Cover Story

New cholesterol guidelines offer more personalized risk calculation, endorse nonstatin therapy

New, anticipated cholesterol guidelines from the American Heart Association, American College of Cardiology and 10 other societies recommend a stepped approach including treatment with statins, ezetimibe and PCSK9 inhibitors in patients with prior CVD at very high risk for another CV event.

The updated guidance also calls for more personalized risk assessment than outlined in the previous version, which was published in 2013.

The guidelines are also notable for carving out a broader role for coronary artery calcium scoring in patients in whom it is unclear whether statin therapy should be initiated, returning LDL targets to prominence in certain cases and adding emphasis on a heart-healthy lifestyle, experts told Cardiology Today.

Keith C. Ferdinand

“I consider the 2018 cholesterol guidelines a step forward. They emphasize, as previous guidelines have done but perhaps in a more forward-thinking manner, the importance of a heart-healthy lifestyle,” Keith C. Ferdinand, MD, professor of medicine at Tulane University School of Medicine and Cardiology Today Editorial Board Member, said in an interview. “They build into their message not only adults who have high cholesterol but also young individuals to prevent the development of atherosclerotic CVD (ASCVD). Also of importance, many clinicians were somewhat dismayed and maybe confused by the lack of the 2013 cholesterol guidelines having goals or thresholds. But now, for specific patients, it helps clinicians target their specific therapies in a little more concrete manner, such as LDL lower than 70 mg/dL in high-risk patients and persons with diabetes.”

Steven E. Nissen, MD, from Cleveland Clinic, said the 2018 cholesterol guidelines endorse the idea that lower LDL is always better.
Source: Cleveland Clinic; reprinted with permission.

Steven E. Nissen, MD, chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at Cleveland Clinic’s Sydell and Arnold Miller Family Heart and Vascular Institute and Cardiology Today Editorial Board Member, said the new guidelines address many of the shortcomings of the 2013 guidelines.

“The 2013 guidelines received a lot of criticism. What is interesting about the new guidelines is that they have addressed many of those concerns correctly and appropriately,” he told Cardiology Today. “The authors are bringing back the idea of LDL targets; you should not just give a statin and walk away. They are recommending more aggressive treatment of patients with LDL greater than 70 mg/dL, using add-ons of nonstatin therapies such as ezetimibe and PCSK9 inhibitors if necessary. That is a big step forward. Many of us have believed for quite some time that lower is better. The guidelines now acknowledge that.”

Role of nonstatin therapies

These are the first guidelines to endorse ezetimibe and the PCSK9 inhibitors alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen) for use in certain patients, based on the results of the IMPROVE-IT, FOURIER and ODYSSEY OUTCOMES trials.

The guidelines state that nonstatin therapies may be considered in patients at very high risk who cannot achieve LDL less than 70 mg/dL on statin therapy; ezetimibe should be tried first, then, if necessary, a PCSK9 inhibitor.

“The attempt to use threshold levels of LDL such as 70 mg/dL when you have patients you are considering adding nonstatin therapy to is a good step forward,” Robert H. Eckel, MD, professor of medicine in the division of endocrinology, metabolism, diabetes and cardiology; professor of physiology and biophysics; Charles A. Boettcher II Chair in Atherosclerosis at the University of Colorado Denver Anschutz Medical Center; director of the lipid clinic at University of Colorado Hospital in Aurora; and past president of the AHA, told Cardiology Today. “The idea of a statin plus ezetimibe plus a PCSK9 inhibitor is not level IA evidence. No one has ever done that trial. Nevertheless, in terms of real-time practice of lipid-related medicine, we all think about LDL goals for our patients, even if they are not evidence-based.”

However, the provision may have unintended consequences, according to Pradeep Natarajan, MD, MMSc, director of preventive cardiology at Corrigan Minehan Heart Center, Massachusetts General Hospital, and assistant professor of medicine at Harvard Medical School.

Pradeep Natarajan

“Prior to these cholesterol guidelines, most insurers did not require the use of ezetimibe prior to considering PCSK9 inhibitors,” he said. “Now we are not just focusing on atherosclerotic CVD and LDL not at a suitable goal, but we are saying there needs to be consideration of additional risk factors and you need to have tried ezetimibe.”

Cost considerations

This is the first cholesterol guideline to address cost considerations.

With regard to PCSK9 inhibitors, for which price has been an issue affecting access to the therapies, the guidelines panel wrote that “all models project higher lifetime cost from use of PCSK9 inhibitors because the cost will exceed any savings from prevention of cardiovascular events.”

Mark Hlatky

“In the past, clinical practice guidelines have not explicitly considered costs. But in some areas where guidance is needed, guidelines now incorporate evidence-based value statements,” cholesterol guidelines writing committee member Mark A. Hlatky, MD, professor of health research policy and medicine at Stanford Health Care, said in an interview. “This is important because it shows that guidelines can consider value when making recommendations.”

Some experts criticized the decision to address cost, questioning whether it is appropriate and noting that some information is already outdated. For example, the PCSK9 inhibitor manufacturers have since reduced the initial prices of the drugs.

However, Hlatky noted that more work will be done in this area.

“When it comes to a value assessment, the guidelines are already out of date,” Seth J. Baum, MD, chief medical officer of Excel Medical Clinical Trials, clinical affiliate professor of biomedical science at Florida Atlantic University in Boca Raton and immediate past president of the American Society of Preventive Cardiology (ASPC), said in an interview. “I personally do not think economics should be in our clinical guidelines. I think that’s a mistake, and a very slippery slope. “

Seth J. Baum

Focus on risk calculation

The new guidelines have a strong focus on risk assessment, keeping from the 2013 guidelines the four categories of patients recommended for statin therapy — those with ASCVD, those with LDL of at least 190 mg/dL, those with type 2 diabetes aged 40 to 75 years and those with estimated 10-year CVD risk of at least 7.5% — but adding more nuance.

There is now a distinction between patients with estimated 10-year CVD risk 7.5% to 19.9%, who are categorized as intermediate risk, and patients with estimated 10-year CVD risk of at least 20%, who are categorized as high risk.

“Continuation of using the ASCVD risk calculator remains important. Treating symptoms would be inadequate, because many patients can have significant vascular disease and have no symptoms at all,” Ferdinand said. “I also think starting statin therapy in certain very high-risk patients without calculating ASCVD risk is equally important. This is especially important in high-risk patients who are relatively young, Their risk by calculation over 10 years may actually be low, but their lifetime risk will be very high.”

Much leeway is given to determine the best course of action for patients at intermediate risk.

In these cases, a patient-clinician risk discussion should take place, which should include risk factors, risk-enhancing factors, potential benefits of statins and lifestyle measures, potential adverse events and drug-drug interactions, costs and patient preferences.

Mary Norine Walsh

“I was very pleased that shared decision-making was such an important part of this document,” Mary Norine Walsh, MD, medical director of the HF and cardiac transplantation programs at St. Vincent Heart Center in Indianapolis, past president of the ACC and Cardiology Today Editorial Board Member, said in an interview.

Among the risk-enhancing factors that can be included in the discussion are family history of premature ASCVD, persistent LDL of at least 160 mg/dL, metabolic syndrome, chronic kidney disease, preeclampsia and premature menopause.

Robert H. Eckel

“It is important that chronic kidney disease was brought into the model of risk,” Eckel said. “We know that [chronic kidney disease] relates to atherosclerotic CVD and this is an important point to bring forward.”

If the risk discussion and assessment of risk-enhancing factors do not produce a clear decision on statin therapy, the guidelines state CAC scoring may be used as a tiebreaker.

Roger S. Blumenthal

“If the patient is unsure of how to proceed or the physician is not sure that the calculation truly reflects the risk, a coronary calcium score is a very reasonable way to proceed,” cholesterol guidelines writing committee member Roger S. Blumenthal, MD, director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, professor of medicine at Johns Hopkins University School of Medicine and Cardiology Today Prevention Section Editor, said in an interview. “For people who are inclined to go on statin therapy and do not have any misgivings about it, I’d much rather them go on it. But in reality, most people are reluctant to go on medicine for 10 years or more. This broad intermediate-risk group includes up to half the patients we see.”

Natarajan said he expects use of CAC scoring to rise now that it has a more prominent place in the guidelines.

“More people will start reaching for coronary artery calcium scoring, because it’s a number you can hold on to,” he said.

Nissen said, however, that widespread use of CAC scoring may not be appropriate.

“The only thing that I am in strong disagreement with is the advocacy for calcium scanning,” he said. “I do not think it is prudent to expose people to ionizing radiation using a test that costs $800 to $1,000 in order to determine whether to use a drug that costs as little as $3 per month. It does not make good public health sense.”

Blumenthal noted that cost concerns may not be warranted. “While a coronary CT angiogram may cost $800 or more, a noncontrast cardiac CT typically costs $70 to $150,” he said. “It is not a screening test but rather a decision aid for those borderline-to-intermediate-risk individuals who are reluctant to go on statin therapy.”

Attention to special populations

The new guidelines also devote attention to considerations for populations related to age, race/ethnicity and other factors.

Lipid-lowering therapy for patients aged 75 years and older was not a major focus in previous guidelines, but the new one states that it may be reasonable to initiate moderate-intensity statins in that population if LDL is 70 mg/dL to 189 mg/dL, and it may be reasonable to stop statin therapy in those patients if there are factors such as cognitive decline or reduced life expectancy that may limit its benefits.

The guidelines also state that lifestyle counseling or therapies may be appropriate for children and adolescents with lipid disorders related to obesity or other lipid abnormalities.

“The committee acknowledged that the previous guidelines may have been in error by not recommending treatment in patients over age 75 years,” Nissen said. “The new guidelines recommend considering treatment in patients over 75 if they are at appropriately high risk. I agree with that. The document also recommends more aggressive treatment of young patients with diabetes, which I also agree with.”

According to the authors, it is reasonable “to review race/ethnic features that then influence ASCVD risk so as to adjust choice of statin or intensity of treatment.”

The guidelines also state that menopause at age 40 years or younger and pregnancy-associated disorders should be considered when evaluating whether to initiate medical therapy for women.

“An important piece of the guidelines is the inclusion of a risk enhancement factor calling attention to women with preeclampsia,” Walsh said in an interview. “That preeclampsia confers elevated CVD risk is not common knowledge.”

Work in progress

A number of knowledge gaps still remain. An important one, experts said, is the effect of reducing triglyceride levels, and what the success of icosapent ethyl (Vascepa, Amarin), a pharmaceutical-grade omega-3 fatty acid, in the REDUCE-IT trial might mean. In that trial, icosapent ethyl reduced risk for ischemic events vs. placebo in patients with elevated triglycerides at high risk despite statin therapy.

“The REDUCE-IT trial was a tremendously positive trial based on the nature of the treatment that was offered, icosapent ethyl, but we have no idea why it’s working,” Eckel said. “It is an exciting time to understand that effect further.”

Ferdinand said there is “a major knowledge gap in terms of when to initiate PCSK9 inhibitors.”

Amit Khera

Clinicians should understand that the guidelines are not static documents, Amit Khera, MD, MSc, professor of internal medicine and director of the UT Southwestern Preventive Cardiology Program, who holds the Dallas Heart Ball Chair in Hypertension and Heart Disease and is president of the ASPC, told Cardiology Today.

“It is ironic, in the modern era, that we want Twitter by the minute, but the guidelines come out every few years, which is a little bit problematic,” he said. “These guidelines did a great job of showing where we are today. But there are obvious gaps, and even a section at the end of the guidelines on unknowns. There are different ways to handle uncertainty. One way is to avoid it altogether and say, ‘don’t do it.’ The other is to say, ‘here is the best approach we know today. For areas without perfect data and perfect literature, here’s how you might approach it broadly’. And I think that’s what they did.” – by Erik Swain, with additional reporting by Darlene Dobkowski

Disclosures: Baum reports he has consulted and served on scientific advisory boards for Amgen, Regeneron and Sanofi and has performed clinical research for alirocumab and evolocumab. Blumenthal, Hlatky, Khera, Nissen and Walsh report no relevant financial disclosures. Eckel reports he serves on advisory boards for Kowa and Sanofi/Regeneron. Ferdinand reports he consults for Amgen and Sanofi. Natarajan reports he received a research grant from Amgen.

New, anticipated cholesterol guidelines from the American Heart Association, American College of Cardiology and 10 other societies recommend a stepped approach including treatment with statins, ezetimibe and PCSK9 inhibitors in patients with prior CVD at very high risk for another CV event.

The updated guidance also calls for more personalized risk assessment than outlined in the previous version, which was published in 2013.

The guidelines are also notable for carving out a broader role for coronary artery calcium scoring in patients in whom it is unclear whether statin therapy should be initiated, returning LDL targets to prominence in certain cases and adding emphasis on a heart-healthy lifestyle, experts told Cardiology Today.

Keith C. Ferdinand

“I consider the 2018 cholesterol guidelines a step forward. They emphasize, as previous guidelines have done but perhaps in a more forward-thinking manner, the importance of a heart-healthy lifestyle,” Keith C. Ferdinand, MD, professor of medicine at Tulane University School of Medicine and Cardiology Today Editorial Board Member, said in an interview. “They build into their message not only adults who have high cholesterol but also young individuals to prevent the development of atherosclerotic CVD (ASCVD). Also of importance, many clinicians were somewhat dismayed and maybe confused by the lack of the 2013 cholesterol guidelines having goals or thresholds. But now, for specific patients, it helps clinicians target their specific therapies in a little more concrete manner, such as LDL lower than 70 mg/dL in high-risk patients and persons with diabetes.”

Steven E. Nissen, MD, from Cleveland Clinic, said the 2018 cholesterol guidelines endorse the idea that lower LDL is always better.
Source: Cleveland Clinic; reprinted with permission.

Steven E. Nissen, MD, chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at Cleveland Clinic’s Sydell and Arnold Miller Family Heart and Vascular Institute and Cardiology Today Editorial Board Member, said the new guidelines address many of the shortcomings of the 2013 guidelines.

“The 2013 guidelines received a lot of criticism. What is interesting about the new guidelines is that they have addressed many of those concerns correctly and appropriately,” he told Cardiology Today. “The authors are bringing back the idea of LDL targets; you should not just give a statin and walk away. They are recommending more aggressive treatment of patients with LDL greater than 70 mg/dL, using add-ons of nonstatin therapies such as ezetimibe and PCSK9 inhibitors if necessary. That is a big step forward. Many of us have believed for quite some time that lower is better. The guidelines now acknowledge that.”

Role of nonstatin therapies

These are the first guidelines to endorse ezetimibe and the PCSK9 inhibitors alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen) for use in certain patients, based on the results of the IMPROVE-IT, FOURIER and ODYSSEY OUTCOMES trials.

PAGE BREAK

The guidelines state that nonstatin therapies may be considered in patients at very high risk who cannot achieve LDL less than 70 mg/dL on statin therapy; ezetimibe should be tried first, then, if necessary, a PCSK9 inhibitor.

“The attempt to use threshold levels of LDL such as 70 mg/dL when you have patients you are considering adding nonstatin therapy to is a good step forward,” Robert H. Eckel, MD, professor of medicine in the division of endocrinology, metabolism, diabetes and cardiology; professor of physiology and biophysics; Charles A. Boettcher II Chair in Atherosclerosis at the University of Colorado Denver Anschutz Medical Center; director of the lipid clinic at University of Colorado Hospital in Aurora; and past president of the AHA, told Cardiology Today. “The idea of a statin plus ezetimibe plus a PCSK9 inhibitor is not level IA evidence. No one has ever done that trial. Nevertheless, in terms of real-time practice of lipid-related medicine, we all think about LDL goals for our patients, even if they are not evidence-based.”

However, the provision may have unintended consequences, according to Pradeep Natarajan, MD, MMSc, director of preventive cardiology at Corrigan Minehan Heart Center, Massachusetts General Hospital, and assistant professor of medicine at Harvard Medical School.

Pradeep Natarajan

“Prior to these cholesterol guidelines, most insurers did not require the use of ezetimibe prior to considering PCSK9 inhibitors,” he said. “Now we are not just focusing on atherosclerotic CVD and LDL not at a suitable goal, but we are saying there needs to be consideration of additional risk factors and you need to have tried ezetimibe.”

Cost considerations

This is the first cholesterol guideline to address cost considerations.

With regard to PCSK9 inhibitors, for which price has been an issue affecting access to the therapies, the guidelines panel wrote that “all models project higher lifetime cost from use of PCSK9 inhibitors because the cost will exceed any savings from prevention of cardiovascular events.”

Mark Hlatky

“In the past, clinical practice guidelines have not explicitly considered costs. But in some areas where guidance is needed, guidelines now incorporate evidence-based value statements,” cholesterol guidelines writing committee member Mark A. Hlatky, MD, professor of health research policy and medicine at Stanford Health Care, said in an interview. “This is important because it shows that guidelines can consider value when making recommendations.”

PAGE BREAK

Some experts criticized the decision to address cost, questioning whether it is appropriate and noting that some information is already outdated. For example, the PCSK9 inhibitor manufacturers have since reduced the initial prices of the drugs.

However, Hlatky noted that more work will be done in this area.

“When it comes to a value assessment, the guidelines are already out of date,” Seth J. Baum, MD, chief medical officer of Excel Medical Clinical Trials, clinical affiliate professor of biomedical science at Florida Atlantic University in Boca Raton and immediate past president of the American Society of Preventive Cardiology (ASPC), said in an interview. “I personally do not think economics should be in our clinical guidelines. I think that’s a mistake, and a very slippery slope. “

Seth J. Baum

Focus on risk calculation

The new guidelines have a strong focus on risk assessment, keeping from the 2013 guidelines the four categories of patients recommended for statin therapy — those with ASCVD, those with LDL of at least 190 mg/dL, those with type 2 diabetes aged 40 to 75 years and those with estimated 10-year CVD risk of at least 7.5% — but adding more nuance.

There is now a distinction between patients with estimated 10-year CVD risk 7.5% to 19.9%, who are categorized as intermediate risk, and patients with estimated 10-year CVD risk of at least 20%, who are categorized as high risk.

“Continuation of using the ASCVD risk calculator remains important. Treating symptoms would be inadequate, because many patients can have significant vascular disease and have no symptoms at all,” Ferdinand said. “I also think starting statin therapy in certain very high-risk patients without calculating ASCVD risk is equally important. This is especially important in high-risk patients who are relatively young, Their risk by calculation over 10 years may actually be low, but their lifetime risk will be very high.”

Much leeway is given to determine the best course of action for patients at intermediate risk.

In these cases, a patient-clinician risk discussion should take place, which should include risk factors, risk-enhancing factors, potential benefits of statins and lifestyle measures, potential adverse events and drug-drug interactions, costs and patient preferences.

Mary Norine Walsh

“I was very pleased that shared decision-making was such an important part of this document,” Mary Norine Walsh, MD, medical director of the HF and cardiac transplantation programs at St. Vincent Heart Center in Indianapolis, past president of the ACC and Cardiology Today Editorial Board Member, said in an interview.

PAGE BREAK

Among the risk-enhancing factors that can be included in the discussion are family history of premature ASCVD, persistent LDL of at least 160 mg/dL, metabolic syndrome, chronic kidney disease, preeclampsia and premature menopause.

Robert H. Eckel

“It is important that chronic kidney disease was brought into the model of risk,” Eckel said. “We know that [chronic kidney disease] relates to atherosclerotic CVD and this is an important point to bring forward.”

If the risk discussion and assessment of risk-enhancing factors do not produce a clear decision on statin therapy, the guidelines state CAC scoring may be used as a tiebreaker.

Roger S. Blumenthal

“If the patient is unsure of how to proceed or the physician is not sure that the calculation truly reflects the risk, a coronary calcium score is a very reasonable way to proceed,” cholesterol guidelines writing committee member Roger S. Blumenthal, MD, director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, professor of medicine at Johns Hopkins University School of Medicine and Cardiology Today Prevention Section Editor, said in an interview. “For people who are inclined to go on statin therapy and do not have any misgivings about it, I’d much rather them go on it. But in reality, most people are reluctant to go on medicine for 10 years or more. This broad intermediate-risk group includes up to half the patients we see.”

Natarajan said he expects use of CAC scoring to rise now that it has a more prominent place in the guidelines.

“More people will start reaching for coronary artery calcium scoring, because it’s a number you can hold on to,” he said.

Nissen said, however, that widespread use of CAC scoring may not be appropriate.

“The only thing that I am in strong disagreement with is the advocacy for calcium scanning,” he said. “I do not think it is prudent to expose people to ionizing radiation using a test that costs $800 to $1,000 in order to determine whether to use a drug that costs as little as $3 per month. It does not make good public health sense.”

Blumenthal noted that cost concerns may not be warranted. “While a coronary CT angiogram may cost $800 or more, a noncontrast cardiac CT typically costs $70 to $150,” he said. “It is not a screening test but rather a decision aid for those borderline-to-intermediate-risk individuals who are reluctant to go on statin therapy.”

PAGE BREAK

Attention to special populations

The new guidelines also devote attention to considerations for populations related to age, race/ethnicity and other factors.

Lipid-lowering therapy for patients aged 75 years and older was not a major focus in previous guidelines, but the new one states that it may be reasonable to initiate moderate-intensity statins in that population if LDL is 70 mg/dL to 189 mg/dL, and it may be reasonable to stop statin therapy in those patients if there are factors such as cognitive decline or reduced life expectancy that may limit its benefits.

The guidelines also state that lifestyle counseling or therapies may be appropriate for children and adolescents with lipid disorders related to obesity or other lipid abnormalities.

“The committee acknowledged that the previous guidelines may have been in error by not recommending treatment in patients over age 75 years,” Nissen said. “The new guidelines recommend considering treatment in patients over 75 if they are at appropriately high risk. I agree with that. The document also recommends more aggressive treatment of young patients with diabetes, which I also agree with.”

PAGE BREAK

According to the authors, it is reasonable “to review race/ethnic features that then influence ASCVD risk so as to adjust choice of statin or intensity of treatment.”

The guidelines also state that menopause at age 40 years or younger and pregnancy-associated disorders should be considered when evaluating whether to initiate medical therapy for women.

“An important piece of the guidelines is the inclusion of a risk enhancement factor calling attention to women with preeclampsia,” Walsh said in an interview. “That preeclampsia confers elevated CVD risk is not common knowledge.”

Work in progress

A number of knowledge gaps still remain. An important one, experts said, is the effect of reducing triglyceride levels, and what the success of icosapent ethyl (Vascepa, Amarin), a pharmaceutical-grade omega-3 fatty acid, in the REDUCE-IT trial might mean. In that trial, icosapent ethyl reduced risk for ischemic events vs. placebo in patients with elevated triglycerides at high risk despite statin therapy.

“The REDUCE-IT trial was a tremendously positive trial based on the nature of the treatment that was offered, icosapent ethyl, but we have no idea why it’s working,” Eckel said. “It is an exciting time to understand that effect further.”

Ferdinand said there is “a major knowledge gap in terms of when to initiate PCSK9 inhibitors.”

Amit Khera

Clinicians should understand that the guidelines are not static documents, Amit Khera, MD, MSc, professor of internal medicine and director of the UT Southwestern Preventive Cardiology Program, who holds the Dallas Heart Ball Chair in Hypertension and Heart Disease and is president of the ASPC, told Cardiology Today.

“It is ironic, in the modern era, that we want Twitter by the minute, but the guidelines come out every few years, which is a little bit problematic,” he said. “These guidelines did a great job of showing where we are today. But there are obvious gaps, and even a section at the end of the guidelines on unknowns. There are different ways to handle uncertainty. One way is to avoid it altogether and say, ‘don’t do it.’ The other is to say, ‘here is the best approach we know today. For areas without perfect data and perfect literature, here’s how you might approach it broadly’. And I think that’s what they did.” – by Erik Swain, with additional reporting by Darlene Dobkowski

Disclosures: Baum reports he has consulted and served on scientific advisory boards for Amgen, Regeneron and Sanofi and has performed clinical research for alirocumab and evolocumab. Blumenthal, Hlatky, Khera, Nissen and Walsh report no relevant financial disclosures. Eckel reports he serves on advisory boards for Kowa and Sanofi/Regeneron. Ferdinand reports he consults for Amgen and Sanofi. Natarajan reports he received a research grant from Amgen.