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The New Dyslipidemia Guidelines: What Is the Debate?
Accepted Manuscript The New Dyslipidemia Guidelines: What is the Debate? Todd J. Anderson , MD, GB John Mancini , MD, Jacques Genest , Jr., MD, Jean Grégoire , MD, Eva M. Lonn , MD, Robert A. Hegele , MD PII:
S0828-282X(14)01570-0
DOI:
10.1016/j.cjca.2014.11.007
Reference:
CJCA 1472
To appear in:
Canadian Journal of Cardiology
Received Date: 22 September 2014 Revised Date:
5 November 2014
Accepted Date: 6 November 2014
Please cite this article as: Anderson TJ, Mancini GJ, Genest Jr. J, Grégoire J, Lonn EM, Hegele RA, The New Dyslipidemia Guidelines: What is the Debate?, Canadian Journal of Cardiology (2014), doi: 10.1016/j.cjca.2014.11.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The New Dyslipidemia Guidelines: What is the Debate?
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Todd J. Anderson, MDa, GB John Mancini, MDb, Jacques Genest Jr., MDc, Jean Grégoire, MD , Eva M.
Lonn, MDe, Robert A. Hegele, MDf
b. University of British Columbia, Vancouver, BC
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c. McGill University Health Centre, Montreal Quebec
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a. Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary Alberta
d. Institut de Cardiologie de Montréal, Université de Montréal, Montreal Quebec e. Population Health Research Institute, McMaster University, Hamilton ON Robarts Research Institute, Western University, London, ON
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Address for correspondence: Todd J. Anderson, Libin Cardiovascular Institute of Alberta, University of Calgary
1403-29th St NW Calgary, Alberta, T2N 2T9 Email: [email protected] Telephone: 403 944-1033 Fascimile: 403 944-1592 1
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Abstract Dyslipidemia is a major risk factor for the development of atherosclerotic disease. Therefore lifestyle interventions and pharmacological approaches to lower cholesterol are widely used in cardiovascular
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disease prevention. The introduction and widespread use of HMG Co-A reductase inhibitors (statins) for individuals at risk of atherosclerotic disease has been an important advance in cardiovascular care. There can be no doubt that better control of dyslipidemia, even in subjects whose low density
lipoprotein cholesterol (LDL-C) level is not particularly high, has reduced overall event rates. On a
background of lifestyle interventions, statins are routinely used to lower risk along with aspirin and
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interventions to control hypertension and diabetes. More than other risk factors, the approach to the identification and treatment of dyslipidemia has been heterogeneous and widely debated. The recent
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release of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Dyslipidemia guidelines has reignited the controversy over the best approach for risk stratification and treatment. In this article we will review the importance of statin therapy for global cardiovascular risk reduction, compare the Canadian Cardiovascular Society (CCS) Dyslipidemia guidelines with other standards, and discuss the points of debate. Despite the seeming variety of recommendations, their common link is a systematic approach to risk stratification and treatment, which will continue to benefit our patients at
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risk.
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Brief Summary Dyslipidemia is a major risk factor for the development of atherosclerotic disease. Therefore lifestyle interventions and pharmacological approaches to lower cholesterol are widely used. The recent release
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of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Dyslipidemia guidelines has raised questions over the best approach for risk stratification and treatment. We review the importance of statin therapy for global cardiovascular risk reduction, and compare the Canadian
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Cardiovascular Society (CCS) Dyslipidemia guidelines with other standards.
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Dyslipidemia and Global Cardiovascular Risk Despite the greater than 50% decrease in age-adjusted cardiovascular mortality over the past several decades, atherosclerotic disease is the leading cause of death in women and second leading cause of
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death in men in Canada. Morover, cardiovascular disease accounts for more than half of all noncommunicable diseases (NCDs) and has become the leading cause of death worldwide, a fact affirmed by the World Health Organization 1. Large cohort studies dating back to the Framingham Heart Study have identified cholesterol as a modifiable risk factor, which can be treated with lifestyle and
pharmacological interventions 2. Total cholesterol levels have fallen in high income countries over the
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past two decades by 8-10% on average. Some countries with the highest levels were able to decrease levels more than this with targeted societal interventions, leading directly to dramatic decreases in
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event rates. As part of the United Nations declaration on NCDs, with a goal of reducing premature death by 25%, their target is a 20% relative reduction in high total cholesterol by 2025. To be truly effective, the treatment of dyslipidemia needs to be incorporated into a comprehensive plan of global risk reduction for patients at risk. This will involve lifestyle modification, policy change and pharmacotherapy.
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Similarities and Differences in Dyslipidemia Guidelines
New dyslipidemia guidelines were released by the European Society of Cardiology/European Atherosclerosis Society (ESC/ESA) in 2011 3, the CCS in 2012 4, the International Atherosclerosis Society (IAS) 5 and the ACC/AHA both in 2013 6. All are similar in many respects, yet have some key differences
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that are worthy of discussion. The 2012 CCS guidelines recommended risk stratification using the total CVD Framingham risk score 7, advocated the use of LDL-C thresholds for the initiation of treatment in low and intermediate risk subjects and expanded the phenotype of high risk subjects to include subjects
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with atherosclerosis, most patients with diabetes, high risk hypertension (per ASCOT inclusion criteria) 8 and pre-dialysis chronic kidney disease (CKD). LDL-C continues to be used as the atherogenic metric, but now both non-HDL-C and apolipoprotein B (apo B) could be measured as alternatives, especially under circumstances when LDL-C calculations are known to be erroneous. Once treatment is initiated, LDL-C (< 2.0 mmol/L or 50% reduction) continues to be the primary target of therapy. The CCS guidelines have been harmonized with other relevant Canadian guidelines as part of the C-CHANGE initiative9.
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The ESC/EAS guidelines was a comprehensive document that encouraged the use of the Systematic Coronary Risk Evaluation (SCORE) total cardiovascular mortality 10 calibrated for high or low risk countries in Europe. Of note that the SCORE risk assessment is also based on the Framingham risk equation. LDL-C thresholds were suggested with non-HDL-C or apo B as alternatives. The European
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guidelines also recognized CKD as very high risk equivalent. Target levels of LDL-C were recommended but unlike the CCS guidelines, the goals were different between those at very high risk (<1.8 mmol/L) compared with those at high risk (<2.5 mmol/L) or intermediate risk (<3.0 mmol/L).
The IAS panel decided to recommend lifetime CV risk based on 4 different tools depending on ethnicity.
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They favoured non-HDL-C as the primary atherogenic metric for risk determination, with LDL-C as a secondary measure. Optimal levels were defined based on criteria from ATP III, but did not recommend
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treatment targets. The intensity of statin therapy should be adjusted according to overall lifetime risk and practitioner practice.
The ACC/AHA guidelines were the latest to be released and created the most controversy6. A major novel aspect of these guidelines was the recommendation to calculate risk using the newly developed Pooled Cohort equation. This approach represents a departure from the use of the Framingham risk score, used for decades. Of the four groups targeted for statin based therapy 3 were the same as the
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CCS guidelines. These include subjects with a) clinical evidence of atherosclerosis; b) most subjects with diabetes and c) individuals with LDL-C ≥ 5.0 mmol/L. The fourth group includes subjects with a 10 year risk of total atherosclerotic events calculated using the Pooled Cohort equation of ≥ 7.5% 11. There was no specific recommendation for CKD and other populations such as genetic dyslipidemia or high-risk
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hypertension. An additional novel aspect of these guidelines was the lack of specific targets of therapy. While these guidelines recommend the use of high or moderate intensity statin regimens based on level
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of risk and anticipate a 50% LDL-C lowering with high intensity statin therapy, there is no recommendation for treating to any specific target. Therefore, lipid measurements after initiation of statin therapy are recommended mainly to ensure adherence. What are the Controversies with the ACC/AHA Guidelines Anyway? 1. Risk Engine was not Validated: An important component of the American guidelines was the introduction of the race and gender specific Pooled Cohort Equations risk engine 11. This was based on recent US cohort studies including Atherosclerosis Risk in Communities (ARIC) study , 5
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Cardiovascular Health Study (CHS), Coronary Artery Disease Risk Development in Young Adults (CARDIA) and the Framingham original and offspring studies. While novel risk factors were considered, the final Pooled Cohort Equations model included the same parameters as Framingham risk models 7. The end-points in the model include hard atherosclerotic vascular
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events including cardiovascular death, myocardial infarction and stroke. The most recent total Framingham risk model also includes heart failure and claudicaton as end-points. As such the intermediate risk threshold of 7.5% proposed as the level for statin therapy corresponds to a higher Framingham risk when compared to the previously used algorithm, however this
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conversion was not made clear in the original document. The new risk engine was proposed to be appropriate for Caucasian or African-American individuals between 40 and 79.
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Shortly after the introduction of the document, concern was raised that the model had not been adequately calibrated. Ridker and Cook demonstrated that the new model overestimated risk compared with the observed event rates in the Physicians Health Study and the Women’s Health Initiative cohorts 12. This was also true for the Multi-Ethnic Atherosclerosis Study (MESA) and Stroke Study. These authors concluded that the overestimation could result in up to 40% of those identified as being eligible for statin therapy based on > 7.5% risk as not actually requiring
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therapy. In a subsequent study that utilized Rotterdam study participants (n=4854), the new Pooled Cohort equations model was applied to the ACC/AHA, ATP-III and ESC guidelines. The new risk engine, again tended to overestimate events 13. Finally, Muntner and colleagues used the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort and
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demonstrated good calibration and moderate to good discrimination for the new model 14. It is well accepted that models often overestimate risk given the increased use of risk reduction therapy including statins in contemporary cohorts. The declining incidence of atherosclerotic
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events and difficulty in adjudication of events in cohort studies, makes accurate evaluation challenging. It does however reinforce our view that risk engines are imprecise tools, which may provide the clinician with rough guidance but do not replace clinical acumen and a robust dialogue with patients, particularly in primary prevention. The new Pooled Cohort Equations tool requires further study with respect to its calibration and discrimination metrics. A recent analysis reaffirmed the importance of age in achieving threshold levels for treatment with the new model 15. However, the reader should remember 6
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that head to head comparisons between risk algorithms tend to yield fairly disparate results 16, which is the reason that different models are utilized by different guidelines committees. The Canadian Cardiovascular Society dyslipidemia guidelines committee decided on the total cardiovascular events Framingham risk model (Table 1). Similarly the European community has
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shown faith in the Systemic Coronary Risk Estimation (SCORE) charts that utilizes fatal
cardiovascular events 17,18. Despite differences these and other models tend to perform
similarly for primary prevention populations where the study population of the model reflects the country of use. Thus, at the present time, the CCS primary panel did not recommend any
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change in the method of risk assessment in light of the ACC/AHA recommendations 19. We strongly urge clinicians screening for cardiovascular risk to adopt an algorithm that is most simple to integrate within their practice and to maximize the numbers of patients who undergo
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a quantitative evaluation of their risk. By doing this, statin use will be more appropriately allocated and risk more optimally reduced.
2. The ACC/AHA guidelines will result in increased statin use: It was recognized at the time of the publication of the new guidelines that the transition from ATP-III to the new recommendations would increase the number of individuals potentially eligible for statin therapy. Pencini et al.
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evaluated the NHANES surveys from 2005 to 2010 and extrapolating the results to the 115 M Americans between the ages of 40-75 years 20. Adoption of the new ACC/AHA guidelines would increase eligibility from 37.5 to 48.6% in this age range. Most of the 12.8 M person increase would be drawn from those without cardiovascular disease (i.e. primary prevention). The
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biggest increase would be in those over the age of 60, particularly men. This is a result of the importance of age in the Pooled Cohort equation calculation of risk (threshold >7.5%). In the Swiss CoLaus study, individuals 50-75 years of age, had risk calculated using the Swiss SCORE
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equation and the new ACC/AHA algorithm 21. Based on their survey, there would be a doubling of treated subjects particularly in those 50-60 years if the American guidelines were utilized. Kavousi compared the ESC, ATP-III and new ACC/AHA guidelines in 4854 subjects from the Rotterdam study with a mean age of 65 years 13. Given the older age of this population the ACC/AHA guidelines would recommend statins for 96% of men and 66% of women an increase of 1.5 to 2 fold compared with the previous guidelines. Finally, we recently evaluated the current CCS and ACC/AHA guidelines in the Firefighters and their Endothelium (FATE) cohort22 Within this cohort, 1267 men without vascular disease between the age of 40 and 79 (mean age 7
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51.9 ± 7.8 yrs) were evaluated for statin eligibility based on the CCS and ACC/AHA guidelines. Firstly the mean FRS was 14.8 ± 10% and this compared with a Pooled Cohort equation risk of 7.7 ± 8.2 %. Secondly, 570 (45%) of subjects would be eligible for statin therapy with the CCS guidelines compared with 422 (33%) by the ACC/AHA guidelines. This was age dependent as
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shown in figure 1. Similarly, mathematical modeling was done by Mancini demonstrating similar rates of statin eligibility between the two guidelines 23. Thus, controversy that the new ACC/AHA guidelines would increase statin use solely on the basis of risk calculation in Canada is
unfounded. This is likely because in the transition from the 2006 to 2009 guidelines 24 there was
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a move from the old Framingham algorithm (that was used in ATP-III) 2 to the total
cardiovascular Framingham model of D’Agostino 7. This was a shift unrecognized by most practitioners, which increased the number of Canadians eligible for statin therapy. Moreover,
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the analysis by Mancini et al. emphasized that the identification of more patients eligible for therapy by the ACC/AHA guidelines was more a result of the dramatic lowering of the LDL-C threshold to 1.8 mmol/L warranting therapy in sufficiently at risk patients as opposed to the new mathematical underpinnings of the Pooled Cohort Equation22. 3. The elimination of atherogenic lipoprotein targets: The new ACC/AHA guidelines were
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distinctly different from most previous recommendations in that they have discarded specific LDL-C (or alternative) targets once subjects are initiated on therapy. The rationale for this change was that no previous randomized trial specifically addressed whether a particular level produced greater event reduction. Secondly, by eliminating targets it was felt that primary care
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treatment would be more straightforward and easier to implement. Thirdly, having targets potentially promotes combination therapy, for which there is currently no good evidence from randomized trials. This is supported by data from meta-analysis of trials of fibrate therapy, AIM-
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HIGH and HPS2-THRIVE. 25-27 While this interpretation is literally correct, it fails to recognize several issues in the history of statin trials: the initial trials were as much studies of the lipid hypothesis as they were trials of statins. Thus the first trials were in patients with the highest risk and highest cholesterol levels but at a time when only moderately potent statins were available, hence the use of the highest dose feasible. As success was shown, and as more potent statins became available, ethical considerations mandated that research subjects had to have lower and lower risk and lower and lower cholesterol levels, again promoting use of the highest available dose. The latter was also influenced by a need to ensure simplicity in large 8
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trials and, to some extent, by marketing designed to promote drug potency differences. There are also five trials of higher versus lower potency statins, which show consistent improvement in outcomes with the higher potency statin. The lowest risk cohort studied to date in the JUPITER study reaped comparable benefit using the most potent statin currently available. Remarkably,
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no lower limit of achieved LDL-C beyond which benefit is accrued has yet been shown. The CCS Dyslipidemia guideline primary panel reviewed these issues in early 2014 and recommended that until further evidence was available, we would continue to support the use of targets. Similarly others have taken this view as well 3,5. Although it is certainly true that randomized
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trials have utilized generally a single statin dose approach, as opposed to a target LDL-C level, the epidemiology suggesting that lower levels of achieved LDL-C result in less events is rather compelling 28. Also, regression studies with intravascular ultrasound (IVUS) demonstrate a linear
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relationship between LDL-C and the amount of regression 29. The crossing point for regression tends to occur at an LDL-C of around 2 mmol/L or a 50% reduction. A very recent meta-analysis utilized individual patient data from 8 statin trials 30. On a fixed dose of statin, there was a very large inter-individual variation in LDL-C reduction with statins. In addition, more than 40% of subjects did not achieve targets of less than 1.8 mmol/L on a fixed statin dose. Those who achieve very low levels of LDL-C had a lower event rate than those who achieved modest levels.
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The same trend was seen for non-HDL-C and apolipoprotein B. The editorial accompanying this paper rightly points out that the majority of the studies in the meta-analysis used fixed dose statins, as opposed to titrated doses 31. Therefore, the lower achieved LDL-C levels may theoretically have been due to some unique interactions between statins and the biology of the
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particular patients. It certainly leaves the door open for trials to address a target level approach. We will be able to test the “lower is better” hypothesis at very low levels of LDL-C once the
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results of ongoing trials utilizing non-statins (e.g. inhibitors of cholesterol absorption, PCSK9 and CETP) are known.
The ACC/AHA guidelines would appear at first blush to support a “fire and forget” approach. The text and algorithms do however suggest that measuring LDL-C after statin initiation is reasonable to help assess compliance and to ensure achievement of an expected percentage lowering of LDL-C. Compliance and adherence are important issues with statin therapy32 and beyond the scope of this review, but are certainly another practical reason that the CCS guidelines panel continues to recommend targets. Additionally, the text and algorithms of the 9
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ACC/AHA guidelines promote LDL-C measurement to ensure achievement of the expected response to moderate and high intensity statin dose choices and, when not achieved or in the face of statin intolerance, support dose escalation or addition of secondary, non-statin drugs.
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Other Questions arising from recent Guidelines: a. Chronic Kidney Disease (CKD): There is limited discussion of the impact of CKD on risk in the new ACC/AHA guidelines. We believe that pre-dialysis CKD should be elevated to a high risk category warranting therapy in the majority of people. This was based on solid
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epidemiology data from Alberta 33 along with the randomized Study Heart and Renal Protection (SHARP) study 34. The latter has the unique feature of showing improved outcome from LDL-C lowering when compared to placebo and the additional
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observation that combination therapy with statin and a cholesterol absorption inhibitor provided a risk lowering comparable to statin-only trials. Thus, CKD is recognized in the CCS and ESC guidelines as a very high risk state. The relationship between LDL-C and events tends to be weaker in non-dialysis dependent CKD patients and the prevailing LDL-C levels tend to be low, rendering traditional risk engines less precise 35. As such therapy is best initiated based on the phenotypic risk defined by levels of GFR and
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proteinuria. The Kidney Disease: Improving Global Outcomes (KDIGO) group do not recommend follow-up of LDL-C except to monitor adherence and similarly do not recommend therapy in dialysis dependent subjects. The KDIGO groups recommends statin therapy for subjects >50 years of age and a GFR < 60 ml/min/1.73m2 but not
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treated with dialysis or transplantation. The group also recommended statin therapy in subjects with a GFR > 60 ml/min/1.73m2 and CKD based on albumin:creatinine ratio as
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low as 3 mg/mmol. These new recommendations treat a broader spectrum of CKD patients than that suggested in the 2012 CCS guidelines. Foster et al. performed an analysis using NHANES data that determined incorporating the KDIGO guidelines would increase the number of statin eligible subjects by approximately 10%. However, this was based on the old ATP-III guidelines and not the 2013 ACC/AHA guidelines 36. The general consensus amongst the renal community is that broader use of statins should be implemented 37, something not addressed by the ACC/AHA guidelines.
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b. Appropriate Atherogenic metric: In the CCS guidelines, LDL-C continues to be the primary target for risk assessment and treatment targets. In addition to apo B the last guideline did add non-HDL-C as an alternate atherogenic marker. In ATP-III, non HDL-C was an alternate target, but the new guideline stated that they could find little evidence
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that non-HDL-C or apo B offered any advantage over LDL-C. The majority of other
guidelines continue to recommend LDL-C with most having non-HDL-C or apo B as
alternatives 17. The exception is the International Atherosclerosis Society that advocates non-HDL-C as the primary metric. Some epidemiological studies would suggest that
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either non-HDL-C or apo B are better risk predictors than LDL-C 38. Sniderman presents evidence that apoB is the best predictor and has advocated for its use 39. ApoB is an attractive marker as it reflects the number of atherogenic particles, can be measured in
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a non-fasting state and is particularly useful in subjects with metabolic syndrome. NonHDL-C can be easily calculated from a standard lipid panel, thus adds no cost and again does not require a fasting sample. There is increasing interest in a non-fasting approach. Mora and colleagues recently reported that there is significant discordance between these measures of atherogenic risk and when two measures were not aligned that risk could be under or over-estimated 40. They suggest that in those women with discordant
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measures, that the alternate measure might be better than LDL-C. At the present time, LDL-C remains a practical metric for atherogenic risk assessment, but both apo B and non-HDL-C offer potential advantages once clinicians become familiar with their use and the circumstances when LDL-C calculations are known to be misleading (e.g. in patients
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with modestly high triglycerides). c. Fasting vs non Fasting samples: All guidelines have recommended fasting levels of lipids
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on which to evaluate risk. This has generally been the gold standard, given their ubiquitous use in clinical trials and the sensitivity of triglyceride levels to the postprandial state, particularly for subjects with insulin resistance. The requirement for fasting creates some burden for patients and also for laboratory facilities that need to accommodate fasting patients early in the morning. Several recent reports have suggested that fasting may not be required. In a large cohort from laboratory based data, Sidhu and Naugler were able to demonstrate that the fasting time had little effect on LDL-C levels with variability in triglycerides of about 20% 41. In a recently published 11
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study, Doran evaluated NHANES subjects with an average follow-up of 14 years 42. There was no difference for the C statistic for mortality between those with <8 hours of fasting compared with > 8 hours. These authors suggest that non-fasting values should be considered. This approach is being contemplated in some provinces in Canada. Given
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the ability to use non-HDL-C on non-fasting samples as well, clinicians should have no reservations about using non fasting values for risk evaluation.
4. Overall Response to the ACC/AHA Dyslipidemia Guidelines: The CCS Dyslipidemia primary panel reviewed the new ACC/AHA guidelines soon after their release in the context of the CCS
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guidelines. We noted the many similarities between the two sets of guidelines, and where there were differences, we did not feel that we needed to change the Canadian standards. The
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American recommendation took a bold departure from previous versions and for that there was positive feedback. However, the departure from target levels of lipoprotein raised questions for many individuals 12,17,18,43,44 . Both the American Association of Clinical Endocrinology and the National Lipid Association did not endorse the new guidelines. It was acknowledged that the ACC/AHA guidelines had a limited scope, a mandate to use evidence based data only from randomized clinical trials and the inability to cover a number of specific topics like genetic
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dyslipidemia. While the four main categories of individuals to treat are clear, many nuances within the guidelines are not fully discussed. Further work is required in some of these areas for
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the next iteration of the guideline.
Reconciling the Debate about the Clinical Approach to Risk Stratification and Treatment
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Given the several controversies identified previously, there remains some confusion as to how to reconcile the new recommendations in the face of the 2012 CCS Dyslipidemia guidelines. The general approach should remain the same and involves the following steps: a) Screening and risk assessment – there is general agreement for screening men > 40 years and women > 50 years or those with risk factors regardless of age. Until further validation of the Pooled Cohort Equation including validation in Canadian cohorts the use of the total Framingham risk score, which is familiar to Canadian physicians and is validated in Canadian cohorts, is preferred. Using the Pooled Cohort Equation or the Framingham risk equation would result in similar number of subjects being treated with statins in Canada. We 12
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continue to recommend the modified Framingham Risk Score. b) Starting statin therapy – there is no debate about the treatment of those with established atherosclerosis, most subjects with diabetes, and those with an LDL > 5.0 mmol/L. Despite the lack of mention in the ACC/AHA guidelines, the CCS, ESC/EAS and KDIGO groups recommend widespread statin therapy for patients with pre-dialysis CKD
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and high -risk hypertension. c) Treating to targets – the CCS dyslipidemia primary panel continues to recommend the use of atherogenic lipoprotein targets, but it is recognized that this is controversial with heterogeneity of opinion. It may be helpful for adherence and medication compliance, which is an
important issue for statins. Of the steps listed above treating to specific targets is probably the least
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important as long as statins are prescribed in adequate, often high, doses and adherence and
attainment of expected effects is monitored. If we were successful in evaluating risk and initiating statins in the most appropriate people, we would achieve the majority of our risk reduction potential at
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the population level. However, the “lower is better” hypothesis, particularly at very low levels of LDL-C and with combination therapy has not yet been proven in a rigorous fashion. This may change once the results of ongoing combination lipid lowering studies with new potent agents are known. Moving forward, a number of issues require further study or comment in dyslipidemia guidelines. It is well known that the use of risk engines in primary prevention is quite low. Would management be
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improved if calculation of risk and recommendations for therapy were built into laboratory information systems or electronic medical records? Would adherence and compliance be improved with patient based information portals where they can access their own health care information and link to prevention strategies? Can the medical community reduce the widespread negative media comments
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about statin intolerance or risk with more evidence-based, myth-busting approaches? The new ACC/AHA guidelines have generated considerable debate and confusion in the medical
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literature about the specifics of risk assessment and treatment of dyslipidemia in CVD prevention . As we have discussed, much of the controversy generated immediately following the release of the new guidelines has since been addressed. It is healthy to accept that there are different approaches to screening and management, given the lack of decisive evidence in certain domains. The discussion should be used to highlight the need to address outstanding questions in the future. However, in the interim our patients can be very well managed with existing guidelines that are updated on an ongoing basis when new knowledge is generated. A guidelines-based approach to screening, treatment and compliance should continue to be the standard for all of our at risk patients. 13
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Figure 1. The percentage of men eligible for statin therapy in the FATE study comparing the Canadian and American dyslipidemia guidelines.
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Table 1 – Comparison of Dyslipidemia Guidelines 2013 ACC/AHA
2011 ESC/EAS
Lipoprotein measurement for risk assessment
Fasting lipid panel for LDL-C with calculation of non-HDL-C
Fasting lipid panel for LDL-C
Lipoprotein target
1° LDL-C 2° non-HDL-C and apoB Total CVD Framingham risk score modified for Family Hx – age 40-75y Fatal and non fatal MI, stroke, PVD and heart failure over 10 yrs Established athero Most diabetes* LDL-C >5.0 mmol/L Most CKD patients FRS ≥ 20%, FRS 10-19% if LDL-C ≥ 3.5 mmol/L
No target LDL-C for compliance Pooled Cohort Risk equation –age 40-75y
Fasting lipid panel with calculation of non-HDLC and optional TC/HDL ratio 1° LDL-C 2° non-HDL-C and apoB SCORE – country specific – aged 40-65 y
Fatal and non fatal MI, stroke, PVD over 10 yrs
Fatal atherosclerotic event over 10 yrs
Established athero Most diabetes LDL-C > 4.9 mmol/L Pooled Cohort equation risk ≥ 7.5%**, LDL-C > 1.8 mmol/L
Very high risk: athero, diabetes, CKD, SCORE risk >10% High risk: SCORE 5-10% and LDL-C >2.5 mmol/L or consider if >1.8 mmol/L Moderate risk: SCORE 1-5% consider for LDL-C > 2.5 mmol/L Very high risk: < 1.8 mmol/L High risk: <2.5 mmol/L Mod risk: < 3.0 mmol/L
FRS <10% (low risk) – 50% reduction in LDL-C FRS > 10% (intermediate and high risk) LDL-C ≤ 2.0 mmol/L
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Treating to targets
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Who to treat with statin
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CV disease outcome predicted by tool
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Assessment tool
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2012 CCS
No target – but statin intensity dictated by risk
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CCS – Canadian Cardiovascular Society 4; ACC – American College of Cardiology; AHA – American Heart Association 6; ESC – European Society of Cardiology; EAS – European Atherosclerosis Society; Athero – clinical atherosclerosis 3; CKD – chronic kidney disease; MI – myocardial infarction, PVD – peripheral vascular disease; FRS – Framingham risk score; * diabetes ≥ 40 years, or ≥ 30 years with 15 years duration of diabetes, or presence of microvascular disease; ** consideration for treatment for risk ≥ 5.0%-7.4%.
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8. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the angloscandinavian cardiac outcomes trial--lipid lowering arm (ASCOT-LLA): A multicentre randomised
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9. Tobe SW, Stone JA, Brouwers M, et al. Harmonization of guidelines for the prevention and treatment
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10. Conroy RM, Pyorala K, Fitzgerald AP, et al. Estimation of ten-year risk of fatal cardiovascular disease in europe: The SCORE project. Eur Heart J. 2003;24(11):987-1003.
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11. Goff DC,Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: A report of the american college of cardiology/american heart association task force on practice guidelines. Circulation. 2013.
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12. Ridker PM, Cook NR. Statins: New american guidelines for prevention of cardiovascular disease.
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Lancet. 2013;382(9907):1762-1765.
13. Kavousi M, Leening MJ, Nanchen D, et al. Comparison of application of the ACC/AHA guidelines, adult treatment panel III guidelines, and european society of cardiology guidelines for cardiovascular disease prevention in a european cohort. JAMA. 2014;311(14):1416-1423.
14. Muntner P, Colantonio LD, Cushman M, et al. Validation of the atherosclerotic cardiovascular disease pooled cohort risk equations. JAMA. 2014;311(14):1406-1415. 17
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15. Karmali KN, Goff DC,Jr, Ning H, Lloyd-Jones DM. A systematic examination of the 2013 ACC/AHA pooled cohort risk assessment tool for atherosclerotic cardiovascular disease. J Am Coll Cardiol.
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2014;64(10):959-968.
16. Allan GM, Garrison S, McCormack J. Comparison of cardiovascular disease risk calculators. Curr Opin Lipidol. 2014;25(4):254-265.
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the management of LDL-related risk. J Am Coll Cardiol. 2014;64(2):196-206.
18. Ray KK, Kastelein JJ, Boekholdt SM, et al. The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: The good the bad and the uncertain: A comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. Eur Heart
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19. Anderson TJ, Gregoire J, Hegele RA, et al. Are the ACC/AHA guidelines on the treatment of blood cholesterol a game changer? A perspective from the canadian cardiovascular society dyslipidemia panel.
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20. Pencina MJ, Navar-Boggan AM, D'Agostino RB S, et al. Application of new cholesterol guidelines to a
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21. Vaucher J, Marques-Vidal P, Preisig M, Waeber G, Vollenweider P. Population and economic impact of the 2013 ACC/AHA guidelines compared with european guidelines to prevent cardiovascular disease. Eur Heart J. 2014;35(15):958-959.
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22. Anderson TJ, Charbonneau F, Title LM, et al. Microvascular function predicts cardiovascular events in primary prevention: Long-term results from the firefighters and their endothelium (FATE) study.
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Circulation. 2011;123(2):163-169.
23. Mancini GB, Ryomoto A. Comparison of cardiovascular risk assessment algorithms to determine eligibility for statin therapy: Implications for practice in canada. Can J Cardiol. 2014;30(6):661-666.
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24. Genest J, McPherson R, Frohlich J, et al. 2009 canadian cardiovascular society/canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult -
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2009 recommendations. Can J Cardiol. 2009;25(10):567-579.
25. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: A systematic review and meta-analysis. Lancet. 2010;375(9729):1875-1884.
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26. AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255-2267.
27. HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, et al. Effects of extended-release niacin
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with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203-212.
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28. Cholesterol Treatment Trialists'Ctt C. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: Meta-analysis of individual data from 27 randomised trials. Lancet. 2012.
29. Ballantyne CM, Raichlen JS, Nicholls SJ, et al. Effect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary angiography: A study to evaluate the effect of rosuvastatin on intravascular ultrasound-derived coronary atheroma burden. Circulation. 2008;117(19):2458-2466. 19
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30. Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: A meta-analysis of statin trials. J Am Coll Cardiol. 2014;64(5):485-494.
that lower is better? J Am Coll Cardiol. 2014;64(5):495-497.
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31. Ben-Yehuda O, DeMaria AN. LDL-cholesterol targets after the ACC/AHA 2013 guidelines: Evidence
32. Mancini GB, Baker S, Bergeron J, et al. Diagnosis, prevention, and management of statin adverse
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2011;27(5):635-662.
33. Tonelli M, Muntner P, Lloyd A, et al. Risk of coronary events in people with chronic kidney disease compared with those with diabetes: A population-level cohort study. Lancet. 2012.
34. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus
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ezetimibe in patients with chronic kidney disease (study of heart and renal protection): A randomised placebo-controlled trial. Lancet. 2011;377(9784):2181-2192.
35. Wanner C, Tonelli M, Kidney Disease: Improving Global Outcomes Lipid Guideline Development
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recommendation statements and clinical approach to the patient. Kidney Int. 2014;85(6):1303-1309.
36. Foster MC, Rawlings AM, Marrett E, et al. Potential effects of reclassifying CKD as a coronary heart disease risk equivalent in the US population. Am J Kidney Dis. 2014;63(5):753-760.
37. Baber U, Muntner P. Lipid-lowering guidelines and statin use in CKD: A time for change. Am J Kidney Dis. 2014;63(5):736-738.
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38. Boekholdt SM, Arsenault BJ, Mora S, et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: A meta-
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analysis. JAMA. 2012;307(12):1302-1309.
39. Sniderman AD, Williams K, Contois JH, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ
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Cardiovasc Qual Outcomes. 2011;4(3):337-345.
40. Mora S, Buring JE, Ridker PM. Discordance of low-density lipoprotein (LDL) cholesterol with
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alternative LDL-related measures and future coronary events. Circulation. 2014;129(5):553-561.
41. Sidhu D, Naugler C. Fasting time and lipid levels in a community-based population: A cross-sectional study. Arch Intern Med. 2012;172(22):1707-1710.
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42. Doran B, Guo Y, Xu J, et al. Prognostic value of fasting vs. non-fasting low density lipoprotein cholesterol levels on long-term mortality: Insight from the national health and nutrition survey III (NHANES-III). Circulation. 2014.
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43. Psaty BM, Weiss NS. 2013 ACC/AHA guideline on the treatment of blood cholesterol: A fresh
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interpretation of old evidence. JAMA. 2014;311(5):461-462.
44. Athyros VG, Katsiki N, Karagiannis A, Mikhailidis DP. The 2013 american college of cardiology/american heart association guidelines for the treatment of dyslipidemia: Mind the gaps! Curr Med Res Opin. 2014:1-5.
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Figure 1 Statin Eligibility in FATE cohort of men 40-79 years
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FATE – Firefighters and their Endothelium; For those aged 75-79 risk assessment based on presumed maximal age of 75 for both risk engines
S0828-282X(14)01570-0
DOI:
10.1016/j.cjca.2014.11.007
Reference:
CJCA 1472
To appear in:
Canadian Journal of Cardiology
Received Date: 22 September 2014 Revised Date:
5 November 2014
Accepted Date: 6 November 2014
Please cite this article as: Anderson TJ, Mancini GJ, Genest Jr. J, Grégoire J, Lonn EM, Hegele RA, The New Dyslipidemia Guidelines: What is the Debate?, Canadian Journal of Cardiology (2014), doi: 10.1016/j.cjca.2014.11.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The New Dyslipidemia Guidelines: What is the Debate?
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Todd J. Anderson, MDa, GB John Mancini, MDb, Jacques Genest Jr., MDc, Jean Grégoire, MD , Eva M.
Lonn, MDe, Robert A. Hegele, MDf
b. University of British Columbia, Vancouver, BC
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c. McGill University Health Centre, Montreal Quebec
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a. Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary Alberta
d. Institut de Cardiologie de Montréal, Université de Montréal, Montreal Quebec e. Population Health Research Institute, McMaster University, Hamilton ON Robarts Research Institute, Western University, London, ON
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Address for correspondence: Todd J. Anderson, Libin Cardiovascular Institute of Alberta, University of Calgary
1403-29th St NW Calgary, Alberta, T2N 2T9 Email: [email protected] Telephone: 403 944-1033 Fascimile: 403 944-1592 1
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Abstract Dyslipidemia is a major risk factor for the development of atherosclerotic disease. Therefore lifestyle interventions and pharmacological approaches to lower cholesterol are widely used in cardiovascular
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disease prevention. The introduction and widespread use of HMG Co-A reductase inhibitors (statins) for individuals at risk of atherosclerotic disease has been an important advance in cardiovascular care. There can be no doubt that better control of dyslipidemia, even in subjects whose low density
lipoprotein cholesterol (LDL-C) level is not particularly high, has reduced overall event rates. On a
background of lifestyle interventions, statins are routinely used to lower risk along with aspirin and
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interventions to control hypertension and diabetes. More than other risk factors, the approach to the identification and treatment of dyslipidemia has been heterogeneous and widely debated. The recent
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release of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Dyslipidemia guidelines has reignited the controversy over the best approach for risk stratification and treatment. In this article we will review the importance of statin therapy for global cardiovascular risk reduction, compare the Canadian Cardiovascular Society (CCS) Dyslipidemia guidelines with other standards, and discuss the points of debate. Despite the seeming variety of recommendations, their common link is a systematic approach to risk stratification and treatment, which will continue to benefit our patients at
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risk.
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Brief Summary Dyslipidemia is a major risk factor for the development of atherosclerotic disease. Therefore lifestyle interventions and pharmacological approaches to lower cholesterol are widely used. The recent release
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of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Dyslipidemia guidelines has raised questions over the best approach for risk stratification and treatment. We review the importance of statin therapy for global cardiovascular risk reduction, and compare the Canadian
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Cardiovascular Society (CCS) Dyslipidemia guidelines with other standards.
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Dyslipidemia and Global Cardiovascular Risk Despite the greater than 50% decrease in age-adjusted cardiovascular mortality over the past several decades, atherosclerotic disease is the leading cause of death in women and second leading cause of
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death in men in Canada. Morover, cardiovascular disease accounts for more than half of all noncommunicable diseases (NCDs) and has become the leading cause of death worldwide, a fact affirmed by the World Health Organization 1. Large cohort studies dating back to the Framingham Heart Study have identified cholesterol as a modifiable risk factor, which can be treated with lifestyle and
pharmacological interventions 2. Total cholesterol levels have fallen in high income countries over the
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past two decades by 8-10% on average. Some countries with the highest levels were able to decrease levels more than this with targeted societal interventions, leading directly to dramatic decreases in
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event rates. As part of the United Nations declaration on NCDs, with a goal of reducing premature death by 25%, their target is a 20% relative reduction in high total cholesterol by 2025. To be truly effective, the treatment of dyslipidemia needs to be incorporated into a comprehensive plan of global risk reduction for patients at risk. This will involve lifestyle modification, policy change and pharmacotherapy.
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Similarities and Differences in Dyslipidemia Guidelines
New dyslipidemia guidelines were released by the European Society of Cardiology/European Atherosclerosis Society (ESC/ESA) in 2011 3, the CCS in 2012 4, the International Atherosclerosis Society (IAS) 5 and the ACC/AHA both in 2013 6. All are similar in many respects, yet have some key differences
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that are worthy of discussion. The 2012 CCS guidelines recommended risk stratification using the total CVD Framingham risk score 7, advocated the use of LDL-C thresholds for the initiation of treatment in low and intermediate risk subjects and expanded the phenotype of high risk subjects to include subjects
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with atherosclerosis, most patients with diabetes, high risk hypertension (per ASCOT inclusion criteria) 8 and pre-dialysis chronic kidney disease (CKD). LDL-C continues to be used as the atherogenic metric, but now both non-HDL-C and apolipoprotein B (apo B) could be measured as alternatives, especially under circumstances when LDL-C calculations are known to be erroneous. Once treatment is initiated, LDL-C (< 2.0 mmol/L or 50% reduction) continues to be the primary target of therapy. The CCS guidelines have been harmonized with other relevant Canadian guidelines as part of the C-CHANGE initiative9.
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The ESC/EAS guidelines was a comprehensive document that encouraged the use of the Systematic Coronary Risk Evaluation (SCORE) total cardiovascular mortality 10 calibrated for high or low risk countries in Europe. Of note that the SCORE risk assessment is also based on the Framingham risk equation. LDL-C thresholds were suggested with non-HDL-C or apo B as alternatives. The European
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guidelines also recognized CKD as very high risk equivalent. Target levels of LDL-C were recommended but unlike the CCS guidelines, the goals were different between those at very high risk (<1.8 mmol/L) compared with those at high risk (<2.5 mmol/L) or intermediate risk (<3.0 mmol/L).
The IAS panel decided to recommend lifetime CV risk based on 4 different tools depending on ethnicity.
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They favoured non-HDL-C as the primary atherogenic metric for risk determination, with LDL-C as a secondary measure. Optimal levels were defined based on criteria from ATP III, but did not recommend
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treatment targets. The intensity of statin therapy should be adjusted according to overall lifetime risk and practitioner practice.
The ACC/AHA guidelines were the latest to be released and created the most controversy6. A major novel aspect of these guidelines was the recommendation to calculate risk using the newly developed Pooled Cohort equation. This approach represents a departure from the use of the Framingham risk score, used for decades. Of the four groups targeted for statin based therapy 3 were the same as the
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CCS guidelines. These include subjects with a) clinical evidence of atherosclerosis; b) most subjects with diabetes and c) individuals with LDL-C ≥ 5.0 mmol/L. The fourth group includes subjects with a 10 year risk of total atherosclerotic events calculated using the Pooled Cohort equation of ≥ 7.5% 11. There was no specific recommendation for CKD and other populations such as genetic dyslipidemia or high-risk
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hypertension. An additional novel aspect of these guidelines was the lack of specific targets of therapy. While these guidelines recommend the use of high or moderate intensity statin regimens based on level
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of risk and anticipate a 50% LDL-C lowering with high intensity statin therapy, there is no recommendation for treating to any specific target. Therefore, lipid measurements after initiation of statin therapy are recommended mainly to ensure adherence. What are the Controversies with the ACC/AHA Guidelines Anyway? 1. Risk Engine was not Validated: An important component of the American guidelines was the introduction of the race and gender specific Pooled Cohort Equations risk engine 11. This was based on recent US cohort studies including Atherosclerosis Risk in Communities (ARIC) study , 5
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Cardiovascular Health Study (CHS), Coronary Artery Disease Risk Development in Young Adults (CARDIA) and the Framingham original and offspring studies. While novel risk factors were considered, the final Pooled Cohort Equations model included the same parameters as Framingham risk models 7. The end-points in the model include hard atherosclerotic vascular
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events including cardiovascular death, myocardial infarction and stroke. The most recent total Framingham risk model also includes heart failure and claudicaton as end-points. As such the intermediate risk threshold of 7.5% proposed as the level for statin therapy corresponds to a higher Framingham risk when compared to the previously used algorithm, however this
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conversion was not made clear in the original document. The new risk engine was proposed to be appropriate for Caucasian or African-American individuals between 40 and 79.
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Shortly after the introduction of the document, concern was raised that the model had not been adequately calibrated. Ridker and Cook demonstrated that the new model overestimated risk compared with the observed event rates in the Physicians Health Study and the Women’s Health Initiative cohorts 12. This was also true for the Multi-Ethnic Atherosclerosis Study (MESA) and Stroke Study. These authors concluded that the overestimation could result in up to 40% of those identified as being eligible for statin therapy based on > 7.5% risk as not actually requiring
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therapy. In a subsequent study that utilized Rotterdam study participants (n=4854), the new Pooled Cohort equations model was applied to the ACC/AHA, ATP-III and ESC guidelines. The new risk engine, again tended to overestimate events 13. Finally, Muntner and colleagues used the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort and
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demonstrated good calibration and moderate to good discrimination for the new model 14. It is well accepted that models often overestimate risk given the increased use of risk reduction therapy including statins in contemporary cohorts. The declining incidence of atherosclerotic
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events and difficulty in adjudication of events in cohort studies, makes accurate evaluation challenging. It does however reinforce our view that risk engines are imprecise tools, which may provide the clinician with rough guidance but do not replace clinical acumen and a robust dialogue with patients, particularly in primary prevention. The new Pooled Cohort Equations tool requires further study with respect to its calibration and discrimination metrics. A recent analysis reaffirmed the importance of age in achieving threshold levels for treatment with the new model 15. However, the reader should remember 6
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that head to head comparisons between risk algorithms tend to yield fairly disparate results 16, which is the reason that different models are utilized by different guidelines committees. The Canadian Cardiovascular Society dyslipidemia guidelines committee decided on the total cardiovascular events Framingham risk model (Table 1). Similarly the European community has
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shown faith in the Systemic Coronary Risk Estimation (SCORE) charts that utilizes fatal
cardiovascular events 17,18. Despite differences these and other models tend to perform
similarly for primary prevention populations where the study population of the model reflects the country of use. Thus, at the present time, the CCS primary panel did not recommend any
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change in the method of risk assessment in light of the ACC/AHA recommendations 19. We strongly urge clinicians screening for cardiovascular risk to adopt an algorithm that is most simple to integrate within their practice and to maximize the numbers of patients who undergo
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a quantitative evaluation of their risk. By doing this, statin use will be more appropriately allocated and risk more optimally reduced.
2. The ACC/AHA guidelines will result in increased statin use: It was recognized at the time of the publication of the new guidelines that the transition from ATP-III to the new recommendations would increase the number of individuals potentially eligible for statin therapy. Pencini et al.
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evaluated the NHANES surveys from 2005 to 2010 and extrapolating the results to the 115 M Americans between the ages of 40-75 years 20. Adoption of the new ACC/AHA guidelines would increase eligibility from 37.5 to 48.6% in this age range. Most of the 12.8 M person increase would be drawn from those without cardiovascular disease (i.e. primary prevention). The
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biggest increase would be in those over the age of 60, particularly men. This is a result of the importance of age in the Pooled Cohort equation calculation of risk (threshold >7.5%). In the Swiss CoLaus study, individuals 50-75 years of age, had risk calculated using the Swiss SCORE
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equation and the new ACC/AHA algorithm 21. Based on their survey, there would be a doubling of treated subjects particularly in those 50-60 years if the American guidelines were utilized. Kavousi compared the ESC, ATP-III and new ACC/AHA guidelines in 4854 subjects from the Rotterdam study with a mean age of 65 years 13. Given the older age of this population the ACC/AHA guidelines would recommend statins for 96% of men and 66% of women an increase of 1.5 to 2 fold compared with the previous guidelines. Finally, we recently evaluated the current CCS and ACC/AHA guidelines in the Firefighters and their Endothelium (FATE) cohort22 Within this cohort, 1267 men without vascular disease between the age of 40 and 79 (mean age 7
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51.9 ± 7.8 yrs) were evaluated for statin eligibility based on the CCS and ACC/AHA guidelines. Firstly the mean FRS was 14.8 ± 10% and this compared with a Pooled Cohort equation risk of 7.7 ± 8.2 %. Secondly, 570 (45%) of subjects would be eligible for statin therapy with the CCS guidelines compared with 422 (33%) by the ACC/AHA guidelines. This was age dependent as
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shown in figure 1. Similarly, mathematical modeling was done by Mancini demonstrating similar rates of statin eligibility between the two guidelines 23. Thus, controversy that the new ACC/AHA guidelines would increase statin use solely on the basis of risk calculation in Canada is
unfounded. This is likely because in the transition from the 2006 to 2009 guidelines 24 there was
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a move from the old Framingham algorithm (that was used in ATP-III) 2 to the total
cardiovascular Framingham model of D’Agostino 7. This was a shift unrecognized by most practitioners, which increased the number of Canadians eligible for statin therapy. Moreover,
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the analysis by Mancini et al. emphasized that the identification of more patients eligible for therapy by the ACC/AHA guidelines was more a result of the dramatic lowering of the LDL-C threshold to 1.8 mmol/L warranting therapy in sufficiently at risk patients as opposed to the new mathematical underpinnings of the Pooled Cohort Equation22. 3. The elimination of atherogenic lipoprotein targets: The new ACC/AHA guidelines were
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distinctly different from most previous recommendations in that they have discarded specific LDL-C (or alternative) targets once subjects are initiated on therapy. The rationale for this change was that no previous randomized trial specifically addressed whether a particular level produced greater event reduction. Secondly, by eliminating targets it was felt that primary care
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treatment would be more straightforward and easier to implement. Thirdly, having targets potentially promotes combination therapy, for which there is currently no good evidence from randomized trials. This is supported by data from meta-analysis of trials of fibrate therapy, AIM-
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HIGH and HPS2-THRIVE. 25-27 While this interpretation is literally correct, it fails to recognize several issues in the history of statin trials: the initial trials were as much studies of the lipid hypothesis as they were trials of statins. Thus the first trials were in patients with the highest risk and highest cholesterol levels but at a time when only moderately potent statins were available, hence the use of the highest dose feasible. As success was shown, and as more potent statins became available, ethical considerations mandated that research subjects had to have lower and lower risk and lower and lower cholesterol levels, again promoting use of the highest available dose. The latter was also influenced by a need to ensure simplicity in large 8
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trials and, to some extent, by marketing designed to promote drug potency differences. There are also five trials of higher versus lower potency statins, which show consistent improvement in outcomes with the higher potency statin. The lowest risk cohort studied to date in the JUPITER study reaped comparable benefit using the most potent statin currently available. Remarkably,
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no lower limit of achieved LDL-C beyond which benefit is accrued has yet been shown. The CCS Dyslipidemia guideline primary panel reviewed these issues in early 2014 and recommended that until further evidence was available, we would continue to support the use of targets. Similarly others have taken this view as well 3,5. Although it is certainly true that randomized
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trials have utilized generally a single statin dose approach, as opposed to a target LDL-C level, the epidemiology suggesting that lower levels of achieved LDL-C result in less events is rather compelling 28. Also, regression studies with intravascular ultrasound (IVUS) demonstrate a linear
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relationship between LDL-C and the amount of regression 29. The crossing point for regression tends to occur at an LDL-C of around 2 mmol/L or a 50% reduction. A very recent meta-analysis utilized individual patient data from 8 statin trials 30. On a fixed dose of statin, there was a very large inter-individual variation in LDL-C reduction with statins. In addition, more than 40% of subjects did not achieve targets of less than 1.8 mmol/L on a fixed statin dose. Those who achieve very low levels of LDL-C had a lower event rate than those who achieved modest levels.
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The same trend was seen for non-HDL-C and apolipoprotein B. The editorial accompanying this paper rightly points out that the majority of the studies in the meta-analysis used fixed dose statins, as opposed to titrated doses 31. Therefore, the lower achieved LDL-C levels may theoretically have been due to some unique interactions between statins and the biology of the
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particular patients. It certainly leaves the door open for trials to address a target level approach. We will be able to test the “lower is better” hypothesis at very low levels of LDL-C once the
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results of ongoing trials utilizing non-statins (e.g. inhibitors of cholesterol absorption, PCSK9 and CETP) are known.
The ACC/AHA guidelines would appear at first blush to support a “fire and forget” approach. The text and algorithms do however suggest that measuring LDL-C after statin initiation is reasonable to help assess compliance and to ensure achievement of an expected percentage lowering of LDL-C. Compliance and adherence are important issues with statin therapy32 and beyond the scope of this review, but are certainly another practical reason that the CCS guidelines panel continues to recommend targets. Additionally, the text and algorithms of the 9
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ACC/AHA guidelines promote LDL-C measurement to ensure achievement of the expected response to moderate and high intensity statin dose choices and, when not achieved or in the face of statin intolerance, support dose escalation or addition of secondary, non-statin drugs.
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Other Questions arising from recent Guidelines: a. Chronic Kidney Disease (CKD): There is limited discussion of the impact of CKD on risk in the new ACC/AHA guidelines. We believe that pre-dialysis CKD should be elevated to a high risk category warranting therapy in the majority of people. This was based on solid
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epidemiology data from Alberta 33 along with the randomized Study Heart and Renal Protection (SHARP) study 34. The latter has the unique feature of showing improved outcome from LDL-C lowering when compared to placebo and the additional
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observation that combination therapy with statin and a cholesterol absorption inhibitor provided a risk lowering comparable to statin-only trials. Thus, CKD is recognized in the CCS and ESC guidelines as a very high risk state. The relationship between LDL-C and events tends to be weaker in non-dialysis dependent CKD patients and the prevailing LDL-C levels tend to be low, rendering traditional risk engines less precise 35. As such therapy is best initiated based on the phenotypic risk defined by levels of GFR and
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proteinuria. The Kidney Disease: Improving Global Outcomes (KDIGO) group do not recommend follow-up of LDL-C except to monitor adherence and similarly do not recommend therapy in dialysis dependent subjects. The KDIGO groups recommends statin therapy for subjects >50 years of age and a GFR < 60 ml/min/1.73m2 but not
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treated with dialysis or transplantation. The group also recommended statin therapy in subjects with a GFR > 60 ml/min/1.73m2 and CKD based on albumin:creatinine ratio as
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low as 3 mg/mmol. These new recommendations treat a broader spectrum of CKD patients than that suggested in the 2012 CCS guidelines. Foster et al. performed an analysis using NHANES data that determined incorporating the KDIGO guidelines would increase the number of statin eligible subjects by approximately 10%. However, this was based on the old ATP-III guidelines and not the 2013 ACC/AHA guidelines 36. The general consensus amongst the renal community is that broader use of statins should be implemented 37, something not addressed by the ACC/AHA guidelines.
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b. Appropriate Atherogenic metric: In the CCS guidelines, LDL-C continues to be the primary target for risk assessment and treatment targets. In addition to apo B the last guideline did add non-HDL-C as an alternate atherogenic marker. In ATP-III, non HDL-C was an alternate target, but the new guideline stated that they could find little evidence
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that non-HDL-C or apo B offered any advantage over LDL-C. The majority of other
guidelines continue to recommend LDL-C with most having non-HDL-C or apo B as
alternatives 17. The exception is the International Atherosclerosis Society that advocates non-HDL-C as the primary metric. Some epidemiological studies would suggest that
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either non-HDL-C or apo B are better risk predictors than LDL-C 38. Sniderman presents evidence that apoB is the best predictor and has advocated for its use 39. ApoB is an attractive marker as it reflects the number of atherogenic particles, can be measured in
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a non-fasting state and is particularly useful in subjects with metabolic syndrome. NonHDL-C can be easily calculated from a standard lipid panel, thus adds no cost and again does not require a fasting sample. There is increasing interest in a non-fasting approach. Mora and colleagues recently reported that there is significant discordance between these measures of atherogenic risk and when two measures were not aligned that risk could be under or over-estimated 40. They suggest that in those women with discordant
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measures, that the alternate measure might be better than LDL-C. At the present time, LDL-C remains a practical metric for atherogenic risk assessment, but both apo B and non-HDL-C offer potential advantages once clinicians become familiar with their use and the circumstances when LDL-C calculations are known to be misleading (e.g. in patients
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with modestly high triglycerides). c. Fasting vs non Fasting samples: All guidelines have recommended fasting levels of lipids
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on which to evaluate risk. This has generally been the gold standard, given their ubiquitous use in clinical trials and the sensitivity of triglyceride levels to the postprandial state, particularly for subjects with insulin resistance. The requirement for fasting creates some burden for patients and also for laboratory facilities that need to accommodate fasting patients early in the morning. Several recent reports have suggested that fasting may not be required. In a large cohort from laboratory based data, Sidhu and Naugler were able to demonstrate that the fasting time had little effect on LDL-C levels with variability in triglycerides of about 20% 41. In a recently published 11
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study, Doran evaluated NHANES subjects with an average follow-up of 14 years 42. There was no difference for the C statistic for mortality between those with <8 hours of fasting compared with > 8 hours. These authors suggest that non-fasting values should be considered. This approach is being contemplated in some provinces in Canada. Given
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the ability to use non-HDL-C on non-fasting samples as well, clinicians should have no reservations about using non fasting values for risk evaluation.
4. Overall Response to the ACC/AHA Dyslipidemia Guidelines: The CCS Dyslipidemia primary panel reviewed the new ACC/AHA guidelines soon after their release in the context of the CCS
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guidelines. We noted the many similarities between the two sets of guidelines, and where there were differences, we did not feel that we needed to change the Canadian standards. The
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American recommendation took a bold departure from previous versions and for that there was positive feedback. However, the departure from target levels of lipoprotein raised questions for many individuals 12,17,18,43,44 . Both the American Association of Clinical Endocrinology and the National Lipid Association did not endorse the new guidelines. It was acknowledged that the ACC/AHA guidelines had a limited scope, a mandate to use evidence based data only from randomized clinical trials and the inability to cover a number of specific topics like genetic
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dyslipidemia. While the four main categories of individuals to treat are clear, many nuances within the guidelines are not fully discussed. Further work is required in some of these areas for
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the next iteration of the guideline.
Reconciling the Debate about the Clinical Approach to Risk Stratification and Treatment
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Given the several controversies identified previously, there remains some confusion as to how to reconcile the new recommendations in the face of the 2012 CCS Dyslipidemia guidelines. The general approach should remain the same and involves the following steps: a) Screening and risk assessment – there is general agreement for screening men > 40 years and women > 50 years or those with risk factors regardless of age. Until further validation of the Pooled Cohort Equation including validation in Canadian cohorts the use of the total Framingham risk score, which is familiar to Canadian physicians and is validated in Canadian cohorts, is preferred. Using the Pooled Cohort Equation or the Framingham risk equation would result in similar number of subjects being treated with statins in Canada. We 12
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continue to recommend the modified Framingham Risk Score. b) Starting statin therapy – there is no debate about the treatment of those with established atherosclerosis, most subjects with diabetes, and those with an LDL > 5.0 mmol/L. Despite the lack of mention in the ACC/AHA guidelines, the CCS, ESC/EAS and KDIGO groups recommend widespread statin therapy for patients with pre-dialysis CKD
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and high -risk hypertension. c) Treating to targets – the CCS dyslipidemia primary panel continues to recommend the use of atherogenic lipoprotein targets, but it is recognized that this is controversial with heterogeneity of opinion. It may be helpful for adherence and medication compliance, which is an
important issue for statins. Of the steps listed above treating to specific targets is probably the least
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important as long as statins are prescribed in adequate, often high, doses and adherence and
attainment of expected effects is monitored. If we were successful in evaluating risk and initiating statins in the most appropriate people, we would achieve the majority of our risk reduction potential at
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the population level. However, the “lower is better” hypothesis, particularly at very low levels of LDL-C and with combination therapy has not yet been proven in a rigorous fashion. This may change once the results of ongoing combination lipid lowering studies with new potent agents are known. Moving forward, a number of issues require further study or comment in dyslipidemia guidelines. It is well known that the use of risk engines in primary prevention is quite low. Would management be
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improved if calculation of risk and recommendations for therapy were built into laboratory information systems or electronic medical records? Would adherence and compliance be improved with patient based information portals where they can access their own health care information and link to prevention strategies? Can the medical community reduce the widespread negative media comments
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about statin intolerance or risk with more evidence-based, myth-busting approaches? The new ACC/AHA guidelines have generated considerable debate and confusion in the medical
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literature about the specifics of risk assessment and treatment of dyslipidemia in CVD prevention . As we have discussed, much of the controversy generated immediately following the release of the new guidelines has since been addressed. It is healthy to accept that there are different approaches to screening and management, given the lack of decisive evidence in certain domains. The discussion should be used to highlight the need to address outstanding questions in the future. However, in the interim our patients can be very well managed with existing guidelines that are updated on an ongoing basis when new knowledge is generated. A guidelines-based approach to screening, treatment and compliance should continue to be the standard for all of our at risk patients. 13
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Figure Legend
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Figure 1. The percentage of men eligible for statin therapy in the FATE study comparing the Canadian and American dyslipidemia guidelines.
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Table 1 – Comparison of Dyslipidemia Guidelines 2013 ACC/AHA
2011 ESC/EAS
Lipoprotein measurement for risk assessment
Fasting lipid panel for LDL-C with calculation of non-HDL-C
Fasting lipid panel for LDL-C
Lipoprotein target
1° LDL-C 2° non-HDL-C and apoB Total CVD Framingham risk score modified for Family Hx – age 40-75y Fatal and non fatal MI, stroke, PVD and heart failure over 10 yrs Established athero Most diabetes* LDL-C >5.0 mmol/L Most CKD patients FRS ≥ 20%, FRS 10-19% if LDL-C ≥ 3.5 mmol/L
No target LDL-C for compliance Pooled Cohort Risk equation –age 40-75y
Fasting lipid panel with calculation of non-HDLC and optional TC/HDL ratio 1° LDL-C 2° non-HDL-C and apoB SCORE – country specific – aged 40-65 y
Fatal and non fatal MI, stroke, PVD over 10 yrs
Fatal atherosclerotic event over 10 yrs
Established athero Most diabetes LDL-C > 4.9 mmol/L Pooled Cohort equation risk ≥ 7.5%**, LDL-C > 1.8 mmol/L
Very high risk: athero, diabetes, CKD, SCORE risk >10% High risk: SCORE 5-10% and LDL-C >2.5 mmol/L or consider if >1.8 mmol/L Moderate risk: SCORE 1-5% consider for LDL-C > 2.5 mmol/L Very high risk: < 1.8 mmol/L High risk: <2.5 mmol/L Mod risk: < 3.0 mmol/L
FRS <10% (low risk) – 50% reduction in LDL-C FRS > 10% (intermediate and high risk) LDL-C ≤ 2.0 mmol/L
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Treating to targets
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Who to treat with statin
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CV disease outcome predicted by tool
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Assessment tool
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2012 CCS
No target – but statin intensity dictated by risk
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CCS – Canadian Cardiovascular Society 4; ACC – American College of Cardiology; AHA – American Heart Association 6; ESC – European Society of Cardiology; EAS – European Atherosclerosis Society; Athero – clinical atherosclerosis 3; CKD – chronic kidney disease; MI – myocardial infarction, PVD – peripheral vascular disease; FRS – Framingham risk score; * diabetes ≥ 40 years, or ≥ 30 years with 15 years duration of diabetes, or presence of microvascular disease; ** consideration for treatment for risk ≥ 5.0%-7.4%.
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Figure 1 Statin Eligibility in FATE cohort of men 40-79 years
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FATE – Firefighters and their Endothelium; For those aged 75-79 risk assessment based on presumed maximal age of 75 for both risk engines