XML Template (2015) [14.1.2015–7:33am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140179/APPFile/SG-CPRJ140179.3d
(CPR)
[1–7] [PREPRINTER stage]
EURO PEAN SO CIETY O F CARDIOLOGY ®
Original scientific paper
Treat-to-target versus dose-adapted statin treatment of cholesterol to reduce cardiovascular risk
European Journal of Preventive Cardiology 0(00) 1–7 ! The European Society of Cardiology 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2047487314567001 ejpc.sagepub.com
Dirk Mu¨ller-Wieland1, Gerd Assmann2, Rafael Carmena3, Jean Davignon4, Arnold von Eckardstein5, Eduardo Farinaro6, Heiner Greten7, Anders G Olsson8, Walter F Riesen9 and Evgenyi Shlyakhto10
Abstract Clinical guidelines should be based on the best available evidence and are of great importance for patient care and disease prevention. In this respect, the 2013 American College of Cardiology/American Heart Association report is highly appreciated and well-recognized. The report included critical questions concerning hypercholesterolaemia, but its translation into a clinical guideline initiated intense debate worldwide because of the recommendation to switch from a treat-to-target approach for low-density-lipoprotein-cholesterol to a statin dose-based strategy.
Keywords Hypercholesterolaemia, cardiovascular prevention Received 13 October 2014; accepted 13 December 2014
What is ‘different’ in the 2013 American College of Cardiology/American Heart Association guideline? In the American College of Cardiology/American Heart Association (ACC/AHA) report1 the authors recommend early and effective low-density lipoprotein (LDL)-cholesterol lowering through statin treatment for the reduction of atherosclerotic cardiovascular disease (ASCVD). They defined four groups that would benefit from statin treatment and recommended using the Pooled Cohort Equations to estimate individual
10-year ASCVD risk.2 This approach translated into two major changes to current recommendations: to substitute current target concentrations for lowering LDL-cholesterol with dose-adapted statin therapy; and to score global risk assessment by including risk for stroke and four clinical scenarios with evidence for statin benefit.
7
1
Hanseatic Heart Centre, Asklepios Clinic St Georg, Hamburg, Germany Department of Medicine and Health, Faculty of Health Sciences, University of Linko¨ping and Stockholm Heart Centre, Sweden 9 Institute for Laboratory Medicine, St Gallen, Switzerland 10 Almazov Research Institute of Cardiology, Russian Federation Agency of Health and Social Development, Saint Petersburg, Russia 8
Department of General Internal Medicine, Head, Endocrinology, Diabetes and Metabolism, Asklepios Clinic St Georg, Hamburg, Germany 2 Assmann-Foundation for Prevention, Mu¨nster, Germany 3 Universitat de Vale`ncia and Director-General of Fundacio´n INCLIVA, Valencia, Spain 4 Institut de recherches cliniques de Montre´al (IRCM), Faculty of Medicine at the Universite´ de Montre´al, Canada 5 Institute of Clinical Chemistry of the University Hospital of Zurich, Switzerland 6 Department Public Health, Medical School University of Naples Federico II, Italy
Corresponding author: Dirk Mu¨ller-Wieland, Department of General Internal Medicine, Head, Endocrinology, Diabetes and Metabolism, Asklepios Clinic St Georg, Asklepios Campus Hamburg, Medical Faculty, Semmelweis University, Lohmu¨hlenstr. 5, Haus O – D-20099 Hamburg, Germany. E-mail: [email protected]
Downloaded from cpr.sagepub.com at FRESNO PACIFIC UNIV on January 20, 2015
XML Template (2015) [14.1.2015–7:33am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140179/APPFile/SG-CPRJ140179.3d
(CPR)
[1–7] [PREPRINTER stage]
2
European Journal of Preventive Cardiology 0(00)
Recommendations of the International Task Force For the Prevention of Cardiometabolic Diseases The following position statement from the International Task Force for the Prevention of Cardiometabolic Diseases (ITF-PCD) focuses on specific aspects of the debate from an international perspective, drawing the following conclusions: 1. Risk-stratified treat-to-target concentrations should remain the goal for lowering LDL-cholesterol. 2. Risk scores for prevention of cardiovascular complications should focus on coronary heart disease events. 3. Under-treatment of high-risk individuals may occur in the absence of LDL-cholesterol target concentrations. 4. Over-treatment of low-risk individuals may occur if statin-based treatment is used in accordance with the ACC/AHA guidelines.1 Considering the joint statements from the International Atherosclerosis Society (IAS) and the International Task Force for the Prevention of Coronary Heart Disease from 2009,3 the ITF-PCD reemphasizes the value of the target-orientated strategy of LDL-cholesterol lowering for clinical practice and individualized patient care. We therefore support the recent recommendations of the European Society of Cardiology/European Atherosclerosis Society (ESC/ EAS),4 the ESC,5 the National Lipid Association6 and the IAS.7 The International Task Force, renamed ITF-PCD in 2014, has long advocated the concept of global cardiovascular risk when making treatment decisions for lipid disorders. Therefore the decision to declare global risk alone as the clinical criterion for initiating cholesterollowering therapy is highly appreciated. Although there are no clinical prospective trials titrating target levels, we want to reinforce positions of different scientific societies, that risk-stratified treat-to-target concentrations should remain the goal for lowering LDL-cholesterol when clinical evidence is translated into clinical practice.3–7 This is an important statement, because otherwise health authorities may limit individualized patient-centred decision-making.
Risk-stratified treat-to-target The Third Report of the National Cholesterol Education Program recommended a target-orientated treatment algorithm for LDL-cholesterol, elevated with respect to the patient’s underlying coronary risk8,9 and based on a substantial bank of evidence
from emerging trials. This general approach was also taken by the ESC/EAS, in which different target LDLcholesterol concentrations were recommended in relation to current cardiovascular risk.4 The ESC/EAS Task Force proposed reducing LDL-cholesterol by 50%, especially when the target concentration cannot be achieved. The recommendation to reduce LDL-cholesterol to a relevant range following initiation of drug treatment is also included in the American Diabetes Association (ADA) recommendations.10 The ACC/AHA group questions the value of targetorientated therapy, with arguments that the end-points in LDL-cholesterol-lowering studies were not designed to prove the value of this strategy, and all were performed with statins. Therefore the authors recommend treating patients with risk-adapted high, medium or low doses of statins according to their potency for percentage reduction of LDL-cholesterol. Overwhelming evidence exists for statins in terms of reducing ASCVD. However, to propose a change in the treatment algorithm from LDL-cholesterol targets to statin doses, based on pure evidence, is not convincing for clinical practice. Although randomized trial comparisons are based on statin doses – the strategy recommended by the ACC/AHA – giving different doses according to individual risk has never been tested prospectively in an appropriate study. Furthermore, response rates to statins have wide inter-individual variability, and should be taken into consideration if fixed doses are recommended; indeed, response rates should be monitored in the clinical setting to achieve appropriate risk reduction, indeed ACC/AHA recommends to control LDL-cholesterol levels to monitor the degree of relative reduction. The argument for achieving the percentage changes in LDL-cholesterol concentrations attained in clinical studies using the maximum dose of statins disregards all other clinical, pathophysiological and molecular evidence about the causal and linear relationship of LDL-cholesterol lowering to reduction of coronary risk. There is direct evidence that more-intensive therapy to lower LDL-cholesterol is of benefit, and that in high-risk patients lower on-treatment target concentrations are associated with lower event rates.11,12 Trial data suggest there is no threshold.13 Individuals with very low LDL-cholesterol have a very low longterm risk, even in the presence of other risk factors,14 and there is indirect evidence that low LDL-cholesterol concentrations induce mechanisms related to plaque stabilization and possibly also plaque regression.15 We are aware of the fact that some drugs, such as niacin and CETP-inhibitors, have not yet been proven to reduce cardiovascular risk in relation to LDL-cholesterol lowering, but there is a lot of indirect evidence that mechanisms lowering LDL cholesterol and probably apo B 100 containing lipoprotein particles by induction of the
Downloaded from cpr.sagepub.com at FRESNO PACIFIC UNIV on January 20, 2015
XML Template (2015) [14.1.2015–7:33am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140179/APPFile/SG-CPRJ140179.3d
(CPR)
[1–7] [PREPRINTER stage]
Mu¨ller-Wieland et al.
3
LDL receptor in liver are associated with cardiovascular risk reduction.6 In conclusion, because of the linear relationship between LDL-cholesterol lowering and reduction of coronary events, treat-to-target recommendations remain justified, considering that a reduction of LDLcholesterol by 30% in low-risk, or >40% in mediumrisk, or even of 50% in high-risk individuals, should be achieved when drug treatment is initiated, with statins being the drug of first choice.
Global risk assessment and statin-benefit groups The ACC/AHA guidelines1 recommend using the Pooled Cohort Equations to estimate 10-year ASCVD risk in White and Black men and women. Based on the results of a systematic review, the guidelines focus on four statin-benefit groups for ASCVD risk reduction: 1. Individuals with clinical ASCVD; 2. Individuals with primary elevations of LDLcholesterol 190 mg/dl (4.9 mmol/l); 3. Individuals 40–75 years of age with diabetes and LDL-cholesterol 70–189 mg/dl (1.8–4.9 mmol/l); 4. Individuals without clinical ASCVD or diabetes, 40–75 years of age, with LDL-cholesterol
70–189 mg/dl (1.8–4.9 mmol/l) and an estimated 10-year risk for ASCVD risk 7.5%. Although the validation of the Pooled Cohort Equations appeared adequate in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study,16 the assumed advantage for clinical management over current risk estimations appears questionable. Using data from several studies, the ASCVD algorithm overestimated cardiovascular risk by 1.5 - to 3-fold.17,18 We found a similar degree of overestimation based on data from the PROCAM study (Figure 1). The observed event rates show that individuals aged 60–69 years without ASCVD but with diabetes, LDL-cholesterol 190 mg/dl (4.9 mmol/l) without diabetes, or ACC/AHA risk 7.5% without diabetes are in the intermediate-risk group (i.e. an event rate of 10–20% over 10 years). All risk groups in the younger categories had observed event rates consistent with low risk. For primary prevention, the ACC/AHA guidelines recommend statin treatment for individuals with diabetes aged 40–70 years, LDL-cholesterol 190 mg/dl (4.9 mmol/l), LDL-cholesterol between 70 mg/dl and 189 mg/dl (1.8–4.9 mmol/l), or an estimated 10-year event rate 7.5%. Figure 2 shows an evaluation of these assumptions using the German PROCAM database. These data indicate that among individuals aged 60–69 years, 55.3% of men and 46.3% of women would
Risk ≥ 7.5% (no diabetes, LDL-C < 190 mg/dl) 20
LDL-C ≥ 190 mg/dl (no diabetes) Diabetes
16.3
17.1
16
Rate (%)
14.3 12 9.9 8.9
8.3 8
5.5 4.6 4 2.2 0 40–49
50–59 Age group (years)
60–69
Figure 1. Observed rates of fatal and non-fatal myocardial infarction over 10 yearsa in men in the PROCAM database, according to the American College of Cardiology/American Heart Association (ACC/AHA) high-risk groups. ACC/AHA definitions (for three different age groups): diabetes (known disease or plasma glucose concentration >120 mg/dl (3.1 mmol/l)); low-density-lipoprotein cholesterol (LDL-C) 190 mg/dl (4.9 mmol/l) without diabetes; and risk 7.5% without diabetes and LDL-C 55 years would fulfil the new ACC/AHA criteria for statins.18 Therefore
refinement in the application for intermediate risk and younger individuals as well as for ethnically diverse populations has been suggested.20 In conclusion, low target values for LDL-cholesterol should be reached in individuals with high coronary risk, and in low-risk groups the benefit versus harm of statin therapy should be individualized. Overall, the new ACC/AHA algorithm overestimates cardiovascular risk in several European and US populations and might induce over-treatment.
Diabetes and statins Risk overestimation based on the ACC/AHA guidelines extends the indication and intensity of statin treatment and increases the number needed to treat to reach benefit, with immediate adverse implications for the cost–benefit ratio. It is important to keep in mind that the number needed to harm will at best remain the same whereas the medical benefit–harm ratio will worsen, and may be of particular relevance in populations with increased statin sensitivity. Exposure to higher quantities and dosages of statins will increase the risk of statin-associated myopathy and diabetes.21 Whereas myopathy may be self-limiting through noncompliance in affected patients, the prodiabetic effects of statins (because of the absence of symptoms) may become a problem if the indication for intensive statin therapy widens. Recent meta-analyses provide consistent evidence that statins increase the incidence or trigger the manifestation of diabetes22 and may be related to intensity of treatment.23 Whether some statins are more diabetogenic than others is unknown. The incidence of diabetes in patients with elevated absolute cardiovascular risk is too low to challenge their large cardiovascular benefit, but may be relevant to individuals at low risk. In statin trials, symptoms, HbA1c or fasting plasma glucose concentrations have been used to evaluate the incidence of diabetes. Although specific, these parameters are not very sensitive, and the risk of diabetes may have been underestimated. One may argue that elevations of glucose or HbA1c beyond the diagnostic cut-offs are soft surrogate rather than hard clinical endpoints. However, the impact of statins on non-macrovascular complications of diabetes related to glycaemic control is little explored. A recent document has reviewed and provided guidance for the use of statins in people at risk of developing new-onset diabetes.24 Physicians should assess the patient’s risk before starting statin therapy, educate them about their risk and encourage lifestyle changes, particularly in view of data showing an increase in
Downloaded from cpr.sagepub.com at FRESNO PACIFIC UNIV on January 20, 2015
XML Template (2015) [14.1.2015–7:33am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140179/APPFile/SG-CPRJ140179.3d
(CPR)
[1–7] [PREPRINTER stage]
Mu¨ller-Wieland et al.
5
(a) 100
Prevalence (%)
80 60 40
Treatment with statin indicated according to ACC/AHA guidelines
6.3% 8.3% 13.5% 11.7% 18.5% 16.9% 30.1% 0.6% 19.7% 55.3% 2.6% 4.9% 13.0% 22.1% Diabetes
LDL-C ≥ 190 mg/dl (no diabetes)
78.9% 24.0%
56.9%
Risk ≥ 7.5% (no diabetes, LDL-C < 190 mg/dl)
20
Risk 5.0 to < 7.5% (no diabetes, LDL-C < 190 mg/dl)
20.7%
Risk < 5% (no diabetes, LDL-C < 190 mg/dl)
0 40–49
50–59 60–69 Age group (years)
(b) 100
5.7% 6.9%
Prevalence (%)
12.5% 6.1% 0.0% 0.1%
80
19.5%
87.4%
11.1% 25.6% 0.0% 33.3% 0.1%
60 40
Treatment with statin indicated according to ACC/AHA guidelines
46.3%
9.3% 1.9% 73.1% 44.4%
20 0 40–49
50–59 60–69 Age group (years)
Figure 2. Prevalence of atherosclerotic cardiovascular disease risk groups, according to the American College of Cardiology/ American Heart Association (ACC/AHA) risk-prediction algorithm, in (a) men and (b) women in the PROCAM database. a Adjusted by a factor of 0.43 for the German population. ACC/AHA definitions (for three different age groups): diabetes (known disease or plasma glucose concentration >120 mg/dl (3.1 mmol/l)); low-density-lipoprotein cholesterol (LDL-C) 190 mg/dl (4.9 mmol/l) without diabetes; risk 7.5% without diabetes and LDL-C
(CPR)
[1–7] [PREPRINTER stage]
EURO PEAN SO CIETY O F CARDIOLOGY ®
Original scientific paper
Treat-to-target versus dose-adapted statin treatment of cholesterol to reduce cardiovascular risk
European Journal of Preventive Cardiology 0(00) 1–7 ! The European Society of Cardiology 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2047487314567001 ejpc.sagepub.com
Dirk Mu¨ller-Wieland1, Gerd Assmann2, Rafael Carmena3, Jean Davignon4, Arnold von Eckardstein5, Eduardo Farinaro6, Heiner Greten7, Anders G Olsson8, Walter F Riesen9 and Evgenyi Shlyakhto10
Abstract Clinical guidelines should be based on the best available evidence and are of great importance for patient care and disease prevention. In this respect, the 2013 American College of Cardiology/American Heart Association report is highly appreciated and well-recognized. The report included critical questions concerning hypercholesterolaemia, but its translation into a clinical guideline initiated intense debate worldwide because of the recommendation to switch from a treat-to-target approach for low-density-lipoprotein-cholesterol to a statin dose-based strategy.
Keywords Hypercholesterolaemia, cardiovascular prevention Received 13 October 2014; accepted 13 December 2014
What is ‘different’ in the 2013 American College of Cardiology/American Heart Association guideline? In the American College of Cardiology/American Heart Association (ACC/AHA) report1 the authors recommend early and effective low-density lipoprotein (LDL)-cholesterol lowering through statin treatment for the reduction of atherosclerotic cardiovascular disease (ASCVD). They defined four groups that would benefit from statin treatment and recommended using the Pooled Cohort Equations to estimate individual
10-year ASCVD risk.2 This approach translated into two major changes to current recommendations: to substitute current target concentrations for lowering LDL-cholesterol with dose-adapted statin therapy; and to score global risk assessment by including risk for stroke and four clinical scenarios with evidence for statin benefit.
7
1
Hanseatic Heart Centre, Asklepios Clinic St Georg, Hamburg, Germany Department of Medicine and Health, Faculty of Health Sciences, University of Linko¨ping and Stockholm Heart Centre, Sweden 9 Institute for Laboratory Medicine, St Gallen, Switzerland 10 Almazov Research Institute of Cardiology, Russian Federation Agency of Health and Social Development, Saint Petersburg, Russia 8
Department of General Internal Medicine, Head, Endocrinology, Diabetes and Metabolism, Asklepios Clinic St Georg, Hamburg, Germany 2 Assmann-Foundation for Prevention, Mu¨nster, Germany 3 Universitat de Vale`ncia and Director-General of Fundacio´n INCLIVA, Valencia, Spain 4 Institut de recherches cliniques de Montre´al (IRCM), Faculty of Medicine at the Universite´ de Montre´al, Canada 5 Institute of Clinical Chemistry of the University Hospital of Zurich, Switzerland 6 Department Public Health, Medical School University of Naples Federico II, Italy
Corresponding author: Dirk Mu¨ller-Wieland, Department of General Internal Medicine, Head, Endocrinology, Diabetes and Metabolism, Asklepios Clinic St Georg, Asklepios Campus Hamburg, Medical Faculty, Semmelweis University, Lohmu¨hlenstr. 5, Haus O – D-20099 Hamburg, Germany. E-mail: [email protected]
Downloaded from cpr.sagepub.com at FRESNO PACIFIC UNIV on January 20, 2015
XML Template (2015) [14.1.2015–7:33am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140179/APPFile/SG-CPRJ140179.3d
(CPR)
[1–7] [PREPRINTER stage]
2
European Journal of Preventive Cardiology 0(00)
Recommendations of the International Task Force For the Prevention of Cardiometabolic Diseases The following position statement from the International Task Force for the Prevention of Cardiometabolic Diseases (ITF-PCD) focuses on specific aspects of the debate from an international perspective, drawing the following conclusions: 1. Risk-stratified treat-to-target concentrations should remain the goal for lowering LDL-cholesterol. 2. Risk scores for prevention of cardiovascular complications should focus on coronary heart disease events. 3. Under-treatment of high-risk individuals may occur in the absence of LDL-cholesterol target concentrations. 4. Over-treatment of low-risk individuals may occur if statin-based treatment is used in accordance with the ACC/AHA guidelines.1 Considering the joint statements from the International Atherosclerosis Society (IAS) and the International Task Force for the Prevention of Coronary Heart Disease from 2009,3 the ITF-PCD reemphasizes the value of the target-orientated strategy of LDL-cholesterol lowering for clinical practice and individualized patient care. We therefore support the recent recommendations of the European Society of Cardiology/European Atherosclerosis Society (ESC/ EAS),4 the ESC,5 the National Lipid Association6 and the IAS.7 The International Task Force, renamed ITF-PCD in 2014, has long advocated the concept of global cardiovascular risk when making treatment decisions for lipid disorders. Therefore the decision to declare global risk alone as the clinical criterion for initiating cholesterollowering therapy is highly appreciated. Although there are no clinical prospective trials titrating target levels, we want to reinforce positions of different scientific societies, that risk-stratified treat-to-target concentrations should remain the goal for lowering LDL-cholesterol when clinical evidence is translated into clinical practice.3–7 This is an important statement, because otherwise health authorities may limit individualized patient-centred decision-making.
Risk-stratified treat-to-target The Third Report of the National Cholesterol Education Program recommended a target-orientated treatment algorithm for LDL-cholesterol, elevated with respect to the patient’s underlying coronary risk8,9 and based on a substantial bank of evidence
from emerging trials. This general approach was also taken by the ESC/EAS, in which different target LDLcholesterol concentrations were recommended in relation to current cardiovascular risk.4 The ESC/EAS Task Force proposed reducing LDL-cholesterol by 50%, especially when the target concentration cannot be achieved. The recommendation to reduce LDL-cholesterol to a relevant range following initiation of drug treatment is also included in the American Diabetes Association (ADA) recommendations.10 The ACC/AHA group questions the value of targetorientated therapy, with arguments that the end-points in LDL-cholesterol-lowering studies were not designed to prove the value of this strategy, and all were performed with statins. Therefore the authors recommend treating patients with risk-adapted high, medium or low doses of statins according to their potency for percentage reduction of LDL-cholesterol. Overwhelming evidence exists for statins in terms of reducing ASCVD. However, to propose a change in the treatment algorithm from LDL-cholesterol targets to statin doses, based on pure evidence, is not convincing for clinical practice. Although randomized trial comparisons are based on statin doses – the strategy recommended by the ACC/AHA – giving different doses according to individual risk has never been tested prospectively in an appropriate study. Furthermore, response rates to statins have wide inter-individual variability, and should be taken into consideration if fixed doses are recommended; indeed, response rates should be monitored in the clinical setting to achieve appropriate risk reduction, indeed ACC/AHA recommends to control LDL-cholesterol levels to monitor the degree of relative reduction. The argument for achieving the percentage changes in LDL-cholesterol concentrations attained in clinical studies using the maximum dose of statins disregards all other clinical, pathophysiological and molecular evidence about the causal and linear relationship of LDL-cholesterol lowering to reduction of coronary risk. There is direct evidence that more-intensive therapy to lower LDL-cholesterol is of benefit, and that in high-risk patients lower on-treatment target concentrations are associated with lower event rates.11,12 Trial data suggest there is no threshold.13 Individuals with very low LDL-cholesterol have a very low longterm risk, even in the presence of other risk factors,14 and there is indirect evidence that low LDL-cholesterol concentrations induce mechanisms related to plaque stabilization and possibly also plaque regression.15 We are aware of the fact that some drugs, such as niacin and CETP-inhibitors, have not yet been proven to reduce cardiovascular risk in relation to LDL-cholesterol lowering, but there is a lot of indirect evidence that mechanisms lowering LDL cholesterol and probably apo B 100 containing lipoprotein particles by induction of the
Downloaded from cpr.sagepub.com at FRESNO PACIFIC UNIV on January 20, 2015
XML Template (2015) [14.1.2015–7:33am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140179/APPFile/SG-CPRJ140179.3d
(CPR)
[1–7] [PREPRINTER stage]
Mu¨ller-Wieland et al.
3
LDL receptor in liver are associated with cardiovascular risk reduction.6 In conclusion, because of the linear relationship between LDL-cholesterol lowering and reduction of coronary events, treat-to-target recommendations remain justified, considering that a reduction of LDLcholesterol by 30% in low-risk, or >40% in mediumrisk, or even of 50% in high-risk individuals, should be achieved when drug treatment is initiated, with statins being the drug of first choice.
Global risk assessment and statin-benefit groups The ACC/AHA guidelines1 recommend using the Pooled Cohort Equations to estimate 10-year ASCVD risk in White and Black men and women. Based on the results of a systematic review, the guidelines focus on four statin-benefit groups for ASCVD risk reduction: 1. Individuals with clinical ASCVD; 2. Individuals with primary elevations of LDLcholesterol 190 mg/dl (4.9 mmol/l); 3. Individuals 40–75 years of age with diabetes and LDL-cholesterol 70–189 mg/dl (1.8–4.9 mmol/l); 4. Individuals without clinical ASCVD or diabetes, 40–75 years of age, with LDL-cholesterol
70–189 mg/dl (1.8–4.9 mmol/l) and an estimated 10-year risk for ASCVD risk 7.5%. Although the validation of the Pooled Cohort Equations appeared adequate in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study,16 the assumed advantage for clinical management over current risk estimations appears questionable. Using data from several studies, the ASCVD algorithm overestimated cardiovascular risk by 1.5 - to 3-fold.17,18 We found a similar degree of overestimation based on data from the PROCAM study (Figure 1). The observed event rates show that individuals aged 60–69 years without ASCVD but with diabetes, LDL-cholesterol 190 mg/dl (4.9 mmol/l) without diabetes, or ACC/AHA risk 7.5% without diabetes are in the intermediate-risk group (i.e. an event rate of 10–20% over 10 years). All risk groups in the younger categories had observed event rates consistent with low risk. For primary prevention, the ACC/AHA guidelines recommend statin treatment for individuals with diabetes aged 40–70 years, LDL-cholesterol 190 mg/dl (4.9 mmol/l), LDL-cholesterol between 70 mg/dl and 189 mg/dl (1.8–4.9 mmol/l), or an estimated 10-year event rate 7.5%. Figure 2 shows an evaluation of these assumptions using the German PROCAM database. These data indicate that among individuals aged 60–69 years, 55.3% of men and 46.3% of women would
Risk ≥ 7.5% (no diabetes, LDL-C < 190 mg/dl) 20
LDL-C ≥ 190 mg/dl (no diabetes) Diabetes
16.3
17.1
16
Rate (%)
14.3 12 9.9 8.9
8.3 8
5.5 4.6 4 2.2 0 40–49
50–59 Age group (years)
60–69
Figure 1. Observed rates of fatal and non-fatal myocardial infarction over 10 yearsa in men in the PROCAM database, according to the American College of Cardiology/American Heart Association (ACC/AHA) high-risk groups. ACC/AHA definitions (for three different age groups): diabetes (known disease or plasma glucose concentration >120 mg/dl (3.1 mmol/l)); low-density-lipoprotein cholesterol (LDL-C) 190 mg/dl (4.9 mmol/l) without diabetes; and risk 7.5% without diabetes and LDL-C 55 years would fulfil the new ACC/AHA criteria for statins.18 Therefore
refinement in the application for intermediate risk and younger individuals as well as for ethnically diverse populations has been suggested.20 In conclusion, low target values for LDL-cholesterol should be reached in individuals with high coronary risk, and in low-risk groups the benefit versus harm of statin therapy should be individualized. Overall, the new ACC/AHA algorithm overestimates cardiovascular risk in several European and US populations and might induce over-treatment.
Diabetes and statins Risk overestimation based on the ACC/AHA guidelines extends the indication and intensity of statin treatment and increases the number needed to treat to reach benefit, with immediate adverse implications for the cost–benefit ratio. It is important to keep in mind that the number needed to harm will at best remain the same whereas the medical benefit–harm ratio will worsen, and may be of particular relevance in populations with increased statin sensitivity. Exposure to higher quantities and dosages of statins will increase the risk of statin-associated myopathy and diabetes.21 Whereas myopathy may be self-limiting through noncompliance in affected patients, the prodiabetic effects of statins (because of the absence of symptoms) may become a problem if the indication for intensive statin therapy widens. Recent meta-analyses provide consistent evidence that statins increase the incidence or trigger the manifestation of diabetes22 and may be related to intensity of treatment.23 Whether some statins are more diabetogenic than others is unknown. The incidence of diabetes in patients with elevated absolute cardiovascular risk is too low to challenge their large cardiovascular benefit, but may be relevant to individuals at low risk. In statin trials, symptoms, HbA1c or fasting plasma glucose concentrations have been used to evaluate the incidence of diabetes. Although specific, these parameters are not very sensitive, and the risk of diabetes may have been underestimated. One may argue that elevations of glucose or HbA1c beyond the diagnostic cut-offs are soft surrogate rather than hard clinical endpoints. However, the impact of statins on non-macrovascular complications of diabetes related to glycaemic control is little explored. A recent document has reviewed and provided guidance for the use of statins in people at risk of developing new-onset diabetes.24 Physicians should assess the patient’s risk before starting statin therapy, educate them about their risk and encourage lifestyle changes, particularly in view of data showing an increase in
Downloaded from cpr.sagepub.com at FRESNO PACIFIC UNIV on January 20, 2015
XML Template (2015) [14.1.2015–7:33am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140179/APPFile/SG-CPRJ140179.3d
(CPR)
[1–7] [PREPRINTER stage]
Mu¨ller-Wieland et al.
5
(a) 100
Prevalence (%)
80 60 40
Treatment with statin indicated according to ACC/AHA guidelines
6.3% 8.3% 13.5% 11.7% 18.5% 16.9% 30.1% 0.6% 19.7% 55.3% 2.6% 4.9% 13.0% 22.1% Diabetes
LDL-C ≥ 190 mg/dl (no diabetes)
78.9% 24.0%
56.9%
Risk ≥ 7.5% (no diabetes, LDL-C < 190 mg/dl)
20
Risk 5.0 to < 7.5% (no diabetes, LDL-C < 190 mg/dl)
20.7%
Risk < 5% (no diabetes, LDL-C < 190 mg/dl)
0 40–49
50–59 60–69 Age group (years)
(b) 100
5.7% 6.9%
Prevalence (%)
12.5% 6.1% 0.0% 0.1%
80
19.5%
87.4%
11.1% 25.6% 0.0% 33.3% 0.1%
60 40
Treatment with statin indicated according to ACC/AHA guidelines
46.3%
9.3% 1.9% 73.1% 44.4%
20 0 40–49
50–59 60–69 Age group (years)
Figure 2. Prevalence of atherosclerotic cardiovascular disease risk groups, according to the American College of Cardiology/ American Heart Association (ACC/AHA) risk-prediction algorithm, in (a) men and (b) women in the PROCAM database. a Adjusted by a factor of 0.43 for the German population. ACC/AHA definitions (for three different age groups): diabetes (known disease or plasma glucose concentration >120 mg/dl (3.1 mmol/l)); low-density-lipoprotein cholesterol (LDL-C) 190 mg/dl (4.9 mmol/l) without diabetes; risk 7.5% without diabetes and LDL-C
