Transcript The Vioxx Debacle - Medicine and Opera

The Vioxx Debacle
Implications for Clinical Trials
Medical Grand Rounds March 3, 2005
Neil A Kurtzman, MD
Grover Murray Professor
University Distinguished Professor
Texas Tech University Medical Center
• Was there a valid medical reason for
•
•
withdrawing Vioxx?
What is the safety profile of the COX-2
inhibitors?
What are the implications of this issue for
clinical trials in general?
• Why do we do clinical trials?
• Safety and efficacy
• Evidence based medicine
• The law requires them
• We must do them even when we know the
result before the study is done
• Consider ACE inhibitors and diabetic
•
•
nephropathy
We knew ACE inhibitors were safe and
efficacious for hypertension before they were
used to treat diabetic nephropathy
So safety was not an issue, efficacy in treating
diabetic nephropathy was
• A 46 yo white type 1diabetic man was referred
•
•
•
•
to me in 1990 by his ophthalmologist because
of proteinuria – 1.5 g/day
He was hypertensive
Cr 1.2
He was blind
He was treated with ACEI and furosemide
• His blood pressure was perfectly controlled
• His blood sugar was always out of control
• His proteinuria gradually (over a few years)
•
•
disappeared – it’s now about 100mg/day
His Cr in 2005 is 1.2
A clinical trial is not necessary to prove that
ACE inhibitors retard the progression of
diabetic nephropathy because a scenario like
the above was never seen before their use
• Similar results have been seen in patients with
•
•
Type 2 DM
Yet because clinical trials proving their
efficacy (in Type 2 DM) had not been done it
was felt justified to conduct trial comparing
ARBs vs non-ACEI drugs in patients with
proteinuria
Evidence Based Medicine was used to justify
dubious studies
• You don’t need a clinical trial to demonstrate
•
•
•
•
the truly efficacious treatments
Morphine for pain
Diuretics for edema
Penicillin for syphilis
Insulin for DKA
• What use are clinical trials?
• They may detect small differences in treatments
• Or no difference
• The are necessary to detect effects that are far in
•
•
•
the future
Prevention studies
They are very hard to do
The Vioxx debacle will make them even harder
• A drug can be unsafe and non-efficacious X
• It can be safe and non-efficacious X
• Safe and efficacious X
• Unsafe and efficacious *
- thus a risk/benefit analysis is required
• Clinical trials examining prevention are
•
•
•
•
fraught with hazard
Consider a drug designed to prevent
Alzheimer’s Disease
It would have to be given 15-20 years before
the disease would be detectable
Any such drug would have side effects
The side effects would be observed before any
therapeutic effect could be seen
• The drug might well be withdrawn before its
•
•
beneficial effects could be noted
Suppose it caused a small but significant
increase AMI, but totally prevented
Alzheimer’s Disease
That would be a price worth paying, but we’d
never find out because the trial would have
been halted
• When we prescribe a drug the question is not
•
•
how safe is it compared to a placebo
It will always be less safe
But how safe compared to other treatments or
to no treatment at all
The Purpose of Medicine
• Prolong life
•
•
•
- prevent premature death
Relieve pain and suffering
What to do when treatment for one exacerbates
the other?
Typically physicians focus on the first purpose
while downplaying the second
• NSAIDS lead to hospital admissions for ulcer
•
•
complications in 0.25 - 1.6% of users per year
They cause at least 7000 deaths per year in the
US
Celecoxib does not prevent ulcer complications
(CLASS JAMA 284:1247, 2000)
VIGOR Study NEJM 343:1520,2000
• Mortality rates were the same for Vioxx and
•
•
•
•
naproxen (0.5 and 0.4%)
CV death rates were also identical (0.2%)
Ischemic CVAs were the same (0.2%)
AMI much less common in the naproxen
group 0.1 vs 0.4%
RR 0.2 (0.1 - 0.6)
• Merck withdrew Vioxx because of an increased
•
•
•
•
•
•
rate of AMI in a colon polyp prevention study
The data from this study have just been
published
Vioxx was compared to a placebo
Thus there could be no offsetting side effect that
would mitigate any bad effect of Vioxx
Sugar pills don’t cause GI bleeding
Any positive therapeutic effect was years away
The increased AMI rate was seen after 18
months
CV Thrombotic Events in Controlled Clinical
Trials of Rofecoxib
Circulation 104:2280, 2001
Includes the VIGOR Trial
COX-2 Selective NSAIDS and Risk of Serious CAD
Lancet 360:1071, 2002
• Retrospective study of about 300,00 0 TennCare
•
•
•
•
•
•
patients
50 – 84 yo
Vioxx >25 mg/day more likely to have CAD
All user RR 1.70 NS (0.98 – 2.95)
New users 1.93 (1.09 – 3.42)
<25 mg/day no increase in risk 1.03 (0.76 – 1.37)
No cause and effect can be concluded
Selective COX-2 Inhibition and CV Disease
Am Heart J 146:591, 2003
• Concludes that there was not an excess of
•
thrombotic CV events among patients taking
Vioxx
Also concludes that naproxen likely has a
cardioprotective effect
Risk of CV Event and Rofecoxib: Cumulative meta-analysis
Lancet 364:2021, 2004
• No mortality data – CV or otherwise
• No risk/benefit analysis
• Concludes that increased risk of AMI was
•
•
•
•
evident from 2000 on
That CV toxicity was not dose dependent
That the VIGOR result were likely not due to a
cardio-protective effect of naproxen
That the drug should have been removed from
the market in 2000
And that it’s all Merck’s fault
• Pages of critical mail appeared in the Lancet’s
•
letters section
Meta-analysis is to analysis as metaphysics is
to physics
Patients Exposed to Rofecoxib and Celecoxib Have
Different Odds of Nonfatal MI
Ann Int Med 142:157, 2005
Rofecoxib vs celecoxib OR 2.72 (CI, 1.24 – 5.95
Rofecoxib vs naproxen
3.39 (1.37 – 8.40)
Selective COX-2 Inhibition and CV Effects
Arch Int Med 165:181, 2005
Retrospective study
Largely African-American
High risk for CV disease
The Risk of MI with COX-2 Inhibitors: A Population Study of Elderly
Patients
Ann Int Med: In press
Also retrospective
From Quebec
Pfizer Says Study Shows
Heart Risk From Celebrex
FDA Is Reviewing Information;
Shares Tumble 11% on News
By SCOTT HENSLEY
Staff Reporter of THE WALL STREET JOURNAL
December 19, 2004 6:34 p.m.
Pfizer Inc. said a government-sponsored study of its arthritis
drug Celebrex in cancer prevention found a significant risk of
cardiovascular problems, an unanticipated result that raises
new questions about the safety of the popular drug.
CV Risk Associated with celecoxib in a Clinical Trial
for Colorectal Prevention
NEJM 2/23/05
CV Events Associated with Rofecoxib in a Colorectal
Adenoma Chemoprevention trial
NEJM 2/23/05
NEJM Feb 23, 2005
Risk of AMI and sudden cardiac death in patients treated
with COX 2 selective and non-selective NSAIDs: nested
control study
Lancet 365:475, 2005
Despite the title, no mortality data in the paper
• Complications of the COX-2 Inhibitors
•
•
Parecoxib and Valdecoxib after Cardiac
Surgery – NEJM 2/23/05
Increased CV events with these drugs after
CABG
That the NEJM published this is a measure of
the hysteria that surrounds this topic
• The data show that:
• Vioxx increases AMI
• Vioxx doesn’t increase AMI
• Celebrex does not increase the rate of AMI
• Celebrex decreases AMI
• Celebrex increases AMI
• Naproxen protects against AMI
• Naproxen does not protect against AMI
• Naproxen is worse than Celebrex
• If a drug that increases the rate of AMI is bad
•
•
•
then a drug that reduces it must be good
Final Report of Aspirin Component of the
Ongoing Physicians Health Study: NEJM
321:129, 1989
Double blind, randomized, placebo-controlled
Test the hypothesis that ASA in low doses
reduces mortality from CV disease in healthy
males
• No effect on CV death rate
• No effect on non CV death rate
• No effect on total deaths
• Marked decrease in both fatal and non fatal MI
• Thus this study provides no evidence
supporting ASA as primary prevention for CV
mortality in healthy males
Warning Label for Adriamycin
Myocardial toxicity manifested in its most severe form by
potentially fatal congestive heart failure may occur either
during therapy or months to years after termination of therapy.
The probability of developing impaired myocardial function
based on a combined index of signs, symptoms and decline in
left ventricular ejection fraction (LVEF) is estimated to be 1 to
2% at a total cumulative dose of 300 mg/m² of doxorubicin, 3
to 5% at a dose of 400 mg/m², 5 to 8% at 450 mg/m² and 6 to
20% at 500 mg/m².* The risk of developing CHF increases
rapidly with increasing total cumulative doses of doxorubicin
in excess of 450 mg/m². This toxicity may occur at lower
cumulative doses in patients with prior mediastinal irradiation
or on concurrent cyclophosphamide therapy or with preexisting heart disease
Myocardial toxicity manifested in its
most severe form by potentially fatal
congestive heart failure may occur either
during therapy or months to years after
termination of therapy.
The probability of developing impaired
myocardial function based on a combined
index of signs, symptoms and decline in left
ventricular ejection fraction (LVEF) is
estimated to be 1 to 2% at a total cumulative
dose of 300 mg/m² of doxorubicin, 3 to 5% at
a dose of 400 mg/m², 5 to 8% at 450 mg/m²
and 6 to 20% at 500 mg/m²
The risk of developing CHF increases
rapidly with increasing total cumulative
doses of doxorubicin in excess of 450
mg/m². This toxicity may occur at lower
cumulative doses in patients with prior
mediastinal irradiation or on concurrent
cyclophosphamide therapy or with preexisting heart disease
• Nobody has called for the removal of
•
•
•
Adriamycin from the market
Cancer is obviously felt to be more important
than pain
But is it?
I would ague that in many cases the reverse is
true
• Most people over 65 have DJD
• Many of these patients have chronic pain that
•
•
is disabling
These are the same patients that are at high
risk for CV disease
Not treating this pain is not an option
• What are the options?
• Acetaminophen – effective in many patients,
•
•
•
but not all
Must be given 3– 4 time/day
Breakthrough pain, especially at night is
common
Some studies show it to be less effective than
NSAIDs
• Nonselective COX inhibitors
• Effective
• Serious GI complications common and
•
sometimes fatal
Probably not a good drug to take every day for
20 years
• COX-2 inhibitors
• They are effective
• Only Vioxx among these drugs available in the
•
US has been shown to decrease adverse GI
events
It’s off the market
• Narcotics
• Effective
• But CNS effect makes their use problematic in
elderly patients
• Surgery and other invasive intervention
•
•
•
common on a pain service
Often effective
Have their own risk profiles
Not every joint can be replaced or manipulated
Lancet 364:665, 2004
• Lumiracoxib appears to have a better safety
•
profile than the other COX-2 inhibitors
But is the FDA in a mood to approve another
COX-2 inhibitor in the wake of the negative
publicity generated by the Vioxx withdrawal?
The Purpose of Medicine
• Prevent premature death
• Relieve pain and suffering
• What to do when these two goals conflict?
• How much pain and suffering is worth how
•
•
•
much of a reduction in life?
How much pain relief and reduced likelihood
of GI bleeding is worth how many MIs in an
elderly population?
No formula or set of practice guidelines will
satisfactorily answer the question
Good judgment is the only answer
• In my view the data thus far available doesn’t
•
justify the removal of Vioxx
Merck made the decision based on liability
consideration rather than on strict medical
reasons
• Implications for clinical trials
• Many long term clinical trials are apt to be
•
•
considered too risky by the drug companies
A drug that may prevent a disease that will not
occur until far in the future may prove to have
side effects before any therapeutic effect can
be seen
This is particularly true if it is being compared
to a placebo
• The placebo will not have its own side effect
•
•
•
profile that might offset those untoward effects
of the study drug
Even if there are off setting effects the study
drug may still be in trouble
Heart attacks seem to worry both the public
and the profession more than GI bleeding
Hysterical reactions to side effects are more
likely to be the rule rather than the exception
• One of the country’s leading cardiologist’s said
•
•
that “Any drug that causes heart attacks
shouldn’t be on the market.”
Suppose it caused one AMI for every 100
cases of lung cancer that it cured
Any treatment requires a risk/benefit analysis
Merck May Return
Vioxx to Market
Move Depends on Whether
FDA Panel Decides Risks
Exist in Similar Medicines
By ANNA WILDE MATHEWS and SCOTT HENSLEY
Staff Reporters of THE WALL STREET JOURNAL
February 18, 2005 1:30 p.m.
FDA Advisers Recommend
Return of Vioxx to U.S. Market
Shares of Merck Surge 13% on News
By ANNA WILDE MATHEWS
Staff Reporter of THE WALL STREET JOURNAL
February 18, 2005 9:12 p.m.
Nothing is easier than to imagine that one has
taken all relevant factors into account, when in
reality there may be other factors which have
influence, even if no data have been collected
on them or they are not quantifiable. Where
there are very significant differences in known
factors between one group and another, it
would be reckless to assume that all remaining
unknown factors are the same.
Thomas Sowell
• Think carefully before you prescribe
• Evaluate clinical trials critically
30
Celebrex Studies
Pfizer's announcement Friday stemmed from a trial conducted by
the National Cancer Institute. The study, called the Adenoma
Prevention with Celecoxib trial, involved patients taking high
doses of Celebrex--400mg and 800mg daily -- to see if the drug
could prevent colon cancer. The National Cancer Institute, which
sponsored the study, stopped giving patients Celebrex after
learning of the increased risk to patients during a review of the
data. Recommended doses of Celebrex are 100mg to 200mg a day
for osteoarthritis pain and swelling and 200mg to 400mg for
rheumatoid arthritis symptoms, Pfizer said.
Pfizer also said this about a separate study: "In a separate longterm study, the Prevention of Spontaneous Adenomatopus Polyps
(PreSAP) trial, there has been no increased risk for Celebrex
patients taking 400mg daily compared with those taking placebo.
These findings are based on an identical analysis used to assess
cardiovascular risk in the APC trial and conducted by the same
independent safety review board. The information from this Pfizer
sponsored trial was also received by Pfizer last night and, as with
the APC information, was immediately shared by the company
with the U.S. Food and Drug Administration."