarly, the sensitivity of the guidelines was poor among women aged 56–65, suggesting this is also a group that deserves improved risk prediction models. Measures of subclinical disease, comprehensive lipid profile, biomarkers, and algorithms focused on 30-year or lifetime risk should be examined for their impact on the sensitivity of future CVD detection, particularly in these risk groups.
Our second major concern is that while the vast majority of older adults (aged 66–75) were recommended for statin therapy, significantly more males than females were recommended statin therapy in this age group. Since the vast majority (nine in ten) of older men had a 10-year risk of 7.5%, the specificity of this recommendation was poor among older men, leading to high rates of potentially unnecessary statin treatment. We found that guideline specificity in older men can be substantially improved with no impact on sensitivity by raising the treatment threshold to 15%. Nonetheless, the high proportion of those recommended for treatment and the low specificity achieved in this age group suggest that efforts should be dedicated to improving discrimination between those who do versus do not require statin treatment.
We found that a slight adjustment of classification thresholds can improve the overall operating characteristics of the current fixed 7.5% threshold guideline. For example, when we use a lower threshold of 5% in adults aged 40–55, a 7.5% threshold in those 56–65, a 10% threshold in women aged 66–75, and a 15% threshold in men aged 66–75, the overall number of adults recommended for treatment increased by only 2.1% (46.8% to 48.9%), while the overall guideline sensitivity increased from 71.2% to 76.8% with only a small decrease in specificity from 57.8% to 56.4%.
We acknowledge that there is no such thing as a perfect threshold; improved sensitivity for predicting future events comes with the tradeoff of reduced specificity and vice-versa. As a result, providers and patients must weigh potential risks of statin therapy (including cost considerations) against their perceived benefit when deciding whether or not to use statin therapy for primary prevention. As the guidelines suggest, the thresholds proposed should be used as starting points in a conversation between patients and providers focusing on shared decision making; however, our study demonstrates that these treatment thresholds should not be fixed at an arbitrary number, but determined with consideration of a patient's age and sex.
Study Limitations
Our analysis has several limitations. First, our study population, adults in the Framingham Offspring Study, which is not nationally representative. Given that the Pooled Cohort Equations are race-specific, similar analyses using alternate, racially diverse populations, should be performed to evaluate the potential need for race-specific thresholds, as well. Second, because adults in the Framingham Offspring Study contributed to the derivation cohort used for the Pooled Cohort Equations, the Pooled Cohort Equations may be more accurate in this population than in a nationally representative cohort. Nevertheless, older age and male sex have been shown to be risk factors for CVD across multiple cohorts so the overall magnitude and direction of our estimates (higher sensitivity in older adults and men) are not likely to change when applied to a broader sample. Finally, adults included in our study were predominantly enrolled in the Framingham Offspring Study in the 1990s. Contemporary changes in risk factor distribution and improvements in CVD prevention efforts may contribute to lower overall rates of CVD than those studied in our cohort, which would lead to an overestimation of PPV and an underestimation of NPV, but should not impact guideline sensitivity and specificity estimates.
Conclusions
Considering the Pooled Cohort Equations in the context of current cholesterol guidelines highlights how differences in the age- and sex-specific distribution of adults recommended for statin therapy affect guideline performance. Establishing age-and sex-specific 10-year risk thresholds to identify adults for statin therapy might improve the balance between avoided events and unnecessary therapy, as well as enhance overall guideline performance.
Perspectives.
Competency in Medical Knowledge
The 2013 American College of Cardiology/American Heart Association cholesterol guidelines emphasize 10-year risk of cardiovascular disease to identify adults eligible for statin therapy, resulting in high rates of statin recommendations in men and older adults.
Competency in Patient Care
The decision to begin statin therapy should be a shared decision between patient and provider, with consideration of a patient's age and sex given differences in guideline performance in different age- and sex-specific groups.
Translational Outlook
Cholesterol treatment recommendations could be improved by applying individualized age- and sex-specific cardiovascular disease risk thresholds.
Acknowledgments
The authors would like to thank Erin Hanley, MS, for her editorial contributions to this manuscript. Ms. Hanley did not receive compensation for her contributions, apart from her employment at the institution where this study was conducted. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract No. N01-HC-25195). This manuscript has been reviewed by Framingham Heart Study Investigators for Scientific content and consistency of data interpretation with previous Framingham Heart Study publications.
Sources of funding: Thus study was supported by unrestricted grants from the Doggone foundation along with research funds from the Duke Clinical Research Institute. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (contract N01-HC-25195). This article has been reviewed by Framingham Heart Study Investigators for scientific content and consistency of data interpretation with previous Framingham Heart Study publications.
Abbreviations and Acronyms
- ACC
American College of Cardiology
- AFCAPS/TEXCAPS
Air Force/Texas Coronary Atherosclerosis Prevention Study
- AHA
American Heart Association
- CVD
cardiovascular disease
- JUPITER
Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin
- MEGA
Primary Prevention of Cardiovascular Disease with Pravastatin in Japan Study
- NPV
negative predictive value
- PPV
positive predictive value
Footnotes
Conflict of Interest Disclosures: Dr. Navar-Boggan reports no conflicts of interest. Dr. Peterson has received funding for research grants from Eli Lilly and Janssen Pharmaceuticals, and funding for serving as a consultant/participant on advisory boards for Merck, Sanofi-Aventis, Janssen Pharmaceuticals, and Boehringer Ingelheim. Dr. D’Agostino, Sr. reports no conflicts of interest. Dr. Pencina has received funding for serving as a consultant for AbbVie. Dr. Sniderman reports no conflicts of interest.
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