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A closer look at an ezetimibe discussion
Although I look forward to receiving JFP each month, I was initially disappointed in Dr. Jonathon M. Firnhaber’s article, “Newer cholesterol-lowering agents: What you must know” (J Fam Pract. 2018;67:339-341,344,345), because of what appeared to be a superficial discussion of the medication ezetimibe. The potential role of PCSK9 inhibitors in extremely high-risk individuals was well discussed, but my first read left me with the impression that ezetimibe should be used more widely.
It seemed that in the section for ezetimibe, the author was suggesting using it for primary prevention. The line, “Consider adding ezetimibe to maximally tolerated statin therapy for patients not meeting LDL-C goals with a statin alone” left me a bit confused, as the most widely used guideline (that by the American College of Cardiology/American Heart Association Task Force on Practice Guidelines) states that there is no goal low-density lipoprotein cholesterol (LDL-C) level for primary prevention in patients without known cardiovascular disease (CVD) because studies have not been done to support this concept.1
But upon rereading the article, I realized the statement was placed at the end of a section that discussed secondary prevention based on the IMPROVE-IT study.2 This trial included only patients with previous acute coronary syndrome, one of the populations at highest risk.
I write just to reinforce the importance of considering what evidence we have for primary prevention. Although there is a value to rechecking LDL-C levels to assess compliance, there really is no convincing evidence that we should treat to a goal LDL-C level in someone who does not already have CVD. So the addition of ezetimibe to a statin in these patients is not recommended. Thus, the often-quoted strategy: “Start them on the right statin, and don’t look back.”
Bill Crump, MD
Madisonville, Ky
1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(suppl 2):S1-S45.
2. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.
Continue to: Authors' response
Author’s response:
Thank you, Dr. Crump, for your feedback. I suspect that most clinicians would welcome more robust outcomes data on ezetimibe, but to date none have been published.
The IMPROVE-IT trial1 offers the best supportive evidence for the use of ezetimibe, but still finds only a 2% absolute risk reduction (ARR) in a composite endpoint (cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization ≥30 days after randomization, or nonfatal stroke), equating to a number needed to treat (NNT) of 50.
The largest meta-analysis of ezetimibe trials—published prior to IMPROVE-IT—combined 31,048 patients to find an ARR for myocardial infarction of 1.1% (NNT=91) and an ARR for stroke of 0.6% (NNT=167), with no difference in cardiovascular death.2
Because of its limited outcomes data, ezetimibe is best reserved for patients unable to tolerate statin therapy, for those in whom statin therapy is contraindicated, or for those not meeting LDL-C reduction goals with a statin alone. This position is also supported by the United Kingdom’s National Institute for Health and Care Excellence (NICE).3
Finally, you are correct that the 2013 American College of Cardiology/American Heart Association Guideline on the Assessment of Cardiovascular Risk does not advocate a number-driven LDL-C goal, but rather recommends a risk-based moderate (30%-50%) or high-intensity (>50%) LDL-C reduction goal.4
Jonathon Firnhaber, MD
Greenville, NC
1. Cannon C, Blazing M, Giugliano R, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.
2. Savarese G, Ferrari G, Rosano G, et al. Safety and efficacy of ezetimibe: a meta-analysis. Int J Cardiol. 2015;201:247-252.
3. National Institute for Health and Care Excellence. Ezetimibe for treating primary heterozygous-familial and non-familial hypercholesterolaemia. Technology appraisal guidance [TA385]. February 24, 2016. www.nice.org.uk/guidance/ta385. Accessed September 12, 2018.
4. 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. J Am Coll Cardiol. 2014;63:2935-2959.
Although I look forward to receiving JFP each month, I was initially disappointed in Dr. Jonathon M. Firnhaber’s article, “Newer cholesterol-lowering agents: What you must know” (J Fam Pract. 2018;67:339-341,344,345), because of what appeared to be a superficial discussion of the medication ezetimibe. The potential role of PCSK9 inhibitors in extremely high-risk individuals was well discussed, but my first read left me with the impression that ezetimibe should be used more widely.
It seemed that in the section for ezetimibe, the author was suggesting using it for primary prevention. The line, “Consider adding ezetimibe to maximally tolerated statin therapy for patients not meeting LDL-C goals with a statin alone” left me a bit confused, as the most widely used guideline (that by the American College of Cardiology/American Heart Association Task Force on Practice Guidelines) states that there is no goal low-density lipoprotein cholesterol (LDL-C) level for primary prevention in patients without known cardiovascular disease (CVD) because studies have not been done to support this concept.1
But upon rereading the article, I realized the statement was placed at the end of a section that discussed secondary prevention based on the IMPROVE-IT study.2 This trial included only patients with previous acute coronary syndrome, one of the populations at highest risk.
I write just to reinforce the importance of considering what evidence we have for primary prevention. Although there is a value to rechecking LDL-C levels to assess compliance, there really is no convincing evidence that we should treat to a goal LDL-C level in someone who does not already have CVD. So the addition of ezetimibe to a statin in these patients is not recommended. Thus, the often-quoted strategy: “Start them on the right statin, and don’t look back.”
Bill Crump, MD
Madisonville, Ky
1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(suppl 2):S1-S45.
2. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.
Continue to: Authors' response
Author’s response:
Thank you, Dr. Crump, for your feedback. I suspect that most clinicians would welcome more robust outcomes data on ezetimibe, but to date none have been published.
The IMPROVE-IT trial1 offers the best supportive evidence for the use of ezetimibe, but still finds only a 2% absolute risk reduction (ARR) in a composite endpoint (cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization ≥30 days after randomization, or nonfatal stroke), equating to a number needed to treat (NNT) of 50.
The largest meta-analysis of ezetimibe trials—published prior to IMPROVE-IT—combined 31,048 patients to find an ARR for myocardial infarction of 1.1% (NNT=91) and an ARR for stroke of 0.6% (NNT=167), with no difference in cardiovascular death.2
Because of its limited outcomes data, ezetimibe is best reserved for patients unable to tolerate statin therapy, for those in whom statin therapy is contraindicated, or for those not meeting LDL-C reduction goals with a statin alone. This position is also supported by the United Kingdom’s National Institute for Health and Care Excellence (NICE).3
Finally, you are correct that the 2013 American College of Cardiology/American Heart Association Guideline on the Assessment of Cardiovascular Risk does not advocate a number-driven LDL-C goal, but rather recommends a risk-based moderate (30%-50%) or high-intensity (>50%) LDL-C reduction goal.4
Jonathon Firnhaber, MD
Greenville, NC
1. Cannon C, Blazing M, Giugliano R, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.
2. Savarese G, Ferrari G, Rosano G, et al. Safety and efficacy of ezetimibe: a meta-analysis. Int J Cardiol. 2015;201:247-252.
3. National Institute for Health and Care Excellence. Ezetimibe for treating primary heterozygous-familial and non-familial hypercholesterolaemia. Technology appraisal guidance [TA385]. February 24, 2016. www.nice.org.uk/guidance/ta385. Accessed September 12, 2018.
4. 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. J Am Coll Cardiol. 2014;63:2935-2959.
Although I look forward to receiving JFP each month, I was initially disappointed in Dr. Jonathon M. Firnhaber’s article, “Newer cholesterol-lowering agents: What you must know” (J Fam Pract. 2018;67:339-341,344,345), because of what appeared to be a superficial discussion of the medication ezetimibe. The potential role of PCSK9 inhibitors in extremely high-risk individuals was well discussed, but my first read left me with the impression that ezetimibe should be used more widely.
It seemed that in the section for ezetimibe, the author was suggesting using it for primary prevention. The line, “Consider adding ezetimibe to maximally tolerated statin therapy for patients not meeting LDL-C goals with a statin alone” left me a bit confused, as the most widely used guideline (that by the American College of Cardiology/American Heart Association Task Force on Practice Guidelines) states that there is no goal low-density lipoprotein cholesterol (LDL-C) level for primary prevention in patients without known cardiovascular disease (CVD) because studies have not been done to support this concept.1
But upon rereading the article, I realized the statement was placed at the end of a section that discussed secondary prevention based on the IMPROVE-IT study.2 This trial included only patients with previous acute coronary syndrome, one of the populations at highest risk.
I write just to reinforce the importance of considering what evidence we have for primary prevention. Although there is a value to rechecking LDL-C levels to assess compliance, there really is no convincing evidence that we should treat to a goal LDL-C level in someone who does not already have CVD. So the addition of ezetimibe to a statin in these patients is not recommended. Thus, the often-quoted strategy: “Start them on the right statin, and don’t look back.”
Bill Crump, MD
Madisonville, Ky
1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(suppl 2):S1-S45.
2. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.
Continue to: Authors' response
Author’s response:
Thank you, Dr. Crump, for your feedback. I suspect that most clinicians would welcome more robust outcomes data on ezetimibe, but to date none have been published.
The IMPROVE-IT trial1 offers the best supportive evidence for the use of ezetimibe, but still finds only a 2% absolute risk reduction (ARR) in a composite endpoint (cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization ≥30 days after randomization, or nonfatal stroke), equating to a number needed to treat (NNT) of 50.
The largest meta-analysis of ezetimibe trials—published prior to IMPROVE-IT—combined 31,048 patients to find an ARR for myocardial infarction of 1.1% (NNT=91) and an ARR for stroke of 0.6% (NNT=167), with no difference in cardiovascular death.2
Because of its limited outcomes data, ezetimibe is best reserved for patients unable to tolerate statin therapy, for those in whom statin therapy is contraindicated, or for those not meeting LDL-C reduction goals with a statin alone. This position is also supported by the United Kingdom’s National Institute for Health and Care Excellence (NICE).3
Finally, you are correct that the 2013 American College of Cardiology/American Heart Association Guideline on the Assessment of Cardiovascular Risk does not advocate a number-driven LDL-C goal, but rather recommends a risk-based moderate (30%-50%) or high-intensity (>50%) LDL-C reduction goal.4
Jonathon Firnhaber, MD
Greenville, NC
1. Cannon C, Blazing M, Giugliano R, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.
2. Savarese G, Ferrari G, Rosano G, et al. Safety and efficacy of ezetimibe: a meta-analysis. Int J Cardiol. 2015;201:247-252.
3. National Institute for Health and Care Excellence. Ezetimibe for treating primary heterozygous-familial and non-familial hypercholesterolaemia. Technology appraisal guidance [TA385]. February 24, 2016. www.nice.org.uk/guidance/ta385. Accessed September 12, 2018.
4. 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. J Am Coll Cardiol. 2014;63:2935-2959.