Transcript Coaated stents: a new era

Polypill
The Polypill: Therapy of the
future?
Valentin Fuster MD
Director, Cardiovascular Institute
Mount Sinai Medical Center
New York, New York
Eric Topol MD
Provost and Chief Academic Officer
The Cleveland Clinic Foundation
Cleveland, Ohio
Harlan Krumholz MD
Professor of Medicine (Cardiology)
Yale University School of Medicine
New Haven, Connecticut
Johnathan Sackner-Bernstein MD
Director of Clinical Research
North Shore University Hospital
Heartbeat – Aug 2003 Long Island, New York
Polypill
The "Polypill" proposal
"A strategy to reduce cardiovascular
disease by more than 80%."
A single pill combining:
• A statin (10-mg atorvastatin or 40-mg
simvastatin or lovastatin)
• Three BP-lowering drugs, at halfstandard dose (thiazide, beta blocker,
and ACE inhibitor)
• 0.8-mg folic acid
• 75-mg aspirin
Heartbeat – Aug 2003
Wald NJ and Law MR. British Medical
Journal 2003 Jun 28; 2002; 326:1419
Polypill
The idea
Wald and Law claim this approach:
• Would not be expensive
• Would not cause significant side
effects
Polypill should be given to
• Patients with cardiovascular disease
• Patients >55 years of age
Heartbeat – Aug 2003
Fuster
Polypill
Radical approach
A combination pill used to make
compliance easier (one pill instead of
three) has been proposed before
The Polypill is being proposed as a means
of prevention across a huge population
"I think that this is not related to the
compliance of the patient and
therefore is a very radical approach."
Heartbeat – Aug 2003
Fuster
Polypill
Theoretically provocative
Radical and provocative population-based
strategy
"To think everyone over age 55 would be
taking a pill on a daily basis with these
six drugs is a bit removed from what we
had been expecting how the field would
go."
"I don't even know if such a pill could be
produced without any chemical
incompatibility."
Topol
Heartbeat – Aug 2003
Polypill
Promotion
The Polypill article directs attention to the
fact there have been effective
interventions in heart disease that are
still not fully applied
Ward and Law are trademarking the name
"Polypill" and are promoting it heavily
Problem in promoting the notion that the
Polypill is almost a vaccine or magic
bullet for heart disease
Heartbeat – Aug 2003
Krumholz
Polypill
Way ahead of themselves
"I think that they get way ahead of
themselves in terms of the evidence."
They extrapolate very far from
observational studies
No proof that three BP pills at half dose will
have the effect they say
If a patient develops intolerance to a pill
with six drugs, how can you tell what
they aren't tolerating?
Krumholz
Heartbeat – Aug 2003
Polypill
Not unreasonable
This is radical, but not unreasonable
Using these medicines more widely is based
on sound data
"We've gotten so caught up with how to
treat populations and how to be costeffective that we've forgotten about the
fact that we're supposed to be treating
patients and describing what the riskbenefit ratio is for them."
Heartbeat – Aug 2003
Sackner-Bernstein
Polypill
Individualizing medicines
Use medicines like these, but individualize
them
Everyone is a candidate, but not everyone
should be treated the same way
The targets as they exist in the treatment
guidelines are a little too lax
Patients need to be looked at individually,
and optimal blood pressure and optimal
LDL levels are the way to reduce risk
Sackner-Bernstein
Heartbeat – Aug 2003
Polypill
Western population
JNC 7 suggests hypertension is a graded
effect, starting from 115/75 mm Hg,
with a gradually increasing risk
HPS suggested any patient with a coronarylike disease should be put on a statin
regardless of cholesterol level
"It seems to me that the concept of
approaching a Western population
aggressively is not an unreasonable
one."
Fuster
Heartbeat – Aug 2003
Polypill
Aggressive approach
An aggressive treatment such as the Polypill
might make sense for someone with
known risk
This strategy goes against the move toward
individualized medicine
The idea of treating more widely may be
appropriate, but a lot of patients don't
need all six drugs
Heartbeat – Aug 2003
Topol
Polypill
Dumbed-up strategy
"This is a dumbed-up strategy for
everybody. I just don't agree that we
have to be so dumb."
It might be cost-effective, but it doesn't take
into account any individualization
Heartbeat – Aug 2003
Topol
Polypill
Best approach
Ward and Law claim this is the best
approach for decreasing CV events
Look at the Finnish success in reducing
cholesterol and CV events by changing
food production
Governments' ability to change food
production, pressure the tobacco
industry, and make populationwide
approaches could be a far more effective
approach
Fuster
Heartbeat – Aug 2003
Polypill
Lifestyle changes
In the West, stamping out tobacco and
changing the food industry are not likely
Meaningful lifestyle changes are extremely
difficult for patients
Pragmatically, for a patient with a BP in the
130s, a pill can bring them down below
115 if they can't change their lifestyle
Heartbeat – Aug 2003
Sackner-Bernstein
Polypill
Social engineering
Social engineering approaches are
important and should be supported
• Food supply
• Exercise and lifestyle change
• Community development
All approaches should not be medicalized
Lifestyle changes should not be discounted
Heartbeat – Aug 2003
Krumholz
Polypill
Blood pressure agents
Must disentangle what is in this Polypill and
what is meant by optimal treatment
Statins have such strong evidence
supporting them that they are an
obvious choice to offer patients at risk
For blood pressure drugs there are no good
treatment studies saying we reduce risk
by bringing someone from systolic 130
to 115
Heartbeat – Aug 2003
Krumholz
Polypill
Blood pressure reduction
Treatment of hypertension usually needs
multiple drugs
According to Ward and Law's meta-analysis,
a half dose of three drugs would reduce:
• Systolic BP 20 mm Hg, diastolic 11 mm Hg
• Stroke by 63%
• Ischemic heart disease events at ages 6069 by 46%
Heartbeat – Aug 2003
Wald NJ et al British Medical Journal
2003 Jun 28; 2002; 326:1427
Polypill
The general population
Previous blood pressure trials were not
on patients with low or normal blood
pressure
"I don't think you can transfer all these
data on the antihypertensives in a
hypertensive population into an
overall population over 55."
Heartbeat – Aug 2003
Fuster
Polypill
Extrapolations
"I think there are lots of assumptions and
extrapolations here that are hard to
fully accept."
• No one has tested the effectiveness of
antihypertensive drugs in
normotensive patients
• No proof half-doses will have a
significant effect
• Unproven assumption each drug is
having an independent benefit
Topol
Heartbeat – Aug 2003
Polypill
Special populations
"What does a half dose of ACE inhibitor and
beta blocker do for African Americans?
Does it do anything? Has it ever been
tested? I mean, the full doses don't look
so great, so I don't know about half
doses."
"This simplistic notion of treating every 55year-old and beyond the same is a little
simplistic."
Heartbeat – Aug 2003
Topol
Polypill
No systematic approach
No systematic approach to learn from all
the people currently on medications in
this country
"50% of the people with risk factors or
with cardiovascular disease should be in
some sort of trial at any given time."
"A lot of these regimens are being used all
the time, and we're really not sure
because they're just being used with an
N of 1."
Krumholz
Heartbeat – Aug 2003
Polypill
Statins and ischemic events
Reduction in
ischemic events
(%)
50 years old
90
80
70
60
50
40
30
20
10
0
1.4
60 years old
70 years old
1.8
2.2
Reduction in LDL (mmol/L)
Heartbeat – Aug 2003
BMJ 2003 Jun 28; 2002; 326:1423
Polypill
Statins for everyone
Data show that once someone is 50, they
have a 75% to 80% chance of having
fat-laden plaques in the proximal
coronary arteries
These are the vulnerable lesions
"I tend to be pretty aggressive with statins
and I think the data are probably the
strongest with the statins for
widespread use of any of these six
components."
Sackner-Bernstein
Heartbeat – Aug 2003
Polypill
Risk/benefit of aspirin
Baseline risk of coronary disease over 5 years
Type of event
1%
3%
5%
Nonfatal AMI
and fatal CHD
1-4
avoided
4-12
avoided
6-20
avoided
Hemorrhagic
strokes
0-2 caused
0-2 caused
0-2 caused
Major GI
bleeds
2-4 caused
2-4 caused
2-4 caused
Heartbeat – Aug 2003
Hayden M et al. Ann Intern Med 2002; 136:161-72.
Polypill
Low-risk people
Are you taking a statin and an aspirin?
• Topol: "I'm not taking aspirin,
although I am taking a statin."
• Krumholz: "I'm not taking either of
them."
The question is whether people at very
low risk should be on any of these
drugs
Heartbeat – Aug 2003
Polypill
Aspirin's importance
Anyone at >1% a year risk gets a
significant benefit from aspirin,
especially for MI or stroke
Statin benefit has mostly been in
secondary prevention
"I would assert that aspirin is the most
important of the six, maybe statins
being second."
Heartbeat – Aug 2003
Topol
Polypill
Aspirin
Guidelines say that at a 10-year risk of
3% or less (0.3% a year) aspirin is no
longer favorable
Anyone over age 55 already exceeds this
level of risk
"In that age group, I would advocate 7580 mg of aspirin"
Heartbeat – Aug 2003
Sackner-Bernstein
Polypill
The Physicians Study
Effect of aspirin on MI and stroke for 22 071 patients
with 60.2-month average follow-up
Aspirin vs placebo
Event
Relative risk
95% CI
P
MI
0.56
0.45-0.70
<0.00001
Stroke
2.14
0.96-4.77
0.06
Total
mortality
0.96
0.60-1.54
NS
Heartbeat – Aug 2003
N Engl J Med 1989; 321:129-35.
Polypill
Vitamin E meta-analysis
Control
Vitamin E
12
Events (%)
10
8
6
4
2
0
Heartbeat – Aug 2003
Death
CV death
Cerebral event
Lancet 2003; 361:2017-2023
Polypill
Folic acid
Folic acid has not been proven in a wide
population
"I guess the philosophy here of Wald and
Law was that 'Oh, it can't hurt
anybody and it may help some.'"
Vitamin supplements have been a bust
Heartbeat – Aug 2003
Topol
Polypill
Beta-carotene meta-analysis
Control
Beta-carotene
8
Events (%)
7
6
5
4
3
2
1
0
Heartbeat – Aug 2003
Death
CV death
Lancet 2003; 361:2017-2023
Polypill
Insufficient evidence
"The USPSTF could not determine the
balance of benefits and harms of
routine use of supplements of vitamins
A, C, or E, multivitamins with folic
acid, or antioxidant combinations for
the prevention of cancer or
cardiovascular disease."
US Preventive Services Task Force
Heartbeat – Aug 2003
Ann Intern Med 2003 Jul 1; 139(1):51-70
Polypill
Decisions on strategy
Wald and Law acknowledge their approach
is radical but insist the data are
suggestive
"Maybe in medicine or in anything a radical
approach has some truth . . . but it
seems to me that we are all in
agreement that maybe the approach is
too radical."
Heartbeat – Aug 2003
Fuster
Polypill
Reasonable
The approach is radical but not
unreasonable
They've raised awareness and forced us to
"go back and think about what we
would consider the data to point to as
the optimal preventive strategy."
Heartbeat – Aug 2003
Fuster
Polypill
Pravastatin/aspirin pill
Pravastatin/aspirin pill received FDA
approval in June 2003
Available in six formulations: 20-mg, 40mg, and 80-mg doses of pravastatin,
each available with either 81 mg or 325
mg of aspirin
Heartbeat – Aug 2003
Topol
Polypill
Unreasonable
The "Polypill" proposal is unreasonable,
instead we need a two-pronged
approach
We need to bring patients in alignment with
our guidelines
We need to have an individualized
discussion between physicians and
patients about how to approach their
goals of therapy
Heartbeat – Aug 2003
Krumholz
Polypill
Conclusions on the Polypill
Fuster:
Too radical
Topol:
Too radical
Krumholz:
Unreasonable
Sackner-Bernstein:
Heartbeat – Aug 2003
Not unreasonable
Krumholz
Polypill
Don't need risk factors?
Is it time to discard the view that risk
factors need to be measured?
Is Western society itself a risk factor?
A lot of truth in this view
"The fact that you start putting people on
pills without measuring anything, I
frankly think this is also too radical."
Heartbeat – Aug 2003
Fuster
Polypill
Smarter medicine
"I'm hoping that we're in a transition to a
much smarter medicine."
Need to get to the biologic basis of
diseases and risk
Questions remain on all the surrogate
measures we currently use
Heartbeat – Aug 2003
Topol
Polypill
Risk perception
Treating without measuring is too radical
It is important to emphasize that being in
Western society is a risk factor
A relatively healthy 52-year-old still has a
6% risk of an MI over the next 10 years
Saying this patient is at "low risk" and is
adequately treated is doing him a
disservice
Heartbeat – Aug 2003
Sackner-Bernstein
Polypill
Absolute benefits
There is still a great heterogeneity in risk,
even in Western society
"We ought to be tying our interventions to
the overall absolute benefit that is likely
to be gained from the intervention."
• Must assess underlying risk and make
therapeutic decisions from that
Heartbeat – Aug 2003
Krumholz
Polypill
Isn't simple
There is much to gain and little to lose
from the widespread use of these
drugs
What is the cost to manufacture a pill like
this?
How difficult is it to make a single pill
with six drugs?
What side effects will you see on people
at low risk?
Fuster
Heartbeat – Aug 2003
Polypill
Simplistic approach
The approach is simplistic
• Potentially exaggerates the benefit
• There remain many unknowns
It might work well in a third-world
environment where more couldn't be
done
Heartbeat – Aug 2003
Topol
Polypill
Ideal for developing countries
Authors conclude that there is no other
preventive method that would have
greater impact than this one
Editorial suggests that this approach is
ideal for developing countries
• Is there a difference in the usefulness
of a Polypill for Western countries and
the developing world?
Heartbeat – Aug 2003
Fuster
Polypill
Burden of proof
"The burden of proof still lies with the
people who are promoting this idea to
demonstrate what exactly can be
achieved through this strategy."
This should not be implemented in any
society without some sort of evidence of
the risks and benefits
Heartbeat – Aug 2003
Krumholz
Polypill
Burden of disease
The burden of cardiovascular disease is
different in different areas
There is much to gain and little to lose in
looking at individual patients and
wondering how to lower their risk
"Using this as a standard strategy broadly
is rife with problems."
Heartbeat – Aug 2003
Sackner-Bernstein
Polypill
How do we move to the future?
On one hand, individualized medicine is
the future. On the other, there is a
problem in the field of prevention
Recent editorial in Science says that the
current system cannot meet today's
needs; how can advances such as
postgenomic medicine be
incorporated?
Heartbeat – Aug 2003
Fuster
Polypill
A new model
The model today is to develop a drug for an
entire population, even though less than
10 in 100 patients actually derive
benefit from the drug
A different model is to develop drugs for
smaller populations defined by specific
genes or proteins
"But we're not there yet, it's theoretical,
and that's postgenomic medicine."
Heartbeat – Aug 2003
Topol
Polypill
The future of drug companies
The patients don't want to take all these
pills, but they would take a pill tailored
to them
Practically, the current model for drug
companies would not support the
pharmacogenetic model
"Big Pharma hasn't gotten it yet, and
whether they're going to accept this
notion remains to be seen."
Heartbeat – Aug 2003
Topol
Polypill
Creating a new system
"How do we create a system in which we
can adopt innovations quickly and
appropriately and ensure that all
patients are getting the very best care
for them?"
There are still too many patients not
getting the interventions we already
know are effective
The challenge will be bringing the
innovations to the patients
Heartbeat – Aug 2003
Krumholz
Polypill
Compromise
Perhaps in the coronary patient some
kind of combination pill could be
developed and used while the genetic
understanding moves ahead
"In a simplistic way we might begin to
distinguish populations where drugs
should be given and drugs should not
be given."
Heartbeat – Aug 2003
Fuster
Polypill
Practical approach
Some sort of compromise is the optimal
approach, using optimal drug therapy
while genomic medicine is developed
There are millions of people who are
willing to take multiple medicines, and
these people should be treated as
aggressively as we believe is
appropriate while we wait for genomic
therapy
Heartbeat – Aug 2003
Sackner-Bernstein
Polypill
The Polypill: Therapy of the
future?
Valentin Fuster MD
Director, Cardiovascular Institute
Mount Sinai Medical Center
New York, New York
Eric Topol MD
Provost and Chief Academic Officer
The Cleveland Clinic Foundation
Cleveland, Ohio
Harlan Krumholz MD
Professor of Medicine (Cardiology)
Yale University School of Medicine
New Haven, Connecticut
Johnathan Sackner-Bernstein MD
Director of Clinical Research
North Shore University Hospital
Heartbeat – Aug 2003 Long Island, New York