- Email: [email protected]
Risk of Adverse Neurocognitive Outcomes With PCSK-9 Inhibitors
JACC VOL. 69, NO. 22, 2017
Letters
2774
JUNE 6, 2017:2769–76
<25
CHD Events (%)
F I G U R E 1 CHD Event Rates in Primary Prevention Trials
mg/dl
were
not
associated
with
adverse
neurocognitive events. The impact of lipid-lowering medication on cognitive function is an area of
10 9 8 7 6 5 4 3 2 1 0 -1
y = 0.0599x - 3.3952 R2 = 0.9305 p=0.0019
ongoing research with mixed evidence. A separate WOSCOPS-P
WOSCOPS-S
including
a
similar
collection
of
clinical trials found a significantly increased risk of adverse
AFCAPS-P
AFCAPS-S
meta-analysis
neurocognitive
events
among
patients
treated with PCSK9 inhibitors (2). The concern over cognitive impact and lipid-
ASCOT-P
altering drugs is based on the reduced availability of lipid-soluble nutrients in the circulation. PCSK9
ASCOT-S
inhibitors offer new lows for lipids, with endpoint 55
75
95
115
135
155
175
195
LDL Cholesterol (mg/dl)
LDL-C values <30 mg/dl in many patients. The study by Robinson et al. (1) compared patients with LDL-C concentrations of <15 mg/dl and <25 mg/dl. The primary endpoint for the PCSK9 inhibitor trials
CHD event rates in primary prevention trials are directly proportional to the on-treatment absolute level of LDL cholesterol. The event rate is predicted to approach 0 at an LDL concentration of approximately 57 mg/dl. AFCAPS ¼ Air Force Coronary Atherosclerosis
reviewed was reduction of calculated LDL-C. Studies accounted for the documented underestimation of
Prevention Study; ASCOT ¼ Anglo-Scandinavian Cardiac Outcome Trial; CHD ¼ coronary
calculated LDL-C by measuring LDL-C by ultracen-
heart disease; LDL ¼ low-density lipoprotein; WOSCOPS ¼ West of Scotland Coronary
trifuge separation. Robinson et al. (1) reported a
Prevention Study. Reprinted with permission from O’Keefe et al. (3).
median
difference
calculated patients
versus and,
of
only
measured thus,
3
mg/dl
LDL-C
suggested
between
across that
all the
Cian P. McCarthy, MBBCh, BAO *John W. McEvoy, MBBCh, MHS
underestimation did not play a significant role.
*Johns Hopkins Ciccarone Center for the Prevention of
measured and calculated values is significantly
However, the variability in differences between
Heart Disease, and Division of Cardiology
greater at lower LDL-C concentrations (3). Based
Department of Medicine
on our data, a calculated LDL-C of 25 mg/dl can
Johns Hopkins University School of Medicine
have an actual measured LDL-C value between 7 and
Blalock 524C
45 mg/dl. This phenomenon is actually supported
600 North Wolfe Street
in their report as the range of discrepancies spanned
Baltimore, Maryland 21287
from 14 mg/dl to þ160 mg/dl for patients with
E-mail: [email protected]
LDL-C
http://dx.doi.org/10.1016/j.jacc.2017.01.076
with 24 mg/dl to þ26 mg/dl when LDL-C was
Please note: Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
REFERENCES
concentrations
of
<15
mg/dl
compared
between 15 and 25 mg/dl. Misclassification of even small numbers of patients could skew the data significantly for this analysis of cognitive abnormalities. It would be important to rely
1. Ford I, Shah ASV, Zhang R, et al. High-sensitivity cardiac troponin, statin therapy, and risk of coronary heart disease. J Am Coll Cardiol 2016;68:2719–28.
on the measured LDL-C concentrations to compare
2. Silverman MG, Ference BA, Im K, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA 2016;316:1289–97.
More importantly, providers and patients should be
3. O’Keefe JH Jr., Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol 2004;43:2142–6.
Risk of Adverse Neurocognitive Outcomes With PCSK-9 Inhibitors
patients with neurocognitive events to those without. aware of the limitations of calculated LDL-C when managing patients with very low concentrations of LDL-C. *Jeffrey W. Meeusen, PhD Leslie J. Donato, PhD Allan S. Jaffe, MD *Department of Laboratory Medicine and Pathology Mayo Clinic 200 First Street Southwest Rochester, Minnesota 55905
The paper by Robinson et al. (1) suggested that
E-mail: [email protected]
low-density lipoprotein cholesterol (LDL-C) values
http://dx.doi.org/10.1016/j.jacc.2017.03.583
JACC VOL. 69, NO. 22, 2017
Letters
JUNE 6, 2017:2769–76
Please note: Dr. Jaffe is a consultant for and has received honoraria from Abbott, Alere Beckman, ET Healthcare, NeurogenomeX, Novartis, Roche, Siemens, Sphingotec, theheart.org, and Singulex. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. P.K. Shah, MD, served as Guest Editor-in-Chief for this paper. Robert Giugliano, MD, served as Guest Editor for this paper.
randomized controlled trial showed that anakinra
REFERENCES
to most other inflammatory diseases, and we may
1. Robinson JG, Rosenson RS, Farnier M, Chaudhari U, Sasiela WJ, Merlet L, et al. Safety of very low low-density lipoprotein cholesterol levels with alirocumab: pooled data from randomized trials. J Am Coll Cardiol 2017;69: 471–82.
consider abandoning the term idiopathic also in this
has a spectacular effect in these patients (5), and the term idiopathic seems inappropriate for a disease treated with anti-interleukin-1 agents. The pathogenesis of pericarditis is now comparable
2. Khan AR, Bavishi C, Riaz H, Farid TA, Khan S, Atlas M, et al. Increased risk of adverse neurocognitive outcomes with proprotein convertase subtilisin-kexin type 9 inhibitors. Circ Cardiovasc Qual Outcomes 2017;10. 3. Meeusen JW, Snozek CL, Baumann NA, Jaffe AS, Saenger AK. Reliability of calculated low-density lipoprotein cholesterol. Am J Cardiol 2015;116: 538–40.
condition. Antonio Brucato, MD *Anna Valenti, MD Bernhard Maisch, MD *Medicina Interna Ospedale Papa Giovanni XXIII (Torre 4 Piano 4) Piazza OMS 1 24127 Bergamo
Acute and Recurrent Pericarditis
Italy
Still Idiopathic?
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Cremer et al. (1) underlined relevant clinical points
REFERENCES
and the role of cardiac magnetic resonance in their
1. Cremer PC, Kumar A, Kontizas A, et al. Complicated pericarditis. J Am Coll Cardiol 2016;68:2311–28.
E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2017.02.072
excellent review. The authors also raised important issues concerning pathogenesis, with which we agree and wish to expand. The term idiopathic pericarditis seems unfortunate in both the first attack and in recurrences and a label of our diagnostic ignorance or unwillingness to search for it. In a biopsy study including 259 patients with large pericardial effusion, the underlying cause was identified by molecular and immunity-histological methods: 12% viral, 35% autoreactive/lymphocytic, 2% bacterial, 15% traumatic, 28% malignant, and 8% other (2). On the other hand, the term idiopathic may be reassuring for the physician but may alarm the
2. Maisch B, Rupp H, Ristic A, et al. Pericardioscopy and epi- and pericardial biopsy- a new window to the heart improving etiological diagnoses and permitting targeted intrapericardial therapy. Heart Fail Rev 2013;18: 317–28. 3. Imazio M, Brucato A, Doria A, et al. Antinuclear antibodies in recurrent idiopathic pericarditis: prevalence and clinical significance. Int J Cardiol 2009; 136:289–93. 4. Caforio AL, Brucato A, Imazio M, et al. Anti-heart and anti-intercalated disk autoantibodies: evidence for autoimmunity in idiopathic recurrent acute pericarditis. Heart 2010;96:779–84. 5. Brucato A, Imazio M, Gattorno M, et al. Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence. JAMA 2016;31:1906–12.
patient, who does not understand why all the other
REPLY: Acute and Recurrent Pericarditis
diseases, such as hypertension, rheumatoid arthritis,
Still Idiopathic?
and others, are not idiopathic, whereas their disease is. In acute pericarditis, most cases of idiopathic
Dr. Brucato and colleagues raise an important issue in
pericarditis are viral in the first attacks, whereas
the nomenclature of pericardial disease: diagnoses of
recurrences are often due to too rapidly tapered
most patients with acute or recurrent pericarditis are
drug regimen. Other cases seem immune mediated
labeled idiopathic. As the authors note, the term
or autoinflammatory. Possible noninvasive clues
idiopathic elicits a sense of complacency among
for autoimmunity are antinuclear (3) or antiheart (4)
physicians. For patients, the response is the opposite.
antibodies (50% of adults), dry eyes, arthralgias, and
They feel frustrated and alarmed that their clinicians
a
an
seem to know so little about their disease. Given this
autoinflammatory pathogenesis involving a pivotal
predicament, why has idiopathic persisted in peri-
role for inflammosome are acute attacks followed
carditis, and what should the criteria be to abandon
by
the term?
subacute
course.
complete
Conversely,
resolution,
clues
strikingly
for
elevated
C-reactive protein, high fever, and pleuropulmonary
Conventionally, excluding patients with cardiac
are
injury syndromes and underlying autoimmune dis-
generally antinuclear-antibodies negative. A recent
ease, most patients’ conditions are referred to as
and
systemic
involvement;
these
patients
2775
Letters
2774
JUNE 6, 2017:2769–76
<25
CHD Events (%)
F I G U R E 1 CHD Event Rates in Primary Prevention Trials
mg/dl
were
not
associated
with
adverse
neurocognitive events. The impact of lipid-lowering medication on cognitive function is an area of
10 9 8 7 6 5 4 3 2 1 0 -1
y = 0.0599x - 3.3952 R2 = 0.9305 p=0.0019
ongoing research with mixed evidence. A separate WOSCOPS-P
WOSCOPS-S
including
a
similar
collection
of
clinical trials found a significantly increased risk of adverse
AFCAPS-P
AFCAPS-S
meta-analysis
neurocognitive
events
among
patients
treated with PCSK9 inhibitors (2). The concern over cognitive impact and lipid-
ASCOT-P
altering drugs is based on the reduced availability of lipid-soluble nutrients in the circulation. PCSK9
ASCOT-S
inhibitors offer new lows for lipids, with endpoint 55
75
95
115
135
155
175
195
LDL Cholesterol (mg/dl)
LDL-C values <30 mg/dl in many patients. The study by Robinson et al. (1) compared patients with LDL-C concentrations of <15 mg/dl and <25 mg/dl. The primary endpoint for the PCSK9 inhibitor trials
CHD event rates in primary prevention trials are directly proportional to the on-treatment absolute level of LDL cholesterol. The event rate is predicted to approach 0 at an LDL concentration of approximately 57 mg/dl. AFCAPS ¼ Air Force Coronary Atherosclerosis
reviewed was reduction of calculated LDL-C. Studies accounted for the documented underestimation of
Prevention Study; ASCOT ¼ Anglo-Scandinavian Cardiac Outcome Trial; CHD ¼ coronary
calculated LDL-C by measuring LDL-C by ultracen-
heart disease; LDL ¼ low-density lipoprotein; WOSCOPS ¼ West of Scotland Coronary
trifuge separation. Robinson et al. (1) reported a
Prevention Study. Reprinted with permission from O’Keefe et al. (3).
median
difference
calculated patients
versus and,
of
only
measured thus,
3
mg/dl
LDL-C
suggested
between
across that
all the
Cian P. McCarthy, MBBCh, BAO *John W. McEvoy, MBBCh, MHS
underestimation did not play a significant role.
*Johns Hopkins Ciccarone Center for the Prevention of
measured and calculated values is significantly
However, the variability in differences between
Heart Disease, and Division of Cardiology
greater at lower LDL-C concentrations (3). Based
Department of Medicine
on our data, a calculated LDL-C of 25 mg/dl can
Johns Hopkins University School of Medicine
have an actual measured LDL-C value between 7 and
Blalock 524C
45 mg/dl. This phenomenon is actually supported
600 North Wolfe Street
in their report as the range of discrepancies spanned
Baltimore, Maryland 21287
from 14 mg/dl to þ160 mg/dl for patients with
E-mail: [email protected]
LDL-C
http://dx.doi.org/10.1016/j.jacc.2017.01.076
with 24 mg/dl to þ26 mg/dl when LDL-C was
Please note: Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
REFERENCES
concentrations
of
<15
mg/dl
compared
between 15 and 25 mg/dl. Misclassification of even small numbers of patients could skew the data significantly for this analysis of cognitive abnormalities. It would be important to rely
1. Ford I, Shah ASV, Zhang R, et al. High-sensitivity cardiac troponin, statin therapy, and risk of coronary heart disease. J Am Coll Cardiol 2016;68:2719–28.
on the measured LDL-C concentrations to compare
2. Silverman MG, Ference BA, Im K, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA 2016;316:1289–97.
More importantly, providers and patients should be
3. O’Keefe JH Jr., Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol 2004;43:2142–6.
Risk of Adverse Neurocognitive Outcomes With PCSK-9 Inhibitors
patients with neurocognitive events to those without. aware of the limitations of calculated LDL-C when managing patients with very low concentrations of LDL-C. *Jeffrey W. Meeusen, PhD Leslie J. Donato, PhD Allan S. Jaffe, MD *Department of Laboratory Medicine and Pathology Mayo Clinic 200 First Street Southwest Rochester, Minnesota 55905
The paper by Robinson et al. (1) suggested that
E-mail: [email protected]
low-density lipoprotein cholesterol (LDL-C) values
http://dx.doi.org/10.1016/j.jacc.2017.03.583
JACC VOL. 69, NO. 22, 2017
Letters
JUNE 6, 2017:2769–76
Please note: Dr. Jaffe is a consultant for and has received honoraria from Abbott, Alere Beckman, ET Healthcare, NeurogenomeX, Novartis, Roche, Siemens, Sphingotec, theheart.org, and Singulex. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. P.K. Shah, MD, served as Guest Editor-in-Chief for this paper. Robert Giugliano, MD, served as Guest Editor for this paper.
randomized controlled trial showed that anakinra
REFERENCES
to most other inflammatory diseases, and we may
1. Robinson JG, Rosenson RS, Farnier M, Chaudhari U, Sasiela WJ, Merlet L, et al. Safety of very low low-density lipoprotein cholesterol levels with alirocumab: pooled data from randomized trials. J Am Coll Cardiol 2017;69: 471–82.
consider abandoning the term idiopathic also in this
has a spectacular effect in these patients (5), and the term idiopathic seems inappropriate for a disease treated with anti-interleukin-1 agents. The pathogenesis of pericarditis is now comparable
2. Khan AR, Bavishi C, Riaz H, Farid TA, Khan S, Atlas M, et al. Increased risk of adverse neurocognitive outcomes with proprotein convertase subtilisin-kexin type 9 inhibitors. Circ Cardiovasc Qual Outcomes 2017;10. 3. Meeusen JW, Snozek CL, Baumann NA, Jaffe AS, Saenger AK. Reliability of calculated low-density lipoprotein cholesterol. Am J Cardiol 2015;116: 538–40.
condition. Antonio Brucato, MD *Anna Valenti, MD Bernhard Maisch, MD *Medicina Interna Ospedale Papa Giovanni XXIII (Torre 4 Piano 4) Piazza OMS 1 24127 Bergamo
Acute and Recurrent Pericarditis
Italy
Still Idiopathic?
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Cremer et al. (1) underlined relevant clinical points
REFERENCES
and the role of cardiac magnetic resonance in their
1. Cremer PC, Kumar A, Kontizas A, et al. Complicated pericarditis. J Am Coll Cardiol 2016;68:2311–28.
E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2017.02.072
excellent review. The authors also raised important issues concerning pathogenesis, with which we agree and wish to expand. The term idiopathic pericarditis seems unfortunate in both the first attack and in recurrences and a label of our diagnostic ignorance or unwillingness to search for it. In a biopsy study including 259 patients with large pericardial effusion, the underlying cause was identified by molecular and immunity-histological methods: 12% viral, 35% autoreactive/lymphocytic, 2% bacterial, 15% traumatic, 28% malignant, and 8% other (2). On the other hand, the term idiopathic may be reassuring for the physician but may alarm the
2. Maisch B, Rupp H, Ristic A, et al. Pericardioscopy and epi- and pericardial biopsy- a new window to the heart improving etiological diagnoses and permitting targeted intrapericardial therapy. Heart Fail Rev 2013;18: 317–28. 3. Imazio M, Brucato A, Doria A, et al. Antinuclear antibodies in recurrent idiopathic pericarditis: prevalence and clinical significance. Int J Cardiol 2009; 136:289–93. 4. Caforio AL, Brucato A, Imazio M, et al. Anti-heart and anti-intercalated disk autoantibodies: evidence for autoimmunity in idiopathic recurrent acute pericarditis. Heart 2010;96:779–84. 5. Brucato A, Imazio M, Gattorno M, et al. Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence. JAMA 2016;31:1906–12.
patient, who does not understand why all the other
REPLY: Acute and Recurrent Pericarditis
diseases, such as hypertension, rheumatoid arthritis,
Still Idiopathic?
and others, are not idiopathic, whereas their disease is. In acute pericarditis, most cases of idiopathic
Dr. Brucato and colleagues raise an important issue in
pericarditis are viral in the first attacks, whereas
the nomenclature of pericardial disease: diagnoses of
recurrences are often due to too rapidly tapered
most patients with acute or recurrent pericarditis are
drug regimen. Other cases seem immune mediated
labeled idiopathic. As the authors note, the term
or autoinflammatory. Possible noninvasive clues
idiopathic elicits a sense of complacency among
for autoimmunity are antinuclear (3) or antiheart (4)
physicians. For patients, the response is the opposite.
antibodies (50% of adults), dry eyes, arthralgias, and
They feel frustrated and alarmed that their clinicians
a
an
seem to know so little about their disease. Given this
autoinflammatory pathogenesis involving a pivotal
predicament, why has idiopathic persisted in peri-
role for inflammosome are acute attacks followed
carditis, and what should the criteria be to abandon
by
the term?
subacute
course.
complete
Conversely,
resolution,
clues
strikingly
for
elevated
C-reactive protein, high fever, and pleuropulmonary
Conventionally, excluding patients with cardiac
are
injury syndromes and underlying autoimmune dis-
generally antinuclear-antibodies negative. A recent
ease, most patients’ conditions are referred to as
and
systemic
involvement;
these
patients
2775