Re: A Systematic Review and Meta-Analysis of Statin Therapy in Children With Familial Hypercholesterolemia

On Jun 26, 6:50 pm, MarilynMann <m...@xxxxxxxxxxx> wrote:

Looking at this more broadly, I get the impression that there are
differences of opinion between people who think we should treat people
early on to prevent subclinical atherosclerosis and other people who
think the value of this approach has not been proven.

An example of the first point of view is the following: Tsimikas &
Witztum, Shifting the diagnosis and treatment of atherosclerosis to
children and young adults: a new paradigm for the 21st century, J Am
Coll Cardiol, 2002; 40:2122-2124. http://content.onlinejacc.org/cgi/content/full/40/12/2122.


Here is a slightly different point of view:

The American Journal of Cardiology
Volume 100, Issue 1, 1 July 2007, Pages 138-142

Editorial

Treating Hypercholesterolemia and Hypertension Based on Lifetime
Global Risk

John B. Kostis MD, a,
aUMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey.
Received 29 January 2007; revised 5 February 2007; accepted 5
February 2007. Available online 21 May 2007.

In the December 1, 2006, issue of the American Journal of Cardiology,
the Editor-in-Chief, William C. Roberts, MD, made a strong case for
early initiation of therapy with statin drugs. He stated that because
life insurance policies were often purchased by individuals in their
20s, statin drugs with or without ezetimibe could be started at the
same time.1 I fully agree with him and emphasize that prevention
should not be limited to decreasing low-density lipoprotein (LDL)
cholesterol, but also to lifestyle change and the treatment of
systemic hypertension and other risk factors.2 Current guidelines such
as the National Cholesterol Education Program Adult Treatment Panel
III and the Seventh Report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure focus on 1 aspect of global risk, whereas the coexistence of
hypertension and hyperlipidemia is common and accounted for most
cardiovascular events.[3], [4], [5], [6] and [7] The dual purpose of
this commentary is to propose the development of a single set of
simple guidelines that could cover most patients needing
pharmacotherapy for primary prevention and remove age from the
algorithms used to decide when pharmacologic treatment is indicated.
Health care providers may consult additional monographs (such as the
current "silo" guidelines) when more details are needed in individual
cases.[8] and [9]

Global Risk

Existing guidelines for primary prevention have not achieved their
objective of controlling risk factors, such as hypertension and
hyperlipidemia. Only 36.8% of patients with hypertension in the United
States have their blood pressure controlled to current guidelines,10
only a minority of patients have controlled LDL to current
recommendations, and a very low percentage have both blood pressure
and cholesterol controlled. In 1 study, <10% of patients achieved both
goals (<5% of black women).11 Reasons for this include lack of
awareness, complexity of guidelines, and skepticism regarding their
applicability to individual patients.12 In addition, the current
approach to risk factors has the important limitation that it does not
consider the individual as a whole. Risk varies widely depending on
the presence of additional risk factors, and individuals who develop
cardiovascular events have modest increases in >1 risk factor. In the
Multiple Risk Factor Intervention Trial (MRFIT), the majority of
coronary heart disease (CHD) events (64% to 100% of fatal CHD and 46%
to 88% of nonfatal myocardial infarctions) occurred in patients
(347,978 men aged 35 to 57 years) with 2 major risk factors.13 In
general, the relative risk reduction of lipid lowering and
antihypertensive therapy is similar for those with or without
additional risk factors. Therefore, the benefit (absolute risk
reduction) of therapy is higher and the number needed to treat to
prevent 1 event is lower in those with higher global risk, usually
those with >1 risk factor. Multidimensional intervention based on what
we know today is necessary to achieve the lowest possible event rate
in primary prevention. New clinical trials showed that targeting >1
risk factor accrued higher benefits.14 Similarly, assessing health
care quality on only 1 risk factor, rather than global risk, is not
optimal.15 It has been estimated that prescribing statins to patients
with high global risk regardless of cholesterol level would result in
the avoidance of more events than treating only those with high
cholesterol.16 Approaches to prevention based on combined modulation
of common risk factors of coronary artery disease may result in a very
large decrease in disease burden.17 Dr. Roberts18 stated that statin
drugs are to atherosclerosis what penicillin was to infectious
diseases. We must not forget that penicillin does not cure all
infectious diseases and LDL lowering does not eliminate the risk of
stroke, end-stage renal disease, heart failure, or even myocardial
infarction.

Exclusion of Age in Deciding Who Should Receive Pharmacologic Therapy

About a year ago, I wrote a tongue-in-cheek commentary entitled
"Disputation on the Use of Age in Determining the Need for Treatment
of Hypercholesterolemia and Hypertension"19 in the style of the
disputation by Martin Luther. The purpose of the commentary was to
emphasize that current guidelines based on absolute risk, which is
determined primarily by age and gender, resulted in undertreatment of
the young. Also, the guidelines are focused on events instead of
preventing the disease. I recommended that age be removed from
algorithms used to decide when pharmacologic treatment is indicated
for hyperlipidemia and hypertension. I received informal feedback from
physicians and scientists working in the field of hypertension and
hyperlipidemia and persons involved in guideline writing. Although
most agreed with me, they identified issues for further discussion.

A number of them stated that although this approach made sense, it was
not based on specific evidence from long-term clinical trials; some
proposed alternate ways of calculating the risk; others were concerned
about the safety and expense of long-term therapy; and many
recommended wider publication of this opinion. In the next several
paragraphs, I focus on these issues.

Evidence for treating younger individuals

A wealth of evidence shows that antihypertensive and lipid-lowering
pharmacologic therapy results in a significant decrease in the rate of
cardiovascular events.[20], [21] and [22] A 1-mmol/dl (38.7-mg/dl)
decrease in LDL cholesterol is associated with an average decrease in
relative risk of major coronary events by a quarter. Because most
clinical trials were of short duration, rarely >5 or 6 years, there is
no specific clinical trial evidence of a benefit of decades-long
therapy. However, a decision must be made using currently available
information. Epidemiology, pathophysiology, and logic suggest we
should treat younger persons with risk factors above a given threshold
even if the 10-year global risk is not high enough to reach the
thresholds of current guidelines. The decision must be made by
weighing the pros and cons of treating versus not treating, rather
than requiring absolute proof for the benefits of treatment while
ignoring the risk of not treating. This approach is used for non-drug
therapy interventions, including diet, exercise, discontinuation of
smoking, and so on. Why would we have a different approach with
pharmacologic therapy? For example, the risks of exercise, ranging
from musculoskeletal problems and injuries to sudden cardiac death,
are not inconsequential.

Examination of effects of clinical trials by age group indicate a
similar relative risk reduction in younger and older age groups,
although absolute risk reduction in the short term is higher in older
age groups. In addition, the effect of pharmacotherapy on intermediate
end points, such as quantitative coronary arteriography, intravascular
ultrasound, and carotid intima-media thickness, were shown across age
groups. Risk factors predict events; treatment of risk factors
decreases events in both young and old. Therefore, if older
individuals are treated, so should younger ones. The differences are
quantitative rather than qualitative, and the real issue is not
efficacy, but cost-effectiveness and safety of long-term pharmacologic
therapy, discussed later.

A cogent argument for treating younger persons derives from
examination of studies of the recently discovered proprotein convertas
subtilisin/kexin type 9 (PCSK-9) mutations.23 This study from the
Assessment of Risk In Communities (ARIC) investigators described
middle-age Americans with lifelong low LDL caused by mutations of the
gene encoding PCSK-9. PCSK-9 is involved in the proteolysis of LDL
receptors between the Golgi apparatus and plasma membrane.24 The
persons involved have nonsense variants of the gene encoding PCSK-9
with loss of function of the protein resulting in higher numbers of
LDL receptors and lower LDL cholesterol. As expected, these persons
have a lower probability of developing coronary artery disease. The
interesting point is that although LDL cholesterol is decreased by 28%
(to 100 mg/dl), the decrease in coronary artery disease is 88%, rather
than the expected 25% to 30%. What is important is not only how low,
but also for how long LDL cholesterol is decreased.25 This suggests
that early initiation of statin therapy would be preferable to current
approaches.

Estimation of risk

Framingham investigators published many reports on standard risk
factors, as well as more recently studied biomarkers.[26] and [27] A
well-known engine for calculating 10-year risk of coronary heart
disease uses age, gender, total cholesterol, high-density lipoprotein
(HDL) cholesterol, smoking, systolic blood pressure, and
antihypertensive therapy as stratification variables.5 This system
places patients appropriately in broad categories, although it does
not include diabetes, family history, or the multitude of "conditional
risk factors" and biomarkers associated with cardiovascular disease.28
The limitation of the Framingham point score is exemplified by
calculating risk in a 49-year-old woman who does not smoke. Her 10-
year risk will remain <10% (1 National Cholesterol Education Program
Adult Treatment Panel III threshold for treatment) even if her blood
pressure is >160 mm Hg (e.g., 200 mm Hg), HDL cholesterol is <40 mg/dl
(e.g., 25 mg/dl), and total cholesterol is >280 mg/dl (e.g., 350 mg/
dl). In this patient, age would account for 3 points; blood pressure,
for 4 points; HDL cholesterol, for 2 points; and total cholesterol,
for 10 points, for a total of 19 points corresponding to 10-year risk
of 8%. Conversely, a 70-year-old man who does not smoke and does not
have hypertension (e.g., systolic blood pressure 110 mm Hg),
hypercholesterolemia (total cholesterol 140 mg/dl), or low HDL
cholesterol (e.g., 59 mg/dl), in other words, "nearly a saint," will
require treatment (12 points for age and no extra points for any other
risk factor, corresponding to 10-year risk of 10%). I stated that
these guidelines were made by old men to treat themselves at the
exclusion of younger individuals, especially women. Parenthetically,
although evidence from clinical trials provides support for statin
therapy in patients at high cardiovascular risk, the evidence does not
show that titration of therapy to LDL targets as recommended by
guidelines is beneficial or safe.29

Some physicians use newly popularized methods of refining the risk to
make decisions regarding pharmacologic therapy. Although diabetes and
metabolic syndrome are common strong predictors of cardiovascular
events, most "conditional" and "emerging" risk factors (e.g.,
homocysteine, fibrinogen, lipoprotein[a], small LDL particle size, C-
reactive protein, lipoprotein-associated phospholipase A2, pregnancy-
associated plasma phosphatase, asymmetric dimethylarginine,
myeloperoxidase, nitrotyrosine, measures of oxidative stress, and gene
polymorphisms) add only small refinements to risk estimates. This
limitation of risk factors that may be statistically and biologically
related to disease, but do not perform well in categorizing patients,
is for the 2 reasons (1) they are strongly related to each other and
to the traditional risk factors and (2) their associations with the
disease, although biologically plausible and statistically
significant, are prognostically weak.[28] and [30] In the Framingham
study, the contribution of 10 contemporary biomarkers (C-reactive
protein, B-type natriuretic peptide, N-terminal proatrial natriuretic
peptide, serum aldosterone, plasma renin activity, fibrinogen,
plasminogen-activator inhibitor type 1, d-dimer, homocysteine. and
urinary albumin-creatinine ratio) added only moderately to the
predictive accuracy of standard risk factors (cigarette smoking,
diabetes mellitus, blood pressure, body mass index, total cholesterol,
HDL cholesterol, serum creatinine, and medication use).27 A clinical
trial of statin therapy in the primary prevention of patients at high
risk in apparently healthy persons with low LDL cholesterol, but
increased C-reactive protein, is being carried out.31 Much more
knowledge of the basic pathophysiological characteristics of
cardiovascular disease (and probably of aging) is necessary before
truly individualized medicine targeting specific disease pathways in
patients can become reality.32 Traditional modifiable risk factors can
account for >90% of the population-attributable risk of myocardial
infarction across continents and cultures.17 Treatment of these
factors above a given threshold defined by global risk (excluding age)
will lead to the prevention of more events.

Others proposed that early detection of atherosclerotic disease using
coronary arteriography, intravascular ultrasound, coronary calcium
score, carotid intima-media thickness, and so forth, be used as
evidence of disease requiring treatment. It was proposed that this
strategy would be better than current strategies because many patients
with a first episode of CHD do not have the traditional risk-factor
profile.33 However, trials with surrogate end points are sometimes
misleading, as was the case with antiarrhythmic and inotropic therapy.
Also, the objective should be to prevent the disease, including these
preclinical manifestations of atherosclerosis. Some proposed that
absolute risk be used for pharmacologic therapy and relative risk be
used for nonpharmacologic therapy. The distinction is not as clear as
it appears because both pharmacologic and nonpharmacologic therapy
have benefits, risks, inconvenience, and expense.34 Using lifetime
global risk is a more appropriate solution.35

Safety of long-term therapy

Concerns were raised about the long-term risk of statin therapy. These
concerns frequently deter both patients and physicians from
prescribing needed therapy. The risks of hepatotoxicity,
rhabdomyolysis, and, to a lesser extent, renal disease, have received
much attention. However, review of all statin trials published in
MEDLINE in English from 1996 to 2005 indicated that although statin
therapy was associated with a small excess risk of transaminase
increases, there was no significant difference in rhabdomyolysis,
myalgias, or creatinine kinase increases.36 Although increases in
liver enzymes are seen with statin therapy, probably in a dose-
dependent fashion, they are usually reversible with discontinuation of
statin therapy or a decrease in dose and severe increases are
extremely rare, about 4 per million.37 Studies included exposures up
to >5 years and included patients with average age of 44 to 76 years
and doses up to 80 mg of simvastatin and atorvastatin. The risk of
rhabdomyolysis is real, but (if cerivastatin is excluded) extremely
rare (<1 death/million prescriptions) and usually occurs in older
rather than younger individuals or among those with polypharmacy or
serious co-morbidities. It is impressive that patients and physicians
choose to avoid an extremely low risk of a usually nonfatal event by
refusing to take or prescribe statins while accepting the much higher
risks of death, heart attack, and stroke that may occur if not
prevented by the use of statins. This is even more interesting because
in primary prevention, low doses of statins are usually needed. The
National Lipid Association Statin Safety Assessment Task Force
emphasized this point by comparing the benefit of statin therapy in
averting several hundred deaths, myocardial infarctions, and strokes
per hundred thousand patient years to the risks of fatal
rhabdomyolysis, liver failure, and kidney disease that are in the
single digits at most.[38] and [39] The decision to treat women of
child-bearing potential is more difficult and may be addressed by
enhanced pharmacovigilance processes, data for longer follow-up, and
detailed discussion with individual patients.

Issue of expense

The cost-effectiveness of antihypertensive and statin therapy is
influenced by the cost of outpatient, inpatient, and long-term care;
absolute risk reduction; duration of therapy; and price of individual
medications. The number needed to treat and duration of treatment
increase when younger patients with low short-term absolute risk are
treated. However, the benefit in terms of total number of years or
quality-adjusted years gained by antihypertensive therapy is higher in
the young.40 In addition, use of generic preparations decreases the
cost markedly.41 It was estimated that multidrug prevention strategies
(including aspirin, 2 blood pressure medications, and a statin) could
halve the risk of death from cardiovascular disease in high-risk
patients at the price of $748 to $890/quality-adjusted life-year, an
order of magnitude lower than the cost of dialysis.42 In a study
carried out in Georgia, treatment of hypertension with a generic
thiazide and blocker at a cost as $7.50/person-year resulted in a
dramatic decrease in death from cardiovascular disease.43 This expense
is much lower than the expense of over-the-counter health supplements
of unproven efficacy and unknown long-term safety.

Assuming that limited resources would prevent treating all who need
drug therapy, it is not clear that short-term (10-year) absolute risk
reduction would be the deciding factor. This issue was recently
examined by ethicists examining the potential of an avian flu pandemic
in the face of inadequate number of vaccine doses.44 The following
ethical principles were considered: "save the most lives," "women and
children first," "first come first served," "save the most quality-
adjusted life-years," "save the worst of," "reciprocity," "save those
most likely to fully recover," "save those instrumental in making
society flourish," "save those contributing to the well-being of
others," and the "life-cycle allocation principle." The later
principle is based on the idea that each person should have an
opportunity to live through all stages of life. Death of a child or
young adult is considered a big loss because the decedent did not have
the opportunity to live all stages of life. A modification (the
"investment refinement") of this principle considers the investment
made by a person in relation to the amount left to live, that is, the
amount of unfulfilled potential.45 Similar principles may be used in
allocating resources for primary prevention of cardiovascular disease.
The last 2 principles mentioned and the save the most life-years
principle strongly favor treating the young. Regardless, when generic
medications are used, the issue is not of limited resources.
Community, patient, and physician education and empowerment of both
physicians and patients will lead to more effective cardiovascular
disease prevention.46

Five simple proposals

The primary aim of this commentary is to propose the following
statements for debate or implementation: (1) use current knowledge and
current therapies to prevent atherosclerotic disease rather than focus
on events; (2) use multifactorial approaches in estimating risk
(global risk); (3) remove age from risk algorithms; (4) consider risks
and benefits of both undertreatment and overtreatment. Avoiding all
possibility of harm will eliminate most beneficial therapies. The
therapeutic calculus should estimate both sides of the equation; and
(5) develop simple global guidelines (with modifications of current
risk factor-specific algorithms as appendixes) that can be easily
understood and used by patients, physicians, and other health care
professionals.

An example may be the "speed limit" approach (applying equally to
young, old, men, and women) to primary prevention47: (1) everybody's
blood pressure and non-HDL cholesterol should be <130 mg/dl; and (2)
everybody's LDL cholesterol and fasting blood glucose should be <100
mg/dl. Remembering these 2 numbers is very easy and can guide primary
prevention in most instances.

* * *
Apparently he has something else coming out but I have not read it:

Kostis JB. A new approach to primary prevention of cardiovascular
disease. Am J Med, in press.

* * *

Marilyn





.

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