n engl j med 371;1 nejm.

org july 3, 2014

77
correspondence
The new engl and journal o f medicine
Application of the New Cholesterol Guidelines
To the Editor: Pencina et al. (April 10 issue)
1

report that 12.8 million more adults in the United
States mostly older adults who do not have
cardiovascular disease would be eligible for
statin therapy under the new guidelines of the
American College of Cardiology and the Ameri-
can Heart Association (ACCAHA) for the man-
agement of cholesterol. The 2013 Kidney Disease:
Improving Global Outcomes (KDIGO) guidelines
on the management of lipid levels in chronic kid-
ney disease are more inclusive.
2
Unlike the ACC
AHA guidelines, which include a lower limit for
the low-density lipoprotein (LDL) cholesterol
level (70 mg per deciliter [1.8 mmol per liter])
and an upper limit for age (75 years), the KDIGO
guidelines do not include these limits, and pri-
mary prevention with either a statin alone (e.g.,
simvastatin at a dose of 40 mg per 24 hours and
a cost of 0.08 [approximately $0.11 in U.S. dol-
lars] per pill) or simvastatin at a dose of 20 mg
plus ezetimibe at a dose of 10 mg (1.95 [ap-
proximately $2.65 in U.S. dollars] per pill)
3
is rec-
ommended for all patients with chronic kidney
disease (defined as a persistent estimated glo-
merular filtration rate of <60 ml per minute per
1.73 m
2
of body-surface area or a urinary albu-
min-to-creatinine ratio [with albumin measured
in milligrams and creatinine measured in grams]
of >30) who are not undergoing dialysis and are
older than 50 years of age. The KDIGO guide-
lines, as compared with the ACCAHA guide-
lines, may further increase the eligibility of older
patients, since the prevalence of chronic kidney
disease among the 18.5 million persons in the
United States who are 75 years of age or older is
60% (approximately 11.1 million persons), and
the baby-boom generation is fast approaching
that age.
4,5
Angel Gallegos-Villalobos, M.D.
IIS-Fundacin Jimnez Daz
Madrid, Spain
angelgallegos.nefro@gmail.com
Jos Portols, M.D., Ph.D.
Hospital Universitario Puerta de Hierro
Madrid, Spain
Alberto Ortiz, M.D., Ph.D.
IIS-Fundacin Jimnez Daz
Madrid, Spain
No potential conflict of interest relevant to this letter was re-
ported.
1. Pencina MJ, Navar-Boggan AM, DAgostino RB, et al. Appli-
cation of new cholesterol guidelines to a population-based sam-
ple. N Engl J Med 2014;370:1422-31.
2. Tonelli M, Wanner C, Kidney Disease: Improving Global
Outcomes Lipid Guideline Development Work Group Members.
Lipid management in chronic kidney disease: synopsis of the
this weeks letters
77 Application of the New Cholesterol Guidelines
80 Mutant COQ2 in Multiple-System Atrophy
83 Albumin Replacement in Severe Sepsis
or Septic Shock
84 Thyroid Hormone Inactivation in Gastrointestinal
Stromal Tumors
87 New FDA Breakthrough-Drug Category
Implications for Patients
90 Procedural Sedation and Analgesia in Children
91 Monitoring Health Outcomes of Assisted
Reproductive Technology
The New England Journal of Medicine
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The new engl and journal o f medicine
n engl j med 371;1 nejm.org july 3, 2014
78
Kidney Disease: Improving Global Outcomes 2013 clinical prac-
tice guideline. Ann Intern Med 2014;160:182.
3. Vademecum from Spain, presenting official, government-
approved price in an EU country (http://www.vademecum.es).
4. Howden LM, Meyer JA. Age and sex composition: 2010. 2010
Census briefs. Washington, DC: Department of Commerce Eco-
nomics and Statistics Administration, May 2011 (http://www
.census.gov/prod/cen2010/briefs/c2010br-03.pdf).
5. Stevens LA, Li S, Wang C, et al. Prevalence of CKD and co-
morbid illness in elderly patients in the United States: results
from the Kidney Early Evaluation Program (KEEP). Am J Kidney
Dis 2010;55:Suppl 2:S23-S33.
DOI: 10.1056/NEJMc1405680
To the Editor: Pencina et al. estimate that the
new ACCAHA guidelines for the management
of cholesterol would increase the number of
U.S. adults who are eligible for statin therapy by
12.8 million. Although we acknowledge that ap-
proximately 475,000 future cardiovascular events
may be prevented by implementation of these
new guidelines, concern should be raised about
the well-established side effects of statin therapy.
In one of the largest trials assessing the risk of
various forms of myopathy among 32,225 per-
sons in the United States in whom statin therapy
had been initiated, Nichols and Koro
1
estimated
that the prevalence of severe myositis was be-
tween 0.21% and 0.30% and the prevalence of
rhabdomyolysis was between 0.12% and 0.13%.
Therefore, it is predictable that the implementa-
tion of the new ACCAHA guidelines would be
associated with up to 38,400 new cases of severe
myositis and up to 16,640 new cases of rhabdo-
myolysis. This would generate a remarkable clin-
ical and economic burden in the United States
that should be accurately weighted before recom-
mending widespread implementation of these
guidelines.
Giuseppe Lippi, M.D.
Academic Hospital of Parma
Parma, Italy
ulippi@tin.it
Camilla Mattiuzzi, M.D.
General Hospital of Trento
Trento, Italy
No potential conflict of interest relevant to this letter was re-
ported.
1. Nichols GA, Koro CE. Does statin therapy initiation increase
the risk for myopathy? An observational study of 32,225 diabetic
and nondiabetic patients. Clin Ther 2007;29:1761-70.
DOI: 10.1056/NEJMc1405680
To the Editor: In an important analysis of data
from the National Health and Nutrition Exami-
nation Surveys, Pencina et al. estimate that the
adoption of the ACCAHA guidelines on the
treatment of blood cholesterol
1
would result in
an 11.1-percentage-point increase in the number
of Americans who would be eligible for statin
therapy (a net increase of 12.8 million U.S. adults)
over the number who would be eligible under the
recommendations of the third Adult Treatment
Panel (ATP III).
2
More stringent optional LDL cholesterol goals
based on the results of large international ran-
domized clinical trials were included in an up-
date to the ATP-III guidelines close to 10 years
ago, and they have been adopted by many physi-
cians.
2
The application of these optional LDL
cholesterol goals may change the eligibility for
treatment in up to 6% of U.S. adults
3
and may
considerably alter estimates of reclassification in
modeling new strategies.
4
We believe that the
comparison of the new guidelines with the op-
tional ATP-III LDL cholesterol goals with respect
to estimates of eligibility for statin therapy
would be of interest to many practitioners and
a valuable addition to the current analysis by
Pencina et al.
Andre R.M. Paixao, M.D.
James A. de Lemos, M.D.
Amit Khera, M.D.
University of Texas Southwestern Medical Center
Dallas, TX
amit.khera@utsouthwestern.edu
Dr. de Lemos reports receiving honoraria and consulting fees
from AstraZeneca and consulting fees from Sanofi, Regeneron
Pharmaceuticals, and Amgen. No other potential conflict of in-
terest relevant to this letter was reported.
1. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA
guideline on the treatment of blood cholesterol to reduce athero-
sclerotic cardiovascular risk in adults: a report of the American
College of Cardiology/American Heart Association Task Force
on Practice Guidelines. Circulation 2013 November 12 (Epub
ahead of print).
2. Grundy SM, Cleeman JI, Merz CN, et al. Implications of re-
cent clinical trials for the National Cholesterol Education Pro-
gram Adult Treatment Panel III Guidelines. J Am Coll Cardiol
2004;44:720-32.
3. Persell SD, Lloyd-Jones DM, Baker DW. Implications of
changing national cholesterol education program goals for the
treatment and control of hypercholesterolemia. J Gen Intern
Med 2006;21:171-6.
4. See R, Lindsey JB, Patel MJ, et al. Application of the Screen-
ing for Heart Attack Prevention and Education Task Force rec-
ommendations to an urban population: observations from the
Dallas Heart Study. Arch Intern Med 2008;168:1055-62.
DOI: 10.1056/NEJMc1405680
The New England Journal of Medicine
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Copyright 2014 Massachusetts Medical Society. All rights reserved.
correspondence
n engl j med 371;1 nejm.org july 3, 2014
79
The Authors Reply: Gallegos-Villalobos et al.
correctly note that the KDIGO guidelines offer
broader recommendations than the ACCAHA
guidelines for adults with chronic kidney disease.
This highlights the issue of diversity among the
guidelines. For example, the guidelines of the
U.S. National Kidney Foundation
1
and the guide-
lines of the European Society of Cardiology and
the European Atherosclerosis Society
2
also pro-
vide broader recommendations for the use of
statin therapy for chronic kidney disease than
the ACCAHA guidelines.
3
However, the draft
guidelines of the U.K. National Institute for
Health and Care Excellence are similar to the
ACCAHA guidelines, since they do not recom-
mend statin therapy for adults with chronic kid-
ney disease more than for the general popula-
tion.
4
This diversity among the guidelines is
likely to introduce heterogeneity in management
of lipid levels and will affect the overall number
of adults for whom treatment is recommended
under each guideline.
Lippi and Mattiuzzi raise the important issue
of the potential harm of providing statin therapy
to 12.8 million additional adults. This might be
of particular concern for the lower-risk adults,
among whom statin therapy may be associated
with a smaller absolute risk reduction but a simi-
lar risk of side effects. It may also be a concern
for adults in whom statin therapy will be inten-
sified as a result of the new guidelines. Higher
doses are associated with a greater risk of rhab-
domyolysis, which is rare, and myositis, which is
common and diminishes adherence to treat-
ment.
5
Although the net benefit is likely to
exceed the net harm, this should not obviate
the continuing need to examine lipid-lowering
strategies to achieve the best final balance of
benefit and risk. Study data to establish the
riskbenefit profile of prolonged statin use are
lacking.
Paixao et al. point out that the ATP-III update
included optional lower LDL targets for adults
at moderately high risk (LDL <70 mg per deci-
liter) and high risk (LDL <100 mg per deciliter
[2.59 mmol per liter]), and these lower targets
may increase the number of persons for whom
treatment is recommended under ATP-III guide-
lines. It remains unclear what proportion of
providers adopted these more stringent targets.
The ACCAHA guidelines also include some
optional guidance (e.g., considering therapy
for patients with a risk of arteriosclerotic car-
diovascular disease of 5%). To be concise, we
did not include comparisons among recommen-
dations that were flagged as optional. However,
we do think that they pose a relevant research
question. In particular, the effect of different
risk thresholds and the importance of the cho-
lesterol level as a trigger for therapy need to be
further investigated. When we reran the analy-
sis using these optional cutoff points, the num-
bers of adults already receiving statin therapy or
for whom statin therapy would be recommend-
ed increased from 43.2 million to 54.2 million
under the ATP-III guidelines and from 56.0 mil-
lion to 65.5 million under the ACCAHA guide-
lines.
Ann Marie Navar-Boggan, M.D., Ph.D.
Duke University
Durham, NC
Allan D. Sniderman, M.D.
McGill University
Montreal, QC, Canada
Michael J. Pencina, Ph.D.
Duke Clinical Research Institute
Durham, NC
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
1. Kidney Disease Outcomes Quality Initiative (K/DOQI) Group.
K/DOQI clinical practice guidelines for management of dyslipid-
emias in patients with kidney disease. Am J Kidney Dis 2003;
41:Suppl 3:S1-S91.
2. European Association for Cardiovascular Prevention & Re-
habilitation, Reiner Z, Catapano AL, et al. ESC/EAS guidelines
for the management of dyslipidaemias: the Task Force for the
Management of Dyslipidaemias of the European Society of Car-
diology (ESC) and the European Atherosclerosis Society (EAS).
Eur Heart J 2011;32:1769-818.
3. Stone NJ, Robinson J, Lichtenstein AH, et al. ACC/AHA
guideline on the treatment of blood cholesterol to reduce athero-
sclerotic cardiovascular risk in adults: a report of the American
College of Cardiology/American Heart Association Task Force
on Practice Guidelines. Circulation 2013 November 12 (Epub
ahead of print).
4. National Clinical Guideline Centre. Lipid modification:
cardiovascular risk assessment and the modification of blood
lipids for the primary and secondary prevention of cardiovas-
cular disease. Clinical guideline (draft for consultation). Febru-
ary 2014 (http://www.nice.org.uk/nicemedia/live/13637/66547/
66547.pdf).
5. Thompson PD, Clarkson P, Karas RH. Statin-associated my-
opathy. JAMA 2003;289:1681-90.
DOI: 10.1056/NEJMc1405680
The New England Journal of Medicine
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Copyright 2014 Massachusetts Medical Society. All rights reserved.