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William B.
White, MD (Farmington,
Connecticut, USA): We have heard a great deal about endothelial
dysfunction in the literature and at this meeting. Dr. Pepine, in your
experience, what has been the best way to assess endothelial
dysfunction, and to evaluate the effects of a drug that could donate
nitric oxide (NO), in patients with clinical conditions such as
cigarette smoking, diabetes mellitus, or hypertension? Are there too
many confounding factors to clearly observe an effect?
Carl J. Pepine, MD (Gainseville, Florida, USA): I do not believe that these confounding factors pose too great a
barrier: the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
(statins) and angiotensin-converting enzyme inhibitors have all been
tested in patients who had these kinds of conditions, and changes in
endothelial function have been demonstrated. It should be possible to
show an improvement and, ultimately, this represents the real clinical
situation where you are targeting a population of patients with
cardiovascular disease, which comprises all of these conditions.
Michael A. Weber, MD (Brooklyn, New York, USA): In relation to this issue, organic nitrates have been used for many
years now for treating angina. How does NO get into the vessel wall?
Does it just diffuse in from the circulating plasma?
Dr. Pepine: Transport of NO is dominated by
diffusion and reaction with hemoglobin. There are various pathways for
nitrate bioactivation and metabolism, including the liver. An important
aspect of virtually all nitrate dosing regimens is the phenomenon of
tolerance, whereby prolonged continuous administration of nitrates for
>12 to 24 hours can result in impaired responsiveness to the nitrate,
demonstrated by reduced vasodilation and blood pressure–lowering
effects. This can be minimized by restricting exposure to the organic
nitrate to a few hours a day so that there is a nitrate-free period of
about 10 hours.
Dr. White: Dr. Weber, I
know you have spent considerable time reviewing the literature on the
cardiovascular effects of nonsteroidal anti-inflammatory drugs (NSAIDs).
What do you believe is the more important issue associated with the use
of NSAIDs in older patients with arthritis: the increase in blood
pressure induced by some of these drugs, or the potential for
prothrombotic alterations that may lead to cardiovascular events?
Dr. Weber: I
believe that we have to worry
about both issues. High doses of some of these drugs, rofecoxib in
particular, have clearly resulted in an increased incidence of
cardiovascular events, and this may have been owing, in part, to
prothrombotic effects and elevations in blood pressure. However, in
arthritis we are dealing with patients who have chronic pain arising
from an inflammatory condition, which itself is a source of threat to
the vasculature. It is not yet clear in my mind, with the exception of
high-dose rofecoxib, what the relative prothrombotic contribution is of
the underlying arthritic inflammatory disease as opposed to the
medication used to treat the disease. Take the example of acetaminophen:
there is no reason to believe that acetaminophen should be
prothrombotic, and yet the Nurses' Health Study demonstrated a
significantly increased risk for cardiovascular events associated with
its frequent use.1
Dr.
White: What might the advantages be of a drug like naproxcinod,
which delivers anti-inflammatory benefits and an NO donor as a single
molecule, versus giving naproxen and a separate oral nitrate? Would you
expect to get the same effect on blood pressure?
Dr. Pepine: That is a good question. NO
donors are some of the more effective blood pressure–lowering agents
that we have used, and they are particularly effective at reducing
systolic blood pressure. However, tolerance is an issue with nitrates
and it can lead to increases in blood pressure. Ultimately, I think that
studies to evaluate the simple administration of an organic nitrate
with a conventional anti-inflammatory agent will need to be conducted.
Dr. Weber: Dr. White, we understand that
low-dose aspirin has antiplatelet activity but also that at higher doses
it can become prothrombotic. Where does the switchover occur, and what
have we learned about how to use aspirin in arthritis?
Dr. White: I believe that with high doses of
any NSAID (greater than the equivalent of aspirin 325 mg/day) you have
to question the balance of benefit versus risk. Additionally, a
particular problem with the assessment of aspirin in clinical arthritis
studies is that patients entering the clinical study who have been
prescribed low-dose aspirin are at high or very high risk before study
randomization. In these studies, patients taking aspirin, compared with
versus those not using aspirin, have a 3-fold increased risk of adverse
cardiovascular events. Hence, it is difficult to distinguish between the
underlying cardiovascular disease process and the effects of drugs used
for treatment in these clinical trials. The ongoing Prospective
Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or
Naproxen (PRECISION) trial is evaluating long-term exposure to
celecoxib, naproxen, and ibuprofen in patients with arthritis, and will
be invaluable given the intent to stratify for low-dose aspirin use.
Question: In the study by Solomon and
coworkers2 that reported the risk of
cardiovascular events based on celecoxib dose and stratified by baseline
cardiovascular risk, what was the age that was used to determine
baseline risk?
Dr. White: Patients who
were >75 years of age with no other risk factors were considered at
moderate risk. Note that the long-term trials that were evaluated in
this study were not conducted in arthritis populations but rather were
conducted in patients with Alzheimer disease, with colonic polyp
progression, or patients in other kinds of cancer prevention studies,
and were conducted exclusively against placebo. Such long-term studies
against placebo in patients with arthritis have not been possible owing
to high withdrawal rates due to pain and lack of efficacy. Indeed,
long-term trials using subjects on high-dose aspirin or acetaminophen as
control groups would also be problematic.3
Dr.
Pepine: I think this touches on an important issue:
physician-diagnosed arthritis versus joint “aches and pains” in elderly
people who consume NSAIDs. Many people >65 years have joint aches and
pains but have not been formally diagnosed with arthritis. These joint
aches and pains are problematic in cardiovascular practice because they
act as a barrier to recommended improvements in lifestyle that include
increased physical activity. So, the need for safe analgesics is not
limited to patients with diagnosed arthritis, but would also include the
population of elderly individuals who are just trying to stay active.
Dr. White: Thanks for that comment. I think
that is an extremely important point. Untreated pain is
counterproductive to the kind of preventive medicine lifestyle that many
of our elderly individuals with underlying hypertension want to lead,
and so we have to come up with some kind of solution for the management
of their problems.
Question: Dr.
White, in your analysis of the data, you showed that acetaminophen use
is associated with an increased risk for cardiovascular events. Do you
think these data are robust enough for us to warn our patients who are
taking large doses of acetaminophen when all of the rheumatological
societies are advocating increasing doses of acetaminophen?
Dr. White: No, I do not believe the data
have that level of robustness. I think they comprise an important
observation that should be further assessed. Indeed, we actually know
very little about older pain drugs, including acetaminophen. The only
reason we know what we do about naproxen and ibuprofen is because they
were used as comparator agents in studies of the cyclooxygenase (COX)-2
inhibitors. However, we have very little understanding of drugs like
indomethacin and acetaminophen, except our own clinical perspective on
what they do to blood pressure and to renal function. The only thing we
know clearly about acetaminophen is that it has a very carefully studied
dose-related hepatotoxicity phenomenon. Is there a 24-hour blood
pressure study with acetaminophen over 12 weeks? No. Is there an
evaluation of the impact of the drug in patients with stage 3 chronic
kidney disease? No. We cannot assume that acetaminophen is entirely
benign because we just do not understand it that well. The epidemiologic
assessment of Curhan and coworkers4 certainly suggests, particularly in
women, that the same relative risks exist for acetaminophen as for the
NSAIDs they might be taking. Alternatively, as Dr. Weber pointed out, it
may be channeling bias (the underlying disease) that is contributing to
the observed risks, or there may be a drug–disease interaction. I would
not discount the recommendations of the American College of
Rheumatology (ACR) or the American Geriatrics Society (AGS) at this
time. I do believe that research with acetaminophen is warranted.
However, because the drug is generic, large-scale outcome studies are
not likely to be performed.
Dr. Pepine: I endorse everything that you just said about acetaminophen. I would
also like to point out that this was the reason that the American Heart
Association (AHA) consensus statement for managing arthritis in patients
with cardiovascular disease does not advocate only acetaminophen, but
consists of other suggested therapies, including opioids.5 Opioids may themselves create problems
in the elderly population. However, we must be aware that we just do
not have all the information for acetaminophen.
Dr. White: Dr. Weber, what else do we need
to understand about naproxcinod in patients with hypertension? What
other studies do you think we should conduct, and what kinds of patients
might we be prescribing it for once it is on the market in the United
States?
Dr.
Weber: I think that the
main patient population will be the individuals described earlier: those
in their 60s who complain of joint aches and pains, who have not
necessarily been given an official diagnosis of arthritis but clearly
have underlying issues and who are going to need chronic pain control.
As yet, we cannot guarantee that naproxcinod would avoid possible
adverse cardiovascular effects. All we can say so far is that it is
looking very different from regular NSAIDs. Certainly, the data on the
lack of a hypertensive effect of naproxcinod are compelling.6, 7, 8 The other attraction, of course, is
that naproxcinod may be a viable alternative to the COX-2 drugs
altogether, if we can confirm the relative safety of this drug from the
gastrointestinal point of view. Again, the data are very encouraging so
far, both in animal models9, 10 and in humans.11, 12 If we can confirm these studies, I
believe that naproxcinod could be an attractive choice for a large
number of patients who present with pain.
Dr.
White: Thank you very much for that analysis. I would like to
extend my appreciation to Dr. Weber and Dr. Pepine for participating in
this very interesting symposium today.
Author
Disclosures 
The
authors who contributed to this article have disclosed the following
industry relationships:
Carl J. Pepine,
MD, has received research/grant support from Abbott Laboratories,
AstraZeneca, Baxter International Inc., Berlex Laboratories/Bayer
HealthCare, Boehringer Ingelheim, Cardium Therapeutics, CV Therapeutics,
Inc., Daiichi-Sankyo Co. Ltd., Eli Lilly and Company, Forest
Laboratories, Inc., GlaxoSmithKline, Merck & Co. Inc., Novartis
Pharmaceuticals Corp., Pfizer Inc, Reliant Pharmaceuticals, Inc., and
sanofi-aventis.
Michael A.
Weber, MD, is a member of the Speakers' Bureau for Boehringer
Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo Co. Ltd., Forest
Laboratories, Inc., GlaxoSmithKline, Novartis Pharmaceuticals Corp., and
sanofi-aventis; and has worked as a consultant to Boehringer Ingelheim,
Bristol-Myers Squibb, Daiichi-Sankyo Co. Ltd., Forest Laboratories,
Inc., Gilead Sciences, Inc., Novartis Pharmaceuticals Corp., and Takeda
Pharmaceuticals North America, Inc.
William B.
White, MD, has worked as a consultant to Boehringer Ingelheim, NicOx
SA, Takeda Global Research and Development Center, Inc., and Teva
Neuroscience, Ltd.; and has received research/grant support from
Novartis Pharmaceuticals Corp.
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