C a rd i o v a s c u l a r Di s e a s e Risk Assessment and P re v e n t i o n Current Guidelines and Limitations Peter Alagona Jr,
MD
a,
*, Tariq Ali Ahmad,
MD
b
KEYWORDS Atherosclerotic cardiovascular disease Cardiovascular disease Peripheral arterial disease Risk assessment Clinical guideline(s) KEY POINTS Even with decades of progress in understanding atherosclerotic cardiovascular disease (ASCVD) and improved cardiovascular (CV) event prevention, the incidence, consequences, and cost of cardiovascular disease remain a significant public health issue. Observational studies have identified major ASCVD risk factors; however, a significant number of those at risk are not identified and most recurrent CV events still take place after aggressive prevention strategies are used. The statin era helped revolutionize clinical practice not only by effective outcome-driven low-density lipoprotein-cholesterol reduction but also by encouraging across-the-board aggressive prevention efforts. There are now numerous clinical guidelines for ASCVD risk stratification and treatment recommendations promulgated over the last 3 decades. Few patients are alike, and providing patient-centered care using all the tools available including, but not exclusively, evidence and clinical recommendations is paramount.
INTRODUCTION
Atherosclerotic cardiovascular disease (ASCVD) affects more than one-third of the adult population, accounts for 35% of all US deaths, and is a leading cause of disability. ASCVD kills more women each year than the next 3 causes of death combined. More than 50% of ASCVD presents as coronary events, including sudden cardiac death, nonfatal myocardial infarction (MI), and revascularization, with the rest being stroke and claudication associated with peripheral arterial disease.1 The last a Penn State Heart and Vascular Institute, Penn State Milton S. Hershey Medical Center, University Drive, Rm C5833, P.O.Box 850, Hershey, PA 17033-0850, USA; b Division of General Internal Medicine, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA * Corresponding author. E-mail address: [email protected]
Med Clin N Am - (2015) -–http://dx.doi.org/10.1016/j.mcna.2015.02.003 medical.theclinics.com 0025-7125/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
2
Alagona Jr & Ahmad
4 decades have witnessed unrelenting advances in the understanding of atherogenesis and development of clinically manifest ASCVD, including epidemiology, natural history, pathophysiology, risk assessment of, and treatments. Hallmarks of this disease process include: Begins decades before clinical manifestations,2,3 Can involve a variety of different vascular beds with myriad presentations, Can be to a substantial degree prevented or modified.4 The atherosclerotic process is complex and appears to be initiated by the entrance and retention of atherogenic apolipoprotein B (apoB) particles (Box 1)5 in the arterial subendothelial space. However, as noted in Fig. 1, the process clearly involves more than simply calculated low-density lipoprotein-cholesterol (LDL-C)6–8; further elucidation of other causative or involved factors and mechanisms may add to the ability to risk-stratify populations, and it is hoped, individual patients, and improve preventive treatment. Observations regarding ischemic heart disease began centuries ago; however, modern appreciation of ASCVD’s causes and disease risk began with the National Heart Act signed into law in 1948, which established the National Heart Institute and provided a $500,000 grant for a 20-year epidemiologic study of cardiovascular (CV) disease, which became known as the Framingham Heart Study (FHS).9 The first subject was enrolled 65 years ago when 44% of deaths in the United States were due to ASCVD. The FHS led to the identification of several major ASCVD risk factors, including cigarette smoking, hypertension, and elevated serum cholesterol; family history was added subsequently. Presented is a brief review of the current state of ASCVD risk assessment and prevention treatment guidelines with attention to limitations that encourage improvement. ATHEROSCLEROTIC CARDIOVASCULAR DISEASE RISK FACTORS
The major, now termed traditional, risk factors (Fig. 2) are the foundation of all ASCVD risk assessment systems or scores and preventive treatment recommendations.10 Starting with the Framingham Risk Score (FRS), most systems use, almost exclusively, these traditional risk factors. Because decreased high-density lipoprotein-cholesterol (HDL-C) is strongly associated with increased risk of CV events and elevated HDL-C is strongly associated with decreased risk,11 some scores include it as a positive or negative factor, depending on levels. The INTERHEART Study12 was a large, international (52 countries), standardized, case-control study evaluating the strength of association between a variety of risk factors and acute MI and whether this association varied by geographic region, ethnic origin, sex, or age. Box 2 lists 9 risk, or protective factors, which identified almost 90% of those at risk of a first MI, clearly significantly Box 1 Apolipoprotein B particles Atherogenic (ApoB) lipoproteins Very low-density lipoprotein (VLDL) Intermediate-density lipoprotein LDL LDL-P Lipoprotein (a)
Cardiovascular Disease Risk Assessment
Fig. 1. Genesis and pathophysiology of ASCVD.
3
4
Alagona Jr & Ahmad
Fig. 2. Traditional risk factors for ASCVD and prevalence of these risk factors in patients with premature CAD; greater than 62% of patient with ASCVD have none or one risk factor. (Courtesy of Paul M. Ridker, MD, Boston, MA.)
better than the 50% to 60% most current scoring systems achieve. A variety of nontraditional markers or potential risk factors have been identified; however, evidence of their ability to significantly improve risk prediction, in large groups or populations, remains elusive.13 Preventive efforts during the last 30 years have led to significant decreases in ASCVD mortality, nonfatal events, and revascularization.14 During the same period, the prevalence of risk factors, including hypercholesterolemia, cigarette smoking, and blood pressure (BP), have slightly decreased,15 with simultaneous increases in the prevalence of obesity, increased body mass index (BMI), increased waist circumference, metabolic syndrome, type II diabetes, and serum triglycerides (TG).16–18 Risk factor identification beginning with the FHS may have increased interest in prevention- by the 1970s; however, the statin era clearly has had a dramatic effect, bringing prevention, the ability on a routine basis to decrease CV events, into the modern era and daily clinical practice. Although lifestyle modification has clearly become a linchpin of population prevention, the ability to quickly lower cholesterol, apoB atherogenic lipoproteins, and achieve significant early outcome benefit has helped encourage more Box 2 Risks/protective factors evaluated in the INTERHEART study ApoB1/ApoA1 ratio Smoking Hypertension (self-reported) Diabetes Abdominal obesity Psychosocial factors Daily consumption of fruits and vegetables Regular alcohol consumption Regular physical activity Collectively, these factors accounted for 90% of the population-attributable risks in men and 94% in women.12
Cardiovascular Disease Risk Assessment
aggressive across-the-board prevention efforts. Secondary prevention trials19 have provided such powerful data that statin treatment is now a universal standard of care. Primary prevention, in patients without known disease but at increased risk, remains somewhat more controversial because of significantly increased number of patients needed to treat to prevent events, potential adverse statin effects and toxicity, and decreased or questionable cost-effectiveness20 which presents a major question, or perhaps the nexus, of risk versus desirability of treatment. Therefore, there is a significant interest in continuing the search for improved risk factor identification, development of more accurate risk assessment systems, and better preventive treatments. LIMITATIONS OF CURRENT RISK ASSESSMENT SYSTEMS/SCORES
The acknowledged major risk factors for ASCVD have remained basically unchanged while simultaneously much of CV medicine has not just evolved but been revolutionized. Many do not realize current risk assessment systems and guidelines: Identify less than 50% of adults who will develop clinically significant ASCVD, Do not identify those in the highest risk group who will have recurrent CV events (residual risk), Use 10-year and not lifetime risk (Fig. 3)21 when life expectancy has increased dramatically, therefore discouraging earlier more aggressive prevention efforts, Recommend use of ASCVD event cut points to guide treatment; however, no specific cut points for increased risk and events exist,22 Use LDL-C exclusively and do not include a variety of novel non-LDL-C markers because controversy remains regarding whether they improve risk stratification in populations studied.12,23–25 45 MEN ≥1 ELEVATED RISK FACTOR
40
MEN ≥2 MAJOR RISK FACTORS
35
30
MEN WITH NO RISK FACTORS
25
WOMEN ≥1 ELEVATED RISK FACTOR
20
15
WOMEN ≥2 MAJOR RISK FACTORS
10
WOMEN WITH NO RISK FACTOS
5
0 55
60
65
70
75
80
85
90
95
A ained Age (Yr)
Fig. 3. This figure reveals significant increased lifetime versus 10-year risk of a cardiovascular event in men and women especially with more than 1 traditional risk factor. (Data from Berry JD, Dyer A, Cai X, et al. Lifetime risks of cardiovascular disease. N Engl J Med 2012;366:321–9.)
5
6
Alagona Jr & Ahmad
One of the limitations of using only traditional risk factors is a failure to quantify, a basic epidemiologic principle, exposure. For example, exposure to one cigarette a day for a total of a year does not lead to statistically significant increases in the long-term risk of smoking-related illness. However, smoking a pack a day for 20 years would be associated with significantly increased risk. A comprehensive patient history should uncover a more accurate smoking history than the common cursory estimate. Nevertheless, this is not common practice. How can a gross and at times questionably inaccurate estimate of exposure to major risk factors not detrimentally affect individual risk stratification? A positive family history of ASCVD in first-degree relatives is considered a major risk factor. However, again it is not graded or quantified and not included in the 2013 guideline. Certainly, when confronted with a patient in daily practice, the number of first-degree relatives, their sex and age at disease onset, or particular type of clinical event might influence further patient evaluation and preventive treatment. Increased incidence of ASCVD in a family may have a disproportionate relationship to risk and events, especially in younger individuals.26,27 All scores include a history of or treated hypertension as a major factor. However, exposure to systolic hypertension is not quantified via its levels, duration, and adequacy of chronic treatment (Table 1). How is the risk of someone with long-term well-controlled BP on one drug versus poorly controlled BP on multiple drugs assessed and compared? If the role and contribution of each risk factor to events is directly related to exposure, and early and prolonged exposure to atherogenic cholesterol is the proximate or initiating cause of atherosclerosis, why has there not been an attempt to better quantify that relationship?5,22 Because the relationship between atherogenic cholesterol and disease is well established, a logical question would be whether LDL-C lowering (apoB, non-HDLC) earlier in life would delay the development of atherosclerosis and further improve outcomes.28 Analysis from the 170,000 participants participating in 27 statin trials conducted by the Cholesterol Treatment Trialists Collaboration (CTT)19 revealed approximately 21% reduction in CVD for every 38.7 mg/dL reduction in LDL-C.20 Unfortunately, even with aggressive LDL-C lowering, residual risk for further CV events remains. The mean age at the time of randomization in statin trials evaluated by the CTT group was 63 years. It is not unreasonable to think that LDL-C lowering beginning earlier in life would decrease events and so-called residual risk. Withholding safe treatment of any type until a certain age, reaching a specific absolute risk level (a crude estimate), or until there is evidence of disease seems illogical. In addition, after sustained LDL-C lowering, clinical trial data are consistent with maintained risk reduction for years afterward.29,30 It would be hard to imagine that better quantification (degree and duration) of a variety of factors, both LDL-C and non-HDL-C, would prove to be a major aid in improving risk stratification. There are substantial data regarding increased risk in certain ethnic groups. People of south Asian decent especially exhibit increased risk.31,32 It is accelerated for those who immigrate or are first generation to many industrialized countries.33 This additional but dramatic effect of ethnicity is rarely considered in risk stratification outside of native countries, even as immigration and worldwide diversity has increased. Is ethnicity worthy of more consideration in the scoring systems?34 The basic lipid panel universally used misses as much as 50% of those at risk for ASCVD events. It is now understood that calculated LDL-C is not uncommonly inaccurate in estimating atherogenic cholesterol35–37 and may occur in a variety of situations, including hypertriglyceridemia, increased waist circumference, metabolic
Cardiovascular Disease Risk Assessment
Table 1 Comparison of variables used in various risk calculation tools
PROCAM Predicts MI Risk
FRS 2009 CCS Canadian Cholesterol Guidelines
Reynolds Risk Score
Pooled Cohort Equation ACC/ AHA 2013 ASCVD
Age
20–75 y range
Any age in years
Up to age of 80 y Any age in years
Sex
M/F
M/F
M/F
M/F
Race
Not included
Not included
Not included
White or other African American
Smokinga
Current nicotine consumption (Y/N)
Smoker or nonsmoker (Y/N)
Smoker or nonsmoker (Y/N)
Smoker or nonsmoker (Y/N)
DMb
Known DM or FRS 120
Diabetic or not (Y/N)
Not included
Diabetic or not (Y/N)
Family historya
Positive/negative Not included (1st degree with MI before 60) (Y/N)
Systolic BPb
100–225 mm Hg
Any BP in mm Hg Any BP in mm Hg Any BP in mm Hg
Weight
40–120 kg
Not included
Not included
Height
140–210 cm
Not included
Not included
Not included
Antihypertensive Receiving therapy or not therapyb (Y/N)
Receiving therapy or not (Y/N)
Not included
Receiving therapy or not (Y/N)
Total cholesterol
Not included
Serum levels in mg/dL
Serum levels in Serum levels in mmol or mg/dL mg/dL
HDL cholesterol
Not included
Serum levels in mg/dL
Serum levels in Serum levels in mmol or mg/dL mg/dL
hsCRP
Not included
Not included
Serum levels in mg/L
Mother or father Not included have MI before age 60 (Y/N)
Not included
Not included
a
Not specific to cigarette smoking or amount. No information on treated/controlled disease versus treated/uncontrolled or duration of controlled/uncontrolled disease. b
syndrome, and diabetes (Table 2). These situations where LDL-C may not be an accurate reflection of the number of circulating atherogenic particles (apoB, LDL particle number [LDL-P]) can lead to misclassification of risk of patients and therefore failure to appropriately address preventive treatment. Non-HDL-C (total cholesterol [TC] HDL-C 5 non-HDL-C) has been recognized as a better risk predictor than LDL-C in a variety of circumstances, especially in women.4 It correlates better with apoB than LDL-C in many circumstances. Although as noted above, there may have been a modest decrease in overall LDL-C across the population since the FHS began, there has been a significant increase in TG. Even modest elevations in TG can be associated with inaccurate calculation of LDL-C. In the 40 years since the Friedewald Formula (Box 3) was developed, adult Americans have steadily increased their weight, waist circumference, BMI, TG, and incidence of cardiometabolic disease. It was anticipated that the new American Heart Association (AHA)/American College of Cardiology (ACC) guideline would recommend non-HDL be used in conjunction with, in addition to, or in
7
8
Alagona Jr & Ahmad
Table 2 Metabolic syndrome* Measure
Categorical Cut Points
1. Elevated waist circumference
40 inches (102 cm) in men 35 inches (88 cm) in women
2. Elevated TG
150 mg/dL
3. Reduced HDL-C
MD
a,
*, Tariq Ali Ahmad,
MD
b
KEYWORDS Atherosclerotic cardiovascular disease Cardiovascular disease Peripheral arterial disease Risk assessment Clinical guideline(s) KEY POINTS Even with decades of progress in understanding atherosclerotic cardiovascular disease (ASCVD) and improved cardiovascular (CV) event prevention, the incidence, consequences, and cost of cardiovascular disease remain a significant public health issue. Observational studies have identified major ASCVD risk factors; however, a significant number of those at risk are not identified and most recurrent CV events still take place after aggressive prevention strategies are used. The statin era helped revolutionize clinical practice not only by effective outcome-driven low-density lipoprotein-cholesterol reduction but also by encouraging across-the-board aggressive prevention efforts. There are now numerous clinical guidelines for ASCVD risk stratification and treatment recommendations promulgated over the last 3 decades. Few patients are alike, and providing patient-centered care using all the tools available including, but not exclusively, evidence and clinical recommendations is paramount.
INTRODUCTION
Atherosclerotic cardiovascular disease (ASCVD) affects more than one-third of the adult population, accounts for 35% of all US deaths, and is a leading cause of disability. ASCVD kills more women each year than the next 3 causes of death combined. More than 50% of ASCVD presents as coronary events, including sudden cardiac death, nonfatal myocardial infarction (MI), and revascularization, with the rest being stroke and claudication associated with peripheral arterial disease.1 The last a Penn State Heart and Vascular Institute, Penn State Milton S. Hershey Medical Center, University Drive, Rm C5833, P.O.Box 850, Hershey, PA 17033-0850, USA; b Division of General Internal Medicine, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA * Corresponding author. E-mail address: [email protected]
Med Clin N Am - (2015) -–http://dx.doi.org/10.1016/j.mcna.2015.02.003 medical.theclinics.com 0025-7125/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
2
Alagona Jr & Ahmad
4 decades have witnessed unrelenting advances in the understanding of atherogenesis and development of clinically manifest ASCVD, including epidemiology, natural history, pathophysiology, risk assessment of, and treatments. Hallmarks of this disease process include: Begins decades before clinical manifestations,2,3 Can involve a variety of different vascular beds with myriad presentations, Can be to a substantial degree prevented or modified.4 The atherosclerotic process is complex and appears to be initiated by the entrance and retention of atherogenic apolipoprotein B (apoB) particles (Box 1)5 in the arterial subendothelial space. However, as noted in Fig. 1, the process clearly involves more than simply calculated low-density lipoprotein-cholesterol (LDL-C)6–8; further elucidation of other causative or involved factors and mechanisms may add to the ability to risk-stratify populations, and it is hoped, individual patients, and improve preventive treatment. Observations regarding ischemic heart disease began centuries ago; however, modern appreciation of ASCVD’s causes and disease risk began with the National Heart Act signed into law in 1948, which established the National Heart Institute and provided a $500,000 grant for a 20-year epidemiologic study of cardiovascular (CV) disease, which became known as the Framingham Heart Study (FHS).9 The first subject was enrolled 65 years ago when 44% of deaths in the United States were due to ASCVD. The FHS led to the identification of several major ASCVD risk factors, including cigarette smoking, hypertension, and elevated serum cholesterol; family history was added subsequently. Presented is a brief review of the current state of ASCVD risk assessment and prevention treatment guidelines with attention to limitations that encourage improvement. ATHEROSCLEROTIC CARDIOVASCULAR DISEASE RISK FACTORS
The major, now termed traditional, risk factors (Fig. 2) are the foundation of all ASCVD risk assessment systems or scores and preventive treatment recommendations.10 Starting with the Framingham Risk Score (FRS), most systems use, almost exclusively, these traditional risk factors. Because decreased high-density lipoprotein-cholesterol (HDL-C) is strongly associated with increased risk of CV events and elevated HDL-C is strongly associated with decreased risk,11 some scores include it as a positive or negative factor, depending on levels. The INTERHEART Study12 was a large, international (52 countries), standardized, case-control study evaluating the strength of association between a variety of risk factors and acute MI and whether this association varied by geographic region, ethnic origin, sex, or age. Box 2 lists 9 risk, or protective factors, which identified almost 90% of those at risk of a first MI, clearly significantly Box 1 Apolipoprotein B particles Atherogenic (ApoB) lipoproteins Very low-density lipoprotein (VLDL) Intermediate-density lipoprotein LDL LDL-P Lipoprotein (a)
Cardiovascular Disease Risk Assessment
Fig. 1. Genesis and pathophysiology of ASCVD.
3
4
Alagona Jr & Ahmad
Fig. 2. Traditional risk factors for ASCVD and prevalence of these risk factors in patients with premature CAD; greater than 62% of patient with ASCVD have none or one risk factor. (Courtesy of Paul M. Ridker, MD, Boston, MA.)
better than the 50% to 60% most current scoring systems achieve. A variety of nontraditional markers or potential risk factors have been identified; however, evidence of their ability to significantly improve risk prediction, in large groups or populations, remains elusive.13 Preventive efforts during the last 30 years have led to significant decreases in ASCVD mortality, nonfatal events, and revascularization.14 During the same period, the prevalence of risk factors, including hypercholesterolemia, cigarette smoking, and blood pressure (BP), have slightly decreased,15 with simultaneous increases in the prevalence of obesity, increased body mass index (BMI), increased waist circumference, metabolic syndrome, type II diabetes, and serum triglycerides (TG).16–18 Risk factor identification beginning with the FHS may have increased interest in prevention- by the 1970s; however, the statin era clearly has had a dramatic effect, bringing prevention, the ability on a routine basis to decrease CV events, into the modern era and daily clinical practice. Although lifestyle modification has clearly become a linchpin of population prevention, the ability to quickly lower cholesterol, apoB atherogenic lipoproteins, and achieve significant early outcome benefit has helped encourage more Box 2 Risks/protective factors evaluated in the INTERHEART study ApoB1/ApoA1 ratio Smoking Hypertension (self-reported) Diabetes Abdominal obesity Psychosocial factors Daily consumption of fruits and vegetables Regular alcohol consumption Regular physical activity Collectively, these factors accounted for 90% of the population-attributable risks in men and 94% in women.12
Cardiovascular Disease Risk Assessment
aggressive across-the-board prevention efforts. Secondary prevention trials19 have provided such powerful data that statin treatment is now a universal standard of care. Primary prevention, in patients without known disease but at increased risk, remains somewhat more controversial because of significantly increased number of patients needed to treat to prevent events, potential adverse statin effects and toxicity, and decreased or questionable cost-effectiveness20 which presents a major question, or perhaps the nexus, of risk versus desirability of treatment. Therefore, there is a significant interest in continuing the search for improved risk factor identification, development of more accurate risk assessment systems, and better preventive treatments. LIMITATIONS OF CURRENT RISK ASSESSMENT SYSTEMS/SCORES
The acknowledged major risk factors for ASCVD have remained basically unchanged while simultaneously much of CV medicine has not just evolved but been revolutionized. Many do not realize current risk assessment systems and guidelines: Identify less than 50% of adults who will develop clinically significant ASCVD, Do not identify those in the highest risk group who will have recurrent CV events (residual risk), Use 10-year and not lifetime risk (Fig. 3)21 when life expectancy has increased dramatically, therefore discouraging earlier more aggressive prevention efforts, Recommend use of ASCVD event cut points to guide treatment; however, no specific cut points for increased risk and events exist,22 Use LDL-C exclusively and do not include a variety of novel non-LDL-C markers because controversy remains regarding whether they improve risk stratification in populations studied.12,23–25 45 MEN ≥1 ELEVATED RISK FACTOR
40
MEN ≥2 MAJOR RISK FACTORS
35
30
MEN WITH NO RISK FACTORS
25
WOMEN ≥1 ELEVATED RISK FACTOR
20
15
WOMEN ≥2 MAJOR RISK FACTORS
10
WOMEN WITH NO RISK FACTOS
5
0 55
60
65
70
75
80
85
90
95
A ained Age (Yr)
Fig. 3. This figure reveals significant increased lifetime versus 10-year risk of a cardiovascular event in men and women especially with more than 1 traditional risk factor. (Data from Berry JD, Dyer A, Cai X, et al. Lifetime risks of cardiovascular disease. N Engl J Med 2012;366:321–9.)
5
6
Alagona Jr & Ahmad
One of the limitations of using only traditional risk factors is a failure to quantify, a basic epidemiologic principle, exposure. For example, exposure to one cigarette a day for a total of a year does not lead to statistically significant increases in the long-term risk of smoking-related illness. However, smoking a pack a day for 20 years would be associated with significantly increased risk. A comprehensive patient history should uncover a more accurate smoking history than the common cursory estimate. Nevertheless, this is not common practice. How can a gross and at times questionably inaccurate estimate of exposure to major risk factors not detrimentally affect individual risk stratification? A positive family history of ASCVD in first-degree relatives is considered a major risk factor. However, again it is not graded or quantified and not included in the 2013 guideline. Certainly, when confronted with a patient in daily practice, the number of first-degree relatives, their sex and age at disease onset, or particular type of clinical event might influence further patient evaluation and preventive treatment. Increased incidence of ASCVD in a family may have a disproportionate relationship to risk and events, especially in younger individuals.26,27 All scores include a history of or treated hypertension as a major factor. However, exposure to systolic hypertension is not quantified via its levels, duration, and adequacy of chronic treatment (Table 1). How is the risk of someone with long-term well-controlled BP on one drug versus poorly controlled BP on multiple drugs assessed and compared? If the role and contribution of each risk factor to events is directly related to exposure, and early and prolonged exposure to atherogenic cholesterol is the proximate or initiating cause of atherosclerosis, why has there not been an attempt to better quantify that relationship?5,22 Because the relationship between atherogenic cholesterol and disease is well established, a logical question would be whether LDL-C lowering (apoB, non-HDLC) earlier in life would delay the development of atherosclerosis and further improve outcomes.28 Analysis from the 170,000 participants participating in 27 statin trials conducted by the Cholesterol Treatment Trialists Collaboration (CTT)19 revealed approximately 21% reduction in CVD for every 38.7 mg/dL reduction in LDL-C.20 Unfortunately, even with aggressive LDL-C lowering, residual risk for further CV events remains. The mean age at the time of randomization in statin trials evaluated by the CTT group was 63 years. It is not unreasonable to think that LDL-C lowering beginning earlier in life would decrease events and so-called residual risk. Withholding safe treatment of any type until a certain age, reaching a specific absolute risk level (a crude estimate), or until there is evidence of disease seems illogical. In addition, after sustained LDL-C lowering, clinical trial data are consistent with maintained risk reduction for years afterward.29,30 It would be hard to imagine that better quantification (degree and duration) of a variety of factors, both LDL-C and non-HDL-C, would prove to be a major aid in improving risk stratification. There are substantial data regarding increased risk in certain ethnic groups. People of south Asian decent especially exhibit increased risk.31,32 It is accelerated for those who immigrate or are first generation to many industrialized countries.33 This additional but dramatic effect of ethnicity is rarely considered in risk stratification outside of native countries, even as immigration and worldwide diversity has increased. Is ethnicity worthy of more consideration in the scoring systems?34 The basic lipid panel universally used misses as much as 50% of those at risk for ASCVD events. It is now understood that calculated LDL-C is not uncommonly inaccurate in estimating atherogenic cholesterol35–37 and may occur in a variety of situations, including hypertriglyceridemia, increased waist circumference, metabolic
Cardiovascular Disease Risk Assessment
Table 1 Comparison of variables used in various risk calculation tools
PROCAM Predicts MI Risk
FRS 2009 CCS Canadian Cholesterol Guidelines
Reynolds Risk Score
Pooled Cohort Equation ACC/ AHA 2013 ASCVD
Age
20–75 y range
Any age in years
Up to age of 80 y Any age in years
Sex
M/F
M/F
M/F
M/F
Race
Not included
Not included
Not included
White or other African American
Smokinga
Current nicotine consumption (Y/N)
Smoker or nonsmoker (Y/N)
Smoker or nonsmoker (Y/N)
Smoker or nonsmoker (Y/N)
DMb
Known DM or FRS 120
Diabetic or not (Y/N)
Not included
Diabetic or not (Y/N)
Family historya
Positive/negative Not included (1st degree with MI before 60) (Y/N)
Systolic BPb
100–225 mm Hg
Any BP in mm Hg Any BP in mm Hg Any BP in mm Hg
Weight
40–120 kg
Not included
Not included
Height
140–210 cm
Not included
Not included
Not included
Antihypertensive Receiving therapy or not therapyb (Y/N)
Receiving therapy or not (Y/N)
Not included
Receiving therapy or not (Y/N)
Total cholesterol
Not included
Serum levels in mg/dL
Serum levels in Serum levels in mmol or mg/dL mg/dL
HDL cholesterol
Not included
Serum levels in mg/dL
Serum levels in Serum levels in mmol or mg/dL mg/dL
hsCRP
Not included
Not included
Serum levels in mg/L
Mother or father Not included have MI before age 60 (Y/N)
Not included
Not included
a
Not specific to cigarette smoking or amount. No information on treated/controlled disease versus treated/uncontrolled or duration of controlled/uncontrolled disease. b
syndrome, and diabetes (Table 2). These situations where LDL-C may not be an accurate reflection of the number of circulating atherogenic particles (apoB, LDL particle number [LDL-P]) can lead to misclassification of risk of patients and therefore failure to appropriately address preventive treatment. Non-HDL-C (total cholesterol [TC] HDL-C 5 non-HDL-C) has been recognized as a better risk predictor than LDL-C in a variety of circumstances, especially in women.4 It correlates better with apoB than LDL-C in many circumstances. Although as noted above, there may have been a modest decrease in overall LDL-C across the population since the FHS began, there has been a significant increase in TG. Even modest elevations in TG can be associated with inaccurate calculation of LDL-C. In the 40 years since the Friedewald Formula (Box 3) was developed, adult Americans have steadily increased their weight, waist circumference, BMI, TG, and incidence of cardiometabolic disease. It was anticipated that the new American Heart Association (AHA)/American College of Cardiology (ACC) guideline would recommend non-HDL be used in conjunction with, in addition to, or in
7
8
Alagona Jr & Ahmad
Table 2 Metabolic syndrome* Measure
Categorical Cut Points
1. Elevated waist circumference
40 inches (102 cm) in men 35 inches (88 cm) in women
2. Elevated TG
150 mg/dL
3. Reduced HDL-C
