PRACTICAL POINTERS
PRIMARY CARE
TREATMENT REDUCES RISK OF CVD REGARDLESS OF THE INITIAL LEVEL OF
THE RISK
SHOULD WE NO LONGER USE THE TERM “HYPERTENSION”?
MORPHINE + GABAPENTIN EFFECTIVE FOR TREATMENT OF NEUROPATHIC PAIN
IS ADDING CLOPIDOGREL TO ASPIRIN BENEFICIAL IN PATIENTS WITH ACUTE
MI?
LOW DOSE ASPIRIN FOR PRIMARY PREVENTION OF CVD IN WOMEN.
WARFARIN OR ASPIRIN BEST FOR TREATING INTRACRANIAL STENOSIS?
VITAMIN D DEFICIENCY RELATED TO MUSCLE WEAKNESS
FOLATE (REDUCING HOMOCYSTEINE LEVELS) TO PREVENT RISK OF FRACTURE
IS THERE ANY HOPE FOR VITAMIN E?
ARCHIVES
INTERNAL MEDICINE EDITED
BY RICHARD T. JAMES JR. MD
ANNALS INTERNAL MEDICINE 400
AVINGER LANE, SUITE 203
www.practicalpointers.org DAVIDSON
NC 28036 USA
Rjames6556@aol.com
Sorting
out and critiquing the details of the three following abstracts was difficult
and time-consuming. They point to a developing sea-change in our approach to
prevention of atherosclerotic disease.
A new
approach is based on the premise that:
1)
Risk is lowered to some extent when each risk factor(clinical and lifestyle) is
reduced, regardless of its initial level. The risk need not be lowered to
“normal”.
2)
When risk factors are lowered, the benefits are additive.
I
believe the disease is largely preventable because the benefits achieved by
reducing every modifiable risk factor (either by drugs or change in lifestyle)
are additive. Risks are reduced linearly. There is no “normal” level. We should
reduce all risk factors as safely and as economically as possible. This should
replace our focus on only one or two risk factors (eg, lipids and blood
pressure).
I
believe a modest reduction in risk factors which we treat with drugs will, if
lifestyle factors are reduced concomitantly, prevent cardiovascular events in
millions of people in the USA.
Please
read the 3 full abstracts. RTJ
3-1 RELATIVE IMPORTANCE OF BORDERLINE AND
ELEVATED LEVELS OF CORONARY HEART DISEASE RISK FACTORS
Prospective cohort study (The Framingham
Study) and a national cross sectional survey (Third National Health and
Nutrition Examination Survey) considered a large group of white, non-Hispanic
persons between ages 35 and 74. (Mean age = 50)
Determined the first CHD event (defined
narrowly as a myocardial infarction or cardiac death over 10-years) related to
five major CHD risk factors: BP,
LDL-cholesterol, HDL-cholesterol, glucose intolerance, and smoking.
Assigned three categories to each risk
factor—elevated, borderline, and optimal.
Optimal Borderline Elevated
Systolic BP under120 120-139 over
139
Diastolic BP under
80 80-89 over 89
LDL-cholesterol under100 100-159 over159
HDL-cholesterol over
59 59-40 under 40
Other borderline factors:
Impaired fasting glucose (110-123)
Past history of smoking
Other elevated risk factors
Diabetes
Smoking
Optimal levels of all 5 risk factors were rarely
present in any age group or in either sex.
Seventy four % of men and 59% of women had
one or more elevated risk factors. Twenty six % of men and 41% of women had at
least one borderline risk factor. (Note:
this adds up to 100%)
The authors estimate that, for ages 35-74, over a
10-year period, nearly 4.7 million white men and
over 1 million white women in the US will experience a
first MI or cardiac death. More than
90% of CHD events will occur in individuals with at least one elevated risk
factor, and 8% in those with only borderline risk factors.
I
believe this study presents too narrow a view of the cardiovascular disease
problem in the US population, The study underestimates risk of atherosclerotic
events.
1)
Ten years is too short a time to assess the overall risk of disease. The
atherosclerotic process begins decades earlier and ends decades later.
2)
Only 5 risk factors were considered. There are many others for which we should
intervene: body mass index, dietary factors, physical fitness, intra-abdominal
fat, triglycerides, C-reactive protein, abstinence from alcohol. The object of
prevention should be to lower every individual risk factor as much as possible
considering safety and cost. The number of risk factors far exceeds those chosen
by the study.
3)
The definition of disease was too narrow. (Only cardiac death and myocardial
infarction). This eliminates
consideration of other acute coronary syndromes, stroke, vascular dementia,
peripheral vascular disease, and aortic aneurysm.
4) The
study arbitrarily divided the cohort into 3 subgroups of risk—elevated,
borderline and optimal and assumed the risk was equal in every individual in
each cohort. The study did not consider the considerable differences in risk of
disease associated with varying levels of the risk factors in each of the 3 groups. Risk rises and
falls linearly. An individual with a LDL-cholesterol of 110 (borderline) has
lower risk than one with a LDL-c of 145 (still borderline). A person with a
systolic BP of 145 (elevated) is at
much lower risk than one with a systolic of 175 (also elevated).
This article
tilts toward the traditional practice of screening to identify higher risk
associated with a relatively few risk
factors, and vigorously treating each
individual risk factor. Is screening, and treating, and retesting every one of
5 “elevated” risk factors the best approach? This is certainly not practical
when applied to the entire at-risk population. (Essentially the whole
population in the USA.) How vigorously should “borderline” factors be treated?
All risk
factors add to risk in all individuals in our high-risk culture. They should be
treated empirically and lowered concomitantly. Laboratory testing may be
minimized.
Atherosclerosis
is an essentially preventable disease.
We have failed miserably in our efforts to prevent it.
We need to
apply a new population-based approach to prevention.
The approach
changes for patients with established atherosclerotic disease. Risk reduction
should be applied vigorously to all factors. RTJ
3-2 THE MIDDLE-AGED AND OLDER AMERICANS; Wrong Prototype for A Preventive Polypill?
(This
editorial comments and expands on the preceding article.)
Most Americans older than age 55 have one
or more risk factors for cardiovascular disease” 1/3 or more have
hypercholesterolemia, 1/5 smoke, most have inactive lifestyles, 1/3 have high
BP. About 1/3 are obese, about 1/10 have diabetes.
Americans have a dizzying array of options to reduce risk. Preventive approaches aimed primarily at identifying and treating individual risk factors were popular in the 1980s and 1990s but had limited success.
Experts now recommend assessment of an individual’s global risk for vascular disease when deciding whether to treat risk factors, and when selecting specific target levels for those risk factors.
In 2003 Wald and Law1 proposed a radical population-based strategy that they
claimed would reduce cardiovascular disease by 80%, and have greater impact on
public health than any other preventive strategy. They advised discarding the
view that risk factors need to be measured (and treated individually if found to
be ‘abnormal’). Instead they advocated
treating all adults older than age 55
with a “Polypill” containing low doses
of a statin, folic acid, aspirin, and 3 antihypertension drugs. (Low-dose
presumably would be associated with fewer adverse effects.) This was based on the premise that risk
factors are present in everyone in
Western societies, and determination of individuals’ global risk is not
necessary, and that 96% of deaths from vascular disease occur in people over
age 55. Monitoring each individual’s risk factor level to assess treatment
benefits is of limited usefulness.
Risk factor interventions with drugs and
lifestyle modifications are effective whatever the initial level of the risk
factor.
The editorialists comment that treating everyone older than age 55
with a low-dose Polypill without measuring risk factors may be too audacious
for Americans. Adverse effects will likely occur from these multi-drug pills in
low risk patients who have little potential for benefit.
When
I first read of the Polypill, I thought
the authors were suggesting the concept “tongue in cheek”. Subsequently the
concept gained considerable attention and comment.
The
premise of the Polypill:
1) All persons have risk factors for CVD. There
is no cut point below which risk is not evident, and no cut point above which
risk does not increase.
2)
The Polypill reduces 4 risk factors (BP, LDL-c, platelet aggregation, and
homocysteine). The benefit from lowering all 4 is additive, although not
equally.
The
Polypill is limited to drug therapy. And only in persons over age 55. The range of risk factors is much larger,
and the atherosclerotic process begins at a much younger age. Many individuals experience a CVD event at
an early age.
Each
risk factor (lifestyle and clinical) adds to risk. When each risk factor is reduced, (even if only modestly) benefit
increases
additively.
Primary
care clinicians and their patients tend to focus on measuring and treating only
a few risk factors (eg, BP and cholesterol).
Indeed “know your cholesterol” has become a national imperative. In the mind of the public achieving a “low”
cholesterol is the best one can do to prevent CVD. But, individuals may have a LDL-c considerably below 100 and
still be at high risk due to presence of other factors.
What
to do? 1) Treat everyone empirically, or 2) Treat only select individuals after
screening. If you concede that everyone is at
risk, you must choose 1). Treating everyone with drug therapy is too
drastic a measure. Lifestyle measures begin at an early age and modifying them
can reduce risk without adverse effects. More clinicians may now be encouraged
to list all risk factors in their individual patients and point out the
additive effect of lowering each of them.
I
believe atherosclerosis is essentially a preventable disease. Our attempts at
control are failing miserably. Americans refuse to adopt preventive lifestyles.
Primary care clinicians have failed to adequately educate the public.
Once
atherosclerotic disease becomes established, treatment changes to all-out
reduction of risk factors. RTJ
3-3 HYPERTENSION—TIME TO MOVE ON
In view of the continuous associations between BP and cardiovascular disease risks, the value of categorical systems for classifying BP is questionable. Such categorical systems provide little useful information about an individual’s risk of actually developing a blood-pressure-related cardiovascular disease. Most guidelines acknowledge that risks are determined by many factors and not by BP alone.
A practical definition of hypertension is the value of BP below which no further benefit of lowering the BP can be demonstrated. There is now compelling epidemiological evidence of continuous associations between usual BP values down to about 115/75 and risks of major cardiovascular disease. Non-hypertensive individuals with multiple risk factors or a history of cardiovascular disease will often be at higher absolute risk of BP-related cardiovascular events than hypertensive patients without other risk factors.
“So why do we persist with this focus on
the treatment of hypertension (defined arbitrarily) rather than the prevention
of blood-pressure-related diseases?”
This
reinforces the argument presented in the preceding article—risk factors are
additive and should not be considered alone.
3-4 MORPHINE, GABAPENTIN, OR THEIR COMBINATION
FOR NEUROPATHIC PAIN
This study assessed the effectiveness of a
combination of morphine + gabapentin vs
either alone and placebo for pain due to diabetic neuropathy and post-herpes
zoster neuralgia.
Treatment with a combination of morphine +
gabapentin resulted in greater relief of pain than treatment with either alone.
Baseline Placebo Gabapentin Morphine Morphine +
gabapentin
Mean daily pain scores 5.7 4.5 4.2 3.7 3.06
On a scale of 1 to 10
McGill Pain Questionnaire 18.9 14.4 10.7 10.7 7.5
On a scale of 0 to 45
The maximum doses of morphine and
gabapentin were lower with the combination than for each given separately.
The combination was associated with
significantly less pain-related interference with mood, and higher scores for
vitality and social functioning. The
combination was also associated with improvement in depression as measured by
the Beck Depression Inventory.
This
may bring considerable relief to some patients with very disturbing pain.
Gabapentin(Neurontin) is an analogue of butyric acid. It modulates
calcium channel subunits thought to be important in neuropathic pain. It has
both analgesic and anti-convulsant action and is approved for treatment of
partial seizure epilepsy and post-herpetic neuralgia.
Gabapentin
and morphine have mechanically distinct analgesic actions. The combination may result in synergistic or
additive pain relief at lower doses and with fewer side effects.
Repeated
administration of gabapentin does not lead to tolerance.
A substantial proportion of patients
receiving fibrinolytic therapy for MI with ST-segment elevation have inadequate
reperfusion or re-occlusion of the infarct-related artery. Aspirin
significantly improves outcomes. But, aspirin is a relatively weak antiplatelet
agent. It has limitations. It irreversibly inhibits cyclo-oxygenase in
platelets thereby inhibiting synthesis of thromboxane, a powerful promoter of platelet
activation. It exerts no effect on thromboxane-independent mediators of
platelet activation. Up to 30% of persons with coronary artery disease are
relatively resistant or unresponsive to aspirin.
Clopidogrel (Plavix) acts differently from aspirin in inhibiting activation and aggregation of platelets. Does addition of clopidogrel benefit patients with acute ST-segment elevation MI who are receiving fibrinolysis and aspirin?
The short-time study enrolled over 3400
patients (mean age 57) who presented within 12 hours after onset of an acute
ST-segment elevation MI. Randomized to: 1) clopidogrel (300 mg loading dose
followed by 75 mg once daily), or 2) placebo.
Over a period of about a week, the addition of clopidogrel improved patency of the affected artery and reduced ischemic complications and death.
Treatment was not associated with an
increased rate of major bleeding or intracranial hemorrhage.
Plavix
has been extensively advertised to the public for ongoing use in patients with
CVD. It is expensive. A 75 mg tablet costs almost $4.
I
believe primary care clinicians may provide a meaningful advanced therapeutic
measure to a patient presenting to the office with an acute MI. While transfer
to the hospital is arranged, the patient may be given: 1) full dose aspirin
(325 mg); 2) clopidogrel (300 mg); 3) a statin drug; and 4) a beta-blocker. A
few packets containing these drugs may be kept handy. .
Use of aspirin in primary prevention in women is controversial. The current
recommendations for use of aspirin in primary
prevention in women are based on limited data.
The Women’s Health Study was a large,
randomized, double-blind placebo-controlled trial of low-dose aspirin in the
primary prevention of cardiovascular disease among over 39 000 apparently
healthy women followed for a mean of 10 years for major cardiovascular events.
For the entire group of women over age 45,
aspirin reduced risk of ischemic stroke. It did not protect against myocardial
infarction and death from cardiovascular causes until after age 65.
Women taking aspirin experienced significantly
more GI hemorrhages (RR = 1.40)
By
my calculation, between 500 and 900 individuals would need to be treated for 10
years to prevent one ischemic stroke. Is this clinically significant? -
especially when the increased risk of hemorrhage is considered. RTJ)
Thus
far, studies indicate that, in men, the prophylactic benefit against first
occurrence of myocardial infarction is much greater than in women. But in men,
aspirin does not provide primary protection against stroke.
3-7 COMPARISON OF WARFARIN AND ASPIRIN FOR
SYMPTOMATIC INTRACRANIAL STENOSIS.
Randomized, double-blind multicenter (59 sites) trial entered over 550 patients (mean age 63). All had experienced a TIA or a non-disabling stroke caused by angiographically verified 50% to 99% stenosis of a major intracranial artery (internal carotid, middle cerebral, vertebral, or basilar).
Randomized to: 1) warfarin—target INR of 2.0 to 3.0, or 2) aspirin 650 mg twice
daily.
Warfarin provided no benefit over aspirin. It was
associated with significantly higher rates of adverse events. “Aspirin should
be used in preference to warfarin for patients with intracranial arterial
stenosis.”
This
is a good example of a pragmatic (real world of practice) trial. Difficulty in
control of warfarin dosage may have been the cause of its lack of benefit.
3-8 RECENT DEVELOPMENTS IN VITAMIN D DEFICIENCY
AND MUSCLE WEAKNESS AMONG ELDERLY PEOPLE
Vitamin D deficiency is common in the
elderly (especially in the house-bound and nursing home patients). Its
prevalence is much greater than previously realized. It may be associated with
poor muscle strength, and a tendency to fall, as well as osteomalacia.
Higher plasma levels of calcidiol are
associated with muscle strength, physical activity, and ability to climb
stairs. Lower levels of calcidiol are associated with falls among the elderly.
A randomized trial reported a 47% reduction in falls and fractures in elderly
women given 800 IU of vitamin D daily (compared with controls receiving calcium
alone) over 12 months.
The author states that supplementation is
often inadequate. 400 IU daily may be ineffective. In contrast, 800 IU has been
shown to significantly reduce the risk.
Treatment with a supplement of 800 IU
daily should be seriously considered.
It
is important to remember that patients with kidney and liver disease require special
consideration. The kidney is the first step in metabolism of cholecalciferol to
calcidiol. And the liver is involved in the final conversion to the active
hormone, calcitriol.
See also:
“Effect of vitamin D on falls” Practical Pointers April 2004 [4-5]
“Effect of four-monthly oral vitamin D
supplementation on fractures and mortality in man and women living in the
community” March 2003 [3-4]
“Occult vitamin D deficiency in postmenopausal U.S.
women with acute hip fracture
April 1999 [4-7]
3-9 HOMOCYSTEINE AND FRACTURE PREVENTION
This issue of JAMA presents evidence that
an elevated homocysteine level might be associated with brittle bones. The
randomized trial of Japanese patients who had suffered hemiplegia due to stroke
compared a group given folate and B12 (effectively lowering homocysteine
levels) with a control group. The untreated group had 5 times the fracture rate
as the treated group.
At baseline, patients had low levels of
serum B12 and folate, and high levels of homocysteine. In the treatment group
serum homocysteine fell by 38%; increased by 31% in the placebo group. Serum
B12 and folate levels increased in the treatment group; fell in the placebo
group.
Homocysteine
is a simple sulfur-containing amino acid. Folate and B12 are co-factors
involved in its metabolism. They facilitate conversion of homocysteine to
methionine (another sulfur-containing amino acid).
Years
ago, the genetic abnormality homocysteinuria was demonstrated to be associated
with atherosclerotic disease and osteoporosis.
Homocysteine acts as an atherogenic and thrombogenic agent. Increased
levels are associated with coronary artery disease, cerebrovascular disease,
peripheral arterial disease and deep-vein thrombosis.
A
substantial portion of the elderly in the USA has a marginal sufficiency of
folate.
Supplementation
with B12 and folate reduces serum homocysteine levels.
The benefit/harm-cost
ratio of folate and B12 supplementation may be very high. Both are relatively
inexpensive and safe.
The
study did not assess vitamin D and calcium intake, although intake of both is
traditionally low in the elderly in Japan, as is the exposure to sunlight.
Their benefit/harm-cost ratio in preventing fractures is high. This would lead
to a reasonable recommendation to supplement the diets of the elderly with B12,
folate, calcium and vitamin D.
Practical
Pointers has abstracted a number of studies in the past 5 years which conclude
that folic acid and B12 do reduce homocysteine levels and produce clinical
benefits:
Homocysteine Levels and the Risk of
Osteoporotic Fractures May 2004 [5-10]
Associated
with reduced risk of congestive heart failure
March 2003 [3-14]
Observing
a reduction in dementia and Alzheimer’s disease February 2002 [2-10]
Reducing
risk of major cardiac events and restenosis after PTCA November 2001 [11-11]
3-10 IS THERE ANY HOPE FOR
VITAMIN E?
Over the past 3 to 6 years, placebo
controlled trials have consistently shown that commonly used antioxidant
vitamins (E, C, and beta carotene, or a combination) do not significantly reduce overall cardiovascular events or cancer.
This editorial comments on a study which
reports a 7-year follow-up on a trial of vitamin E (daily 400 IU of
alpha-tocopherol—a natural source). The
study was based on a cohort of patients age 50 to 75 who had established
cardiovascular disease or diabetes. There was no statistical benefit from the
vitamins in reducing risk of total cancer incidence or cardiovascular events.
A subgroup finding reported a possible harmful effect—an increased risk of heart
failure associated with vitamin E.
“In nearly 60 000 patients studied to
date, there is no compelling evidence that higher doses of vitamin E reduce
cardiovascular risk or cancer”. Indeed, there is a hint that the antioxidant
may increase risk of heart failure.
“Vitamin E supplements should not be used in patients with vascular disease or diabetes.”
The
“antioxidant” theory has become entrenched in the minds of the public in the
USA. It may take a while to un-entrench the idea. The editorialists comment that enthusiasts may continue to claim
that vitamin E has a protective effect again specific cancers (lung,
oropharyngeal and prostate.).
Sorting
out and critiquing the details of the three following abstracts was difficult and
time-consuming. They point to a developing sea-change in our approach to
prevention of atherosclerotic disease.
A
new approach is based on the premise that:
1)
Risk is lowered to some extent when each risk
factor(clinical and lifestyle)
is reduced, regardless of its initial level. The risk need not be
lowered to “normal”.
2)
When risk factors are lowered, the benefits are additive.
I believe the disease is largely preventable
because the benefits achieved by reducing every modifiable risk factor (either
by drugs or change in lifestyle) are additive. Risks are reduced linearly.
There is no “normal” level. We should reduce all risk factors as safely and as
economically as possible. This should replace our focus on only one or two risk
factors (eg, lipids and blood pressure).
I
believe a modest reduction in risk factors which we treat with drugs will, if
lifestyle factors are reduced concomitantly, prevent cardiovascular events in
millions of people in the USA.
================================================================================
All Adults in the USA Have One or More
Risk Factors for Atherosclerotic Disease.
3-1 RELATIVE IMPORTANCE OF BORDERLINE AND
ELEVATED LEVELS OF CORONARY HEART DISEASE RISK FACTORS
This study, based on data collected in the 1980s-90s, investigated the relative contributions of borderline (suboptimal but below current treatment thresholds) and elevated vascular risk factors to the CHD burden in the USA.
Conclusion: The great majority of Americans have elevated
risk factors for cardiovascular disease.
Borderline risk factors alone account for a small proportion of CHD
events.
1. Prospective cohort study (The
Framingham Study) and a national cross sectional survey (Third National Health
and Nutrition Examination Survey) considered a large group of white,
non-Hispanic persons between ages 35 and 74. (Mean age = 50)
2. Determined the first CHD event (defined
narrowly as a myocardial infarction or cardiac death) related to five major CHD
risk factors: BP, LDL-cholesterol,
HDL-cholesterol, glucose intolerance, and smoking.
3. Assigned three categories to each risk
factor—elevated, borderline, and optimal.
Optimal Borderline Elevated
Systolic BP under120 120-139 over
139
Diastolic BP under
80 80-89 over 89
LDL-cholesterol under100 100-159 over159
HDL-cholesterol over
59 59-40 under 40
Other borderline factors:
Impaired fasting glucose (110-123)
Past history of smoking
Other elevated risk factors
Diabetes
Smoking
4. Estimated the absolute rates of CHD events likely
to occur in each of the 3 cohorts over a 10-year period.
1. Risk factor
profiles:
Optimal levels of all 5 risk factors were rarely present in any age group or in either sex.
Seventy four % of men and 59% of women had one or more elevated risk factors. Twenty six % of men and 41% of women had at least one borderline risk factor. (Note this adds up to 100%)
Those that had one or more elevated risk
factors also had one or more borderline risk factors.
2. CHD event
rates:
Rates increased progressively from those
seen in persons with only borderline risk factors to those seen in persons with
increasing numbers of elevated risk factors.
In men, CHD event rates rose as the number
of borderline risk factors increased.
Ten year absolute risk of myocardial
infarction or cardiac death exceeded 10%
in men older than age 45 at baseline who had any one elevated risk
factor and borderline levels of the other 4 risk factors. And in those who had
at least 2 elevated risk factors.
In women with 1 or more elevated risk factors, presence of any borderline risk factors further increased risk.
3. Estimated
population at high global risk in the USA:
Over 1/3 of men age 35-74 would be
categorized as being at increased global risk (the likelihood of over 10% of
them having an event in the next 10 years). And 14% would be at extremely high
risk (> 20% in 10 years)
Overall, 63% of men over age 55 would
exceed the 10% risk of events over the next 10 years.
Overall, 13% of women over age 55 would exceed the 10% threshold.
4. Projected
burden of CHD events due to elevated risk factors:
The authors estimate that, for ages 35-74,
over a 10-year period, nearly 4.7 million white men and over 1 million white
women in the US with elevated risk factors will experience a first MI or
cardiac death.
A significant number of events will also
occur in younger persons.
More than 90% of CHD events will occur in
persons with 1 or more elevated risk factors. About 8% of MI and cardiac deaths
will occur in individuals with multiple borderline risk factors (without a
single elevated risk factor).
More than 25% of CHD events will occur in
persons with only a single elevated risk factor.
More than 66% will occur in people with 2
or more elevated risk factors.
1. No borderline
or elevated risk factors:
An optimal CHD risk factor profile is rare
among US adults. Individuals in this category experience very few CHD events.
2. Borderline
risk factors:
Isolated borderline risk factors without any elevated risk factors account for only about 10% of the burden of myocardial infarction and cardiac death over 10 years. The authors comment that the event rate in subjects with only borderline risk factors may be greater over a longer time (eg, 20 or 30 years.).
Borderline risk factors contributed
incrementally to risk in the presence of other elevated risk factors.
The study weighted each of the borderline
risk factors equally. This may not be appropriate.
A focus on borderline risk factors by drug
therapy would seem misplaced in persons without previous
CHD events.
Lifestyle measures to reduce borderline levels of risk factors may be
more appropriate.
Although clinical trial data indicate that
lowering levels of borderline risk factors can improve outcomes, the number
needed to treat to prevent one event may be high.
3. Elevated risk
factors:
Most CHD events were noted in persons with
one or more elevated risk factors.
For women age 35-72 the 10-year absolute CHD event rates do not
cross the 10% threshold (which is regarded as high) even when 2 risk factors
are elevated.
“Overall, our data support the current
practice of assessing CHD risk by measuring several risk factors and using an
appropriately calibrated risk prediction algorithm to guide intervention.”
The data are also consistent with current
national guidelines noting that absolute CHD event rates are lower than 10%
over 10 years in individuals with 0 or 1 elevated risk factors.
4. Age:
Nearly 15% of myocardial infarctions and
cardiac deaths in men occurred prematurely (before age 55).
In men, one sixth of CHD events occur before age 55.
and one tenth occur in women under age 55.
As the population ages, the incidence of atherosclerotic events increases in women and eventually surpasses that in men.
5. Public health
implications:
About 1/6 of CHD events in men and 1/10 of
CHD events in women occur before age 55.
(Efforts should be made to
identify elevated major risk factors long before middle age and to intervene
appropriately.) “Our data indicate that about 2/3 of men and 1/3 of women
age 35 to 44 have an elevated modifiable risk factor that could be targeted for
intervention.”
Isolated borderline risk factors account
for only about 1/10 the burden of acute myocardial infarction and cardiac
death. (Still, 10% of 6 million is about
600 000 events over ten years. RTJ )
Non-pharmacologic measures to reduce borderline risk factors may be more
appropriate.
“Overall, our data support the current
practice of assessing CHD risk by measuring several risk factors and using an
appropriately calibrated risk prediction algorithm to guide interventions.”
The data are also consistent with current
national guidelines noting that absolute CHD event rates over 10 years are
lower than 10% in individuals with 0 to 1 elevated risk factor.
The great majority of Americans have
elevated risk factors for cardiovascular disease.
Borderline CHD risk factors alone account
for a small proportion of CHD events over a 10-year period.
Framingham Heart Study, Framingham, Mass.
Risk Is Lowered Continuously As The Risk Factor Is
Lowered.
3-2 THE MIDDLE-AGED AND OLDER AMERICANS; Wrong Prototype for A Preventive Polypill?
(This
editorial comments and expands on the preceding study.)
Most Americans older than age 55 have one
or more risk factors for cardiovascular disease” 1/3 or more have
hypercholesterolemia, 1/5 smoke, most have inactive lifestyles, 1/3 have high BP.
About 1/3 are obese, about 1/10 have diabetes.
Americans have a dizzying array of options
to reduce risk. Preventive approaches aimed primarily at identifying and
treating individual risk factors were popular in the 1980s and 1990s but had
limited success. Social and
environmental changes curbed some factors such as smoking, but increased
obesity and sedentary lifestyles. Treatment recommendations that targeted
single risk factors were incomplete and contained discrepancies from guidelines
targeting other risk factors. There were no clear treatment thresholds for
factors such as BP, lipid levels, abdominal obesity, and physical activity.
Although relative treatment benefits were
proved similar for different levels of certain risk factors, absolute benefits
were greatest with treatment for higher-risk persons.
Optimal assessment of absolute risk
requires knowledge of multiple risk factors.
Recognizing these issues, experts now
recommend assessment of an individual’s global
risk for vascular disease when deciding whether to treat risk factors, and when
selecting specific target levels for those risk factors. For example, recent
recommended treatment thresholds and target levels for low-density cholesterol
(LDL) vary depending on whether individuals have low, high, or very high risk
for coronary heart disease.
Both the single risk-factor based and the
global risk-factor-based approaches rely on measurement of the individual’s
risk factors.
In 2003 Wald and Law1 proposed a radical population-based strategy that they
claimed would reduce cardiovascular disease by 80%, and have greater impact on
public health than any other preventive strategy. They advised discarding the
view that risk factors need to be measured and treated individually if found to
be ‘abnormal’. Instead they advocated
treating all adults older than age 55
with a “Polypill” containing low doses
of a statin, folic acid, aspirin, and 3 antihypertension drugs. (Low-dose
presumably would be associated with fewer adverse effects. This was based on
the premise that risk factors are present in everyone in western societies, determination of individuals’ global
risk is not necessary, and that 96% of deaths from vascular disease occur in
people over age 55. Monitoring each individual’s risk factor level to assess
treatment benefits is of limited usefulness.
Risk factor interventions with drugs and
lifestyle modifications are effective whatever the initial level of the risk
factor.
The editorialists go on: Current guidelines recommend identifying and
treating elevated risk factors. Many doctors feel obligated to treat higher
levels more intensively than borderline levels. A shotgun approach would
probably cause collateral damage from adverse drug events in low-risk people
who have little potential to benefit from treatment. The benefits and
feasibility of low-dose combination therapies administered regardless of risk
factor level are not proven. “We believe that the benefits are probably less
and harms are probably greater than those proposed by Wald and Law.”
The editorialists nevertheless welcome
development and testing combination pills aimed at treating more than one risk
factor simultaneously.
Many risk factors are clear. Americans
have them in abundance. Despite this, treating everyone older than age 55 with
a low-dose Polypill without measuring risk factors may be too audacious for
Americans. Adverse effects will likely occur from these multi-drug pills in low
risk patients who have little potential for benefit.
The editorialist nevertheless welcomes
development of combination pills aimed at treating more than one risk factor
simultaneously.
We should not forget the lifestyle
measures which are no-risk and are of great benefit in reducing risk.
1 “A Strategy to
Reduce Cardiovascular Disease by More than 80%” (The Polypill) BMJ
2003;326: 1419
2 See also “Risk
Factor Thresholds: Their Existence Under a Scrutiny BMJ 2002;324: 1570-76
These articles by Wald and Law suggested that risk
factors make poor screening tools. They
highlight that risk rises continuously
as the level of the risk factor rises. And lowers continuously as the risk
factor is lowered.
The levels below which no further benefit can be
obtained are undefined. But certainly individuals with what might be considered
a “low-risk level” of risk factors can obtain benefit from lowering them
further.
The population-attributable risk associated with a
certain level (borderline or elevated) of a risk factor depends not only on its
relative risk, but also on the prevalence of the risk factor in the population.
Since risk factors are universally present in the population, they recommend
treatment of everyone over age 55.
The object is not to “normalize” risk factors, but to
reduce all of them as much as reasonably possible.
A given change in the variables reduces the risk of
disease by a constant proportion of the existing risk irrespective of the
starting level of the variable. Certain key dose-response relations have no
threshold and yield straight lines when risk of disease is plotted on a
logarithmic scale. Irrespective of the level of a risk factor, a given change
results in the same proportional reduction in risk regardless of the initial
risk.
Terms
like hypertension and
hypercholesterolemia, that focus medical attention on the tails of the
distributions of physiological variables are best avoided. The lower the risk
factor (down to levels well below average) the lower the risk of disease.
Average Western values should not be regarded as normal.
“Blood
pressure lowering drugs should not be limited to people with high BP, nor
cholesterol lowering drugs to people with high serum cholesterol levels. The
constant proportional relation means that there is value in modifying risk
factors regardless of the level of the risk factor.”
Offering
preventive treatment only to people with relatively high values of a variable
means that only a small proportion of those destined to have disease events
will be targeted. People at a given age with relatively high values of the
physiological variables are at similar risk as people a few years older with
average levels. Present practice is illogical in offering preventive treatment
to the former, but not to the latter.
Because
there are substantial benefits from lowering variables from any starting value,
all the reversible risk factors should be changed, not just those judged
“abnormal”.
The
goal should not be to “normalize” risk factors, but simply to reduce them as
much as possible with safety and low cost.
3-3 HYPERTENSION—TIME TO MOVE ON
Over the past few decades, guidelines for
the treatment of hypertension have progressively been redefined. A larger and larger proportion of the
population has been gradually encompassed.
Today, between a fifth and a quarter of
most adult populations would meet the definition of “hypertension”.
The JNC-7 has recently gone a step further
and created a new class—“prehypertension”.
In view of the continuous associations between BP and cardiovascular disease
risks, the value of categorical systems for classifying BP is questionable.
Such categorical systems provide little useful information about an individual’s risk of actually developing
a blood-pressure-related cardiovascular disease. Most guidelines acknowledge that risks are determined by many
factors and not by BP alone. This multiplicity of disease determinants is not
usually noted in criteria used for the diagnosis or classification of
hypertension.
A practical definition of hypertension is
the value of BP below which no further benefit of lowering the BP can be
demonstrated. There is now compelling epidemiological evidence of continuous associations between usual BP
values down to about 115/75 and risks of major cardiovascular disease.
Non-hypertensive individuals with multiple risk factors or a history of
cardiovascular disease will often be at higher absolute risk of BP-related cardiovascular events than hypertensive
patients without other risk factors.
The population burden of diseases related
to BP in non-hypotensive patients is generally greater than that in
hypertensives.
Clear evidence now shows that BP-lowering
drugs reduce the risk of major vascular events in
a broad range of non-hypertensive individuals with
high-risk disorders such as cerebrovascular disease, diabetes and coronary
heart disease. The absolute benefits of BP-lowering for such patients
(irrespective of their initial BP) are substantially greater than those seen in
patients with uncomplicated hypertension.
“So why do we persist with this focus on
the treatment of hypertension (defined arbitrarily) rather than the prevention of
blood-pressure-related diseases?”
The Combination Achieved Better Analgesia At Lower
Doses Of Each Drug Than Either Given Alone
3-4 MORPHINE, GABAPENTIN, OR THEIR COMBINATION
FOR NEUROPATHIC PAIN
The available drugs for neuropathic pain (NP) are incompletely effective and
have dose-limiting adverse effects.
This study assessed the effectiveness of a
combination of morphine + gabapentin vs
either alone and placebo for pain due to diabetic neuropathy and post-herpes
zoster neuralgia.
Conclusion: The combination achieved better analgesia at lower doses than
either used alone.
1. Randomized, double-blind, active placebo-controlled crossover trial of 57 patients (35 with diabetic neuropathy and 22 with post-herpetic neuralgia.
2. Randomized sequentially in 4 periods each given for
5 weeks separated by 4 days washout:
Drugs were given 3 times daily in random
sequence:
1) Lorazepam (Atenolol; a
benzodiazepine) 0.1 to 0.2 mg as an active placebo.
2) Morphine alone (oral sustained-released
capsules 15 or 30 mg) Ceiling dose =
120 mg.
3) Gabapentin (Neurontin) alone 300 or 400 mg. Ceiling dose = 3200 mg.
4) The combination. Ceiling dose 60 mg
morphine + 2400 mg gabapentin.
3. Doses were titrated upward to maximum
tolerance or to the ceiling.
4. At baseline, patients completed a diary
which rated intensity of their pain 3 times daily after discontinuing all
previous medication. They kept a similar diary during the study.
5. Outcome measurer = intensity of pain on
a scale of 0 to 10, and on the McGill Pain Questionnaire on a scale of 0 to 45.
1. 41 patients completed the trial.
2. On a scale of 1 to 10 Baseline Placebo Gabapentin Morphine Morphine + gabapentin
Mean daily pain scores 5.7 4.5 4.2 3.7 3.06
3. McGill Pain Questionnaire
On a scale of 0 to 45 18.9 14.4 10.7 10.7 7.5
4. Doses of morphine and gabapentin were lower with
the combination than for each given separately.
5. Main adverse effects = constipation, sedation, and
dry mouth.
1. Treatment with a combination of
morphine + gabapentin resulted in greater relief of pain than treatment with
either alone.
2. The combination was associated with
significantly less pain-related interference with mood, and higher scores for
vitality and social functioning. The
combination was also associated with improvement in depression as measured by
the Beck Depression Inventory.
3. Doses of morphine + gabapentin were
significantly lower than in treatment with either alone.
4. The study also confirmed the beneficial
effects of morphine when used alone for patients with neuropathic pain.
6. Gabapentin significantly enhanced the
efficacy of morphine in patients with diabetic neuropathy and post-herpetic
neuralgia.
The combination of morphine + gabapentin
achieved better analgesia at lower doses of each drug than either given as a
single agent.
Addition of Clopidogrel Improved Patency of The
Affected Artery and Reduced Ischemic Complications.
3-5 ADDITION OF CLOPIDOGREL TO ASPIRIN AND
FIBRINOLYTIC THERAPY FOR MYOCARDIAL INFARCTION WITH ST-SEGMENT ELEVATION
A substantial proportion of patients
receiving fibrinolytic therapy for MI with ST-segment elevation have inadequate
reperfusion or re-occlusion of the infarct-related artery. Initial reperfusion
fails to occur in about 20% of patients. This is associated with a doubling of
mortality rates. The artery becomes re-occluded in another 5% to 8% during the
index hospitalization. This further increases mortality.
Platelet activation and aggregation play a
key role in initiating and propagating coronary artery thrombosis. In patients
with ST-elevation acute MI, aspirin reduces death from vascular causes by 23%
and the odds of reinfarction by 46%. It also reduces rate of angiographic
re-occlusion by 22%.
Clopidogrel (Plavix) acts differently from aspirin in inhibiting activation and
aggregation of platelets. It reduces rate of death and ischemic complications
in patients with symptomatic atherosclerotic disease, in patients who have
undergone PTCA, and in patients with unstable angina and non-ST-segment
elevation MI.
This study asks: Does addition of clopidogrel benefit patients with acute
ST-segment elevation MI who are receiving fibrinolysis and aspirin?
Conclusion: Addition of clopidogrel improved
patency of the affected artery and reduced ischemic complications.
1. Enrolled over 3400 patients (mean age 57) who presented within 12 hours after onset of an ST-segment elevation MI. Essentially all were treated with aspirin, fibrinolytic therapy (within a median of 2.5 hours), and received heparin for 48 hours. The great majority also received a statin drug, a beta-blocker, and an ACE inhibitor.
2. Randomized to: 1) clopidogrel (300 mg loading dose followed
by 75 mg once daily), or 2) placebo.
3. Patients were to receive study medication daily up
to and including the day of coronary angiography.
For patients who did not undergo angiography, the
study drug was to be administered up to and including day 8 or hospital
discharge. (This was a short-time study.
RTJ)
4. Almost all received angiography at a
median of 3.5 days.
5. Primary efficacy endpoint = composite
of an occluded infarct-related artery on angiography, or death, or recurrent MI
before angiography.
1. Placebo
(%) Clopidogrel (%) Absolute difference (%) NNT
Primary efficacy endpoint 21.7 15.0 6.7 15
At 30 days 11.6 14.1 2.5 40
2. Rates of bleeding and intracranial hemorrhage were
similar.
1. “Our study demonstrates the benefit of adding clopidogrel to aspirin and fibrinolytic therapy of MI with ST-segment elevation.” The benefit was consistent across a broad range of subgroups.
2. Treatment was not associated with an
increased rate of major bleeding or intracranial hemorrhage.
3. Clopidogrel is a potent anti-platelet
agent that has a synergistic antithrombotic effect when combined with aspirin.
4. The authors mention that newer
fibrinolytic agents (tenecteplase, reteplase) are equivalent but not superior
to older fibrin-specific agents (alteplase, streptokinase). All four were used
in the study.
In patients younger than age 76 who have
an acute ST-segment elevation MI, who received aspirin and a standard
fibrinolytic regimen, the addition of clopidogrel improved patency rate of the
infarct-related artery, and reduced ischemic complications.
“Concurrent Antiplatelet and Fibrinolytic
Therapy”, an editorial in this issue of NEJM (pp 1248-50) comments and expands
on the study:
Aspirin is a relatively weak antiplatelet agent. It
has limitations. It irreversibly inhibits cyclo-oxygenase in platelets thereby
inhibiting synthesis of thromboxane, a powerful promoter of platelet
activation. It exerts no effect on thromboxane-independent mediators of
platelet activation. Up to 30% of persons with coronary artery disease are
relatively resistant or unresponsive to aspirin.
All mediators of platelet activation cause
conformational changes in the platelet-surface glycoprotein IIb/IIIa receptor. This
change retards platelets from binding to circulating fibrinogen.
Reduced Ischemic Stroke, but Did Not Reduce MI, Except
in Women Over Age 65
3-6 RANDOMIZED TRIAL OF LOW-DOSE ASPIRIN IN THE
PRIMARY PREVENTION OF CARDIOVASCULAR
DISEASE IN WOMEN.
Cardiovascular disease is the leading
cause of death among both women and men.
Aspirin is effective in treatment of acute myocardial infarction
and in secondary prevention of
cardiovascular disease among both men and women.
Its use in primary prevention in women is controversial. The current
recommendations for use of aspirin in primary
prevention in women are based on limited data.
The Women’s Health Study was a large,
randomized, double-blind placebo-controlled trial of low-dose aspirin in the
primary prevention of cardiovascular disease among over 39 000 apparently
healthy women followed for a mean of 10 years for major cardiovascular events.
Conclusion: In primary prevention, aspirin lowered risk
of stroke in women over age 45; but did not lower risk of myocardial infarction
or cardiovascular death until after age 65.
1. Entered over 38 000 women age 45 or
older (mean = 54) . All were initially healthy. 10% were over age 65.
2. Randomized to: 1) Aspirin 100 mg daily on alternate days,
or 2) Placebo
3. Followed for 10 years to determine
first major cardiovascular event (non-fatal MI, non-fatal stroke, or death from
cardiovascular causes.
1. During 10-year follow-up:
A. Entire group Aspirin (n = 19 934) Placebo (n = 19 942)
Major cardiovascular events 477 522*
Stroke
Ischemic 221 266
Hemorrhagic 51 41*
Fatal 23 22*
Non-fatal 198 244
Myocardial infarction
Fatal 14 12*
Non-fatal