6.

18 NSAIDs and Cardiovascular Toxicity

C L Leos, Auburn University, Auburn, AL, USA
2010 Elsevier Ltd. All rights reserved.

6.18.1 Background 323

6.18.2 NSAID Mechanism of Action 324
6.18.3 Cardiovascular Toxicities 325
6.18.3.1 Hypertension 325
6.18.3.1.1 Drugdrug interactions in hypertension 328
6.18.3.2 Congestive Heart Failure 330
6.18.3.3 Acute Myocardial Infarction 332
6.18.4 Conclusion 334
References 334

Abbreviations NF-kappa B nuclear factor-kappa B

AA arachidonic acid NSAID nonsteroidal anti-inflammatory
ACEI angiotensin-converting enzyme agent
inhibitor nsNSAID nonselective NSAID
ADR adverse drug reaction PG prostaglandin
AMI acute myocardial infarction PGE2 prostaglandin E2
APC Adenoma Prevention with PGE-M metabolites of PGE2
Celecoxib PGF2 prostaglandin F2
ARB angiotensin receptor blocker PGG2 prostaglandin G2
AT1 angiotensin 1 PGH2 prostaglandin H2
AT2 angiotensin 2 PGI2 prostacyclin
BK bradykinin RAAS renninangiotensinaldosterone
cAMP cyclic adenosine monophosphate system
CHF congestive heart failure RR relative risk
COX-1 cyclooxygenase 1 TxA2 thromboxane A2
COX-2 cyclooxygenase 2 TxB2 thromboxane B2
CVA cerebrovascular accident UMC Uppsala Monitoring Center
GFR glomerular filtration rate WHO World Health Organization
GI gastrointestinal

6.18.1 Background would be nearly impossible to quantify. Most of these

Nonsteroidal anti-inflammatory drugs (NSAIDs) are
some of the most frequently prescribed medications
currently on the market. Various drugs in this class
are routinely listed in the top 200 prescription med-
ications dispensed. Celecoxib (Celebrex, Pfizer,
Inc) reached the US sales topping $1.4 billion in
2007 (up 7.6% from 2006) (Drug information online).
Many of the drugs in this class are available as lower
strength dosage forms over the counter in the United
States, and routine consumption of these medications
medications are available as both single entities and
in combination with other medications for the treat-
ment of generalized pain, fever, osteo- and
rheumatoid arthritis, dysmenorrhea, cystic fibrosis,
gout, ankylosing spondylitis, headaches of all kinds,
and inhibition of platelet aggregation. Products man-
ufactured under multiple brand names and generic
labels are available in various dosage forms for use in
patients as young as 6 months.
Within the last three decades, there has been a
large amount of research done to find the ideal

323
324 Mechanisms of Drug-Induced Cardiovascular Toxicity
NSAID. This would be one with limited gastrointest-
inal (GI) effects, minimal drugdrug interactions,
and limited effect on other organ systems. Owing to
the complex nature of these medications and the
actions they inhibit, this has been a difficult task
and has resulted in the removal of multiple drugs in
this class from the US market.
6.18.2 NSAID Mechanism of Action
NSAIDs are classified by the enzymes they inhibit.
To date, there are two recognized enzymes respon-
sible for the conversion of arachidonic acid (AA) to
the eicosanoids responsible for the inflammatory cas-
cade and maintenance of cardiovascular homeostasis:
cyclooxygenases 1 and 2 (COX-1 and COX-2).
These eicosanoids are generally produced within
the tissue they act upon and are thereby termed as
autocrine in nature. Based on this fact, it is evident
that COX-1 and COX-2 are found in various tissues
in the body and are specific to the needs of those
tissues.
COX-1 is a constitutive enzyme and is responsible
for basic physiologic processes including protection
of the GI tract from endogenous stomach acids, renal
perfusion, vasoconstriction, and platelet aggregation.
Based on these actions, the COX-1 enzyme is present
in the stomach, intestines, kidneys, blood vessels, and
platelets. The COX-2 isoenzyme has an amino acid
sequence that is 60% homologous to COX-1
(Catella-Lawson et al. 1999). This enzyme has been
termed inducible as it is readily found in response to
inflammatory mediators, tumor promoters, and
growth factors (Hla and Neilson 1992; Jones et al.
1993; Smith et al. 1996) and is expressed by vascular
endothelium, macrophages, leukocytes, and fibro-
blasts. Products of these two enzymes include
prostaglandin G2 (PGG2) and prostaglandin H2
(PGH2), both of which are precursors for a number
of other prostaglandins (PGs) and thromboxanes
including prostaglandin E2 (PGE2), prostaglandin
F2 (PGF2), thromboxane A2 (TxA2), and prosta-
cyclin (PGI2) (Figure 1).
PGE2 is produced by many body tissues. In terms
of the cardiovascular system, PGE2 is responsible for
peripheral vasodilation and angiogenesis, and has
been implicated in inflammatory processes (Harada
et al. 1998). PGF2 is a vasoactive eicosanoid found in
equilibrium with PGE2 resulting in further periph-
eral vasodilation. TxA2 is produced primarily by
platelets and promotes platelet aggregation. In the
Arachidonic acid
COX-1 COX-2
PGG2
COX-1 COX-2
PGH2
Prostaglandins
PGD2, PGE2, PGF2, PGI2
TxA2
Figure 1 The isoenzymes COX-1 and COX-2 are 60%
homologous and responsible for the formation of PGG2 and
PGH2 from arachidonic acid. PGG2 and PGH2 are precursors
to many various prostaglandins controlling vasodilation and
vasoconstriction in various body tissues and TxA2, which is
responsible for vasoconstriction and platelet aggregation.
COX-1, cyclooxygenase 1; COX-2, cyclooxygenase 2; PGD2,
prostaglandin D2; PGE2, prostaglandin E2; PGF2,
prostaglandin F2; PGG2, prostaglandin
G2; PGH2, prostaglandin H2; PGI2, prostaglandin I2 also
known as prostacyclin; TxA2, thromboxane A2.
course of platelet degranulation, TxA2 recruits addi-
tional platelets to the site of vascular damage and
then induces localized vasoconstriction through
decreased formation of cyclic adenosine monopho-
sphate (cAMP). PGI2 is primarily synthesized by the
vascular endothelium and works in opposition to
TxA2. This endogenous chemical induces vasodila-
tion by increased production of cAMP and decreases
platelet aggregation by inhibition of vessel adhesion
factors.
The chemical structures for the various NSAIDs
vary, but all are classified based on their selectivity
for either COX-1 or COX-2. Those that are more
selective for COX-2 are generally thought to exhibit
fewer adverse drug effects than those with mixed
COX-1 and COX-2 actions. As COX-1 is found
largely in the GI tract, side effects of COX-1 enzy-
matic inhibition include ulceration and bleeding.
Fundamentally, nonselective NSAIDs inhibit both
COX-1 and COX-2 resulting in the decreased pro-
duction of protective PGs in the GI system. Research
into the two isoenzymes has driven the desire to
develop medications with higher COX-2 specificity
to decrease the number of hospitalizations and deaths
 NSAIDs and Cardiovascular Toxicity 325

Table 1 NSAID selectivity

Generic name Brand name(s) Available dosage forms Ratioa

Flurbiprofen Ansaid, Ocufen Oral, ophthalmic 10.27

Ketoprofen Actron, Orudis, Oruvail Oral 8.16
Fenoprofen Nalfon Oral 5.14
Tolmetin Tolectin Oral 3.93
Acetylsalicylic acid Aspirin (various) Oral, topical, rectal 3.12
Oxaprozin Daypro Oral 2.52
Naproxen Naprosyn, Aleve, Naprelan, Anaprox Oral 1.79
Indomethacin Indocin Oral, parenteral 1.78
Ibuprofen Motrin, Advil, Nuprin Oral 1.69
Ketorolac Acular, Toradol Oral, ophthalmic, parenteral 1.64
Piroxicam Feldene Oral 0.79
Nabumatone Relafen Oral 0.64
Etodolac Lodine Oral 0.11
Celecoxib Celebrex Oral 0.11
Meloxicam Mobic Oral 0.09
Mefenamic acid Ponstel Oral 0.08
Diclofenac Voltaren, Cataflam, Solaraze Oral, ophthalmic, topical 0.05
Rofecoxib Vioxx Oral 0.05
Nimesulide Various (not available in the United States) Oral 0.04
a
Expressed as the IC50 of COX-2 to the IC50 of COX-1 in whole blood. Ratios < 1 indicate increased selectivity for COX-2.
Adapted from Feldman, M.; McMahon, A. T. Ann. Intern. Med. 2000, 132, 134143.

due to GI bleeds and perforated ulcers. The selectiv-
ity of the various NSAIDs is described in Table 1.
6.18.3 Cardiovascular Toxicities
Owing to the complex nature of the eicosanoid sys-
tem and the numerous body systems affected by
these endogenous chemicals, toxicities of the drugs
in this class are numerous. Next to GI effects, those of
the cardiovascular system are the most predominant
followed by those of the renal system. Documented
cardiovascular adverse effects include hypertension,
heart failure exacerbations, myocardial infarction,
and stroke. Although the exact mechanisms of these
effects are still somewhat unclear, there is an ever
growing body of research and evidence pointing
toward a few key theories.
6.18.3.1 Hypertension
Hypertension is a driving factor in most cardiovas-
cular diseases. The ALLHAT study (ALLHAT
Collaborative Research Group 2000) showed that
sustained increases in systolic blood pressure result
in a 1020% increase in the risk of congestive heart
failure (CHF). Other large studies have shown that
the risk of stroke increases 1520% and angina 12%
with even modestly elevated blood pressures (Collins
et al. 1990; Hypertension Detection and Follow-Up
Program Cooperative Group 1984).
The role of PG vasculature functions has been
studied using the nonselective NSAID, indomethacin,
to inhibit PG synthesis. Blumberg et al. (1977) studied
the capacity of perfused mesenteric arterial vascular
beds to synthesize PGs. Strips of rat stomach and chick
rectum were perfused with the mesenteric artery beds
of anesthetized rabbits. Angiotensin 2 (AT2) was then
injected across the assay tissues where a considerable
muscular contraction was noted. The mesenteric efflu-
ent was then assayed and was found to contain
significant amounts of PGE in comparison to baseline.
The influence of AT2, bradykinin (BK), and AA on
mesenteric vascular resistance was also studied. To do
this, indomethacin was introduced into the interven-
tion group of tissues, and these results were then
compared to a control group (no indomethacin).
Infusion of indomethacin resulted in a significant
increase of perfusion pressures with AT2 when com-
pared to the control group (up to 37  11 mmHg vs
21  4 mmHg). The responses of the same tissues
to BK and AA were significantly blunted by
indomethacin compared to that of the control
tissues (16  3 mmHg vs 37  7 mmHg and
3  3 mmHg vs 42  4 mmHg, respectively). It
was expected that inhibition of PG synthesis by indo-
methacin would enhance the vasopressor actions of
AT2, and indeed, this is what happened. The changes
326 Mechanisms of Drug-Induced Cardiovascular Toxicity
in perfusion pressures were dose dependent with AT2
(increased pressures), BK (decreased pressures), and
AA. Based on this information, the authors were able
to conclude that PGE is locally synthesized and
involved in the vasodilation of the microcirculation.
It was also apparent that indomethacin worked to
augment the vasoconstrictive actions of AT2 and inhib-
ited the vasodilatory actions of BK and AA through
reduced concentrations of PGE locally. It was also
determined that BK and PGE worked synergistically
to promote a greater vasodilation in the presence of
AT2. This study illustrates one of the proposed
mechanisms of NSAID-induced hypertension: inhibi-
tion of vasodilatory PGE synthesis and increased
peripheral vascular resistance.
The second proposed mechanism of NSAID-
induced hypertension is decreased natriuresis.
Renal homeostasis (specifically fluid balance) is lar-
gely regulated by localized PG synthesis in the renal
cortex and is intimately involved in both local
(within the kidney) and systemic blood pressure
maintenance through the reninangiotensinaldos-
terone system (RAAS). Distal tubule reabsorption of
sodium and water, antagonism of antidiuretic hor-
mone, and redistribution of renal blood flow from
cortical to juxtamedullary regions are all regulated
by PG and easily antagonized with NSAID adminis-
tration (Clive and Stroff 1984; Oates et al. 1988). Side
effects of NSAID use in susceptible patients, such as
those with CHF, include edema and sodium reten-
tion resulting in increased systolic and diastolic
pressures. These effects will usually occur early in
treatment and are easily reversible with the cessation
of the offending agent. Most occurrences are minor
(subclinical in nature) with a prevalence of sympto-
matic edema occurring in 35% of reported cases
(Whelton and Hamilton 1991).
PGE2 and PGF2 work to inhibit chloride trans-
port in the ascending loop of Henle and in the
collecting duct, thereby decreasing sodium reabsorp-
tion (Stokes 1979; Stokes and Kokko 1977). This
action in the loop of Henle is analogous to the
mechanism of action of loop diuretics. PGE1 also
works to antagonize the actions of vasopressin (anti-
diuretic hormone) resulting in a decreased water
permeability and resorption in the collecting duct.
The actions of these PGs induce a large endogenous
natriuresis that is further augmented by the action of
PGI2 in the glomerulus to maintain the glomerular
filtration rate (GFR). Inhibition of these endogenous
natriuretics combined with the drug-induced
increase in peripheral vascular resistance could
certainly increase systemic blood pressures, quite
possibly to clinical significance.
In a retrospective review of New Jersey Medicaid
patients receiving NSAID therapy, it was found that
patients aged 65 years and older were more likely to
have antihypertensive therapy initiated when com-
pared to controls (Gurwitz et al. 1994). The primary
objective of this case-control study was to determine
if the use of NSAIDs increased the risk for initiation
of predefined antihypertensive medications in an
older patient population. A total of 9411 patient
records were reviewed from November 1981 to
February 1990 and compared to a control group of
9629 patients. NSAID users were divided into three
groups: former, recent, and current users depending
on the record of NSAID prescriptions in relation to
the initiation of an antihypertensive medication.
Recent users (within 60 days) were two times more
likely to have been initiated on an antihypertensive
medication (OR 2.01, 95% CI, 1.892.14). A dose
response relationship was also observed in this study
with the odds of antihypertensive medication initia-
tion increasing based on the observed daily dose of
the NSAID. The odds ratio for lower doses was 1.83,
medium doses 2.12, and high doses 2.39. All of these
ratios were statistically significant with a number
needed to harm of 20 patients in the high-dose
category. Clinically, this would mean that for every
20 patients started on NSAID therapy, one patient
will require a new antihypertensive medication to be
added to their existing drug regimen. Given the
massive numbers of patients taking NSAIDs (either
prescribed by a practitioner or self-care over-the-
counter use), the number of patients requiring addi-
tional antihypertensive therapy could be staggering.
The authors suggest that the results of their study
may show that NSAIDs increase the risk of hyper-
tension in an elderly population; however, the study
design (retrospective review) prevents a conclusion
of an actual causal relationship.
The preceding study did not differentiate
between the different NSAIDs in terms of COX-1
versus COX-2 effects in their patient population.
Wang et al. (2007) performed a retrospective cohort
study evaluating the incidence of new onset hyper-
tension patients taking celecoxib versus those taking
nonselective NSAIDs (nsNSAIDs). Patients with a
previous diagnosis of hypertension or any NSAID
use within 180 days of the index date were excluded.
Celecoxib users were matched with nsNSAID users
in a 1:2 fashion for age, sex, number of unique drugs,
and a propensity score calculated to determine the

probability of celecoxib use (e.g., sex age, and prior
GI events, GI harmful drug use, GI protective drug
use, comorbidities). After a multivariate analysis of
the 51 444 patients (17 148 were celecoxib users and
34 296 were nsNSAID users) was performed, it was
determined that celecoxib and nsNSAID users had
similar hazard ratios of being diagnosed with hyper-
tension within a 1 year time frame (OR 1.025; 95%
CI 0.9311.128; p 0.613). These results were also
controlled for aspirin use among these patients yield-
ing no significant changes in the data.
Zhao et al. (2001) performed a retrospective
review of adverse drug reactions (ADRs) associated
with celecoxib and rofecoxib, two COX-2-specific
inhibitors. The primary objective was to see if the
differences in ADRs found in the literature would be
corroborated in real-life practice. This was evaluated
by analysis of a worldwide ADR reporting system
maintained by the World Health Organization/
Uppsala Monitoring Center (WHO/UMC). An algo-
rithm was developed by the WHO/UMC in hopes of
detecting early patterns in reported data and exam-
ines the variation of these patterns over time. The
predefined end points monitored by these algorithms
included water retention, abnormal renal function,
acute renal failure, nephritis, cardiac failure, and
hypertension. Two thousand seven hundred and
twenty ADRs for rofecoxib and 8434 ADRs for cel-
ecoxib were evaluated over the course of 11 months
for celecoxib and 7 months for rofecoxib based on
their approval dates by the US Food and Drug
Administration. The rate of adverse events exceeded
the expectations for both celecoxib and rofecoxib, but
rofecoxibs rates of ADRs far exceeded those of cel-
ecoxib. The majority of these ADRs were related to
the renal system providing credence to the theories
of hypertension induced by these drugs. Patients
taking rofecoxib were more likely to retain water,
3.4 times more likely to experience abnormal renal
function, and 5 times more likely to have an episode
of cardiac failure when compared to celecoxib
patients. Overall, rofecoxib experienced ADRs at a
rate significantly greater than celecoxib in five out of
six renal-related classifications. The severity of the
ADRs reported with rofecoxib was also greater than
celecoxib with fatal renal failure and fatal cardiac
failure (2.8 and 4.4 times higher, respectively.) To
put these findings into perspective, the authors com-
pleted a similar analysis of ibuprofen and diclofenac
(both nsNSAIDs). The ibuprofen and diclofenac
findings were then compared to those of rofecoxib
and celecoxib. Celecoxib was found to have a similar
NSAIDs and Cardiovascular Toxicity 327
safety profile to ibuprofen and diclofenac, whereas
rofecoxib was found to exhibit greater risks of renal
(and therefore cardiac) toxicity than the nsNSAIDs
and celecoxib. The authors concluded that their
results were appropriate based on other data pre-
viously collected on these two COX-2 inhibitors.
Since the introduction of the newer COX-2-
specific inhibitors (coxibs) to the market, postmarket-
ing surveillance of cardiovascular events has
intensified. The ability of nsNSAIDs to increase
blood pressure is well documented in the literature,
but it is unknown how the coxibs compare to their
older relatives. Safety data from existing coxib trials
have discussed the incidence of hypertension, but
none have been powered to detect a true incidence
among their study participants. In a meta-analysis of
COX-2 inhibitors and their effects on blood pressure,
Aw et al. (2005) attempted to address this question.
Fifteen trials published before 2004 that reported
blood pressure data, continued for greater than 4
weeks, included more than 50 patients, and were pub-
lished in the English language were included. A
clinically relevant increase in blood pressure was
determined to be an increase of 20 mmHg systolic
(or an absolute value > 140 mmHg) or 15 mmHg dia-
stolic (or an absolute value > 90 mmHg). In the trials
comparing coxibs to the nsNSAIDs, the relative risk
(RR) of developing hypertension was no greater in the
coxib groups than in the nsNSAID groups. But, in
trials comparing rofecoxib to celecoxib, the RR of
developing a clinically important increase in systolic
blood pressure was 1.5 (95% CI, 1.02.26). Upon
further assessment, it was determined that patients
taking rofecoxib were statistically more likely to
develop hypertension when compared to placebo
and celecoxib (OR 2.63, 95% CI 1.424.85 and OR
1.78, 95% CI 1.172.69, respectively). It was also noted
that there was a disproportionate increase in systolic
blood pressure compared to diastolic blood pressure.
This was of special concern to the authors as there is a
known relationship between increased systolic blood
pressure and cardiovascular risk as defined by the
Framingham data (Kannel 2000).
When evaluating the contributions of rofecoxib
and celecoxib data to the pool, it was postulated
that the differences seen between these two drugs
may be related to their specific pharmacokinetic
and pharmacodynamic properties. Rofecoxib is
metabolized by cytosol reductase and can competi-
tively (especially at higher doses) inhibit the
metabolism of aldosterone. This would potentially
increase the action of aldosterone in vivo, increasing
328 Mechanisms of Drug-Induced Cardiovascular Toxicity
sodium and water resorption in the collecting duct,
and exacerbate cardiac remodeling (Liew and Krum
2002). It has also been noted that celecoxib may
inhibit carbonic anhydrase in the proximal convo-
luted tubule resulting in a diuretic effect similar to
that of acetazolamide (FitzGerald and Patrono 2001).
This could potentially offset the negative effect on
natriuresis caused by COX inhibition. These two
distinctions in pharmacology could also lend to the
noticeable differences in the ADR profiles between
celecoxib and rofecoxib. It could be postulated that
the possible diuretic-like action of celecoxib could
lend toward its favorable clinical profile compared to
rofecoxib, but the degree of clinical relevancy is still
unknown.
6.18.3.1.1 Drugdrug interactions
in hypertension
Given the mechanism of action of COX inhibitors
and their use in vitro to study the roles of various PGs
(especially those with actions similar to medications
used to treat cardiovascular diseases), it is reasonable
to assume that NSAIDs would likely inhibit certain
antihypertensive medications. Research has focused
on drugs such as thiazide and loop diuretics, beta-
adrenergic receptor blockers, angiotensin-converting
enzyme inhibitors (ACEIs), and angiotensin receptor
blockers (ARBs). All of these drugs involve actions
upon the kidney and could therefore be greatly
affected by alterations in PG actions.
Watkins et al. (1980) published their data assessing
the hypotensive effect of thiazide diuretics and
propranolol with concomitant indomethacin adminis-
tration. Patients were stabilized on either propranolol
or a combination of amiloride and hydrochlorothiazide
in this crossover study. Indomethacin (50 mg adminis-
tered twice daily) was initiated in both groups, and
patients were monitored for changes in weight, supine
and erect blood pressure, and PGF2-M urinary excre-
tion. (PGF2-M is the major urinary excreted
metabolite of PGF2 and is more easily quantified
than its parent compound.) One of the original 15
patients was forced to withdraw from the study sec-
ondary to an acute GI bleed; therefore, only 14 patients
completed the study. During the 2 weeks of indo-
methacin administration in both groups, patients
experienced a statistically significant increase in body
weight of 1 kg that was reversed upon cessation of
indomethacin. There was a significant increase in the
mean supine blood pressure in both groups (13/
9 mmHg in the thiazide group and 14/5 mmHg in
the propranolol group) that returned to baseline
when indomethacin was discontinued. Twenty-four
hour excretion of PGF2-M fell 67% in the proprano-
lol group and 57% in the thiazide-treated group while
taking indomethacin indicating an inhibition of PG
synthesis. No significant changes were found in crea-
tinine clearance, urinary sodium excretion, or plasma
electrolyte concentrations during the study. The
authors hypothesized that the actions of both antihy-
pertensive medications may be partially dependent on
vasodilatory PG synthesis (such as PGI2) to exert their
full effect. Alternatively, it was also thought that the
antihypertensive effects of these medications could
have been blunted by the sodium and water retention
that occurred with indomethacin administration. The
authors did not control dietary sodium intake during
the study period, but the increase in blood pressure was
consistent with the weight gain in both groups. Overall,
the authors hypothesized that the administration of
propranolol or thiazide diuretics likely induced the
production of PG in the kidney adding to their inher-
ent antihypertensive effects. These findings seemed to
correlate with the findings of Durao et al. (1977) who
proposed that chronic beta-adrenergic receptor block-
ade may induce vasodilatory PG synthesis since
indomethacin could attenuate the actions of proprano-
lol in humans. The question of whether thiazides
induce PG synthesis continues to be debated and is
yet to be fully understood.
To evaluate the possibility of NSAIDthiazide
interactions, a triple crossover study of hydrochloro-
thiazide, indomethacin, naproxen, and sulindac was
completed in 10 patients with essential hypertension
(Koopmans et al. 1984). No changes in blood pres-
sures were seen with sulindac or naproxen at 2 or 4
weeks, but after 2 weeks of indomethacin adminis-
tration, a statistically significant increase in supine
blood pressure of 6/3 mmHg was found, and the
readings subsequently decreased to pretreatment
levels at week 4 of indomethacin treatment. There
was also a significant increase in weight with indo-
methacin (at both 2 and 4 week assessments) that was
not seen with sulindac or naproxen when compared
to baseline. Based on this information, the authors
concluded that concomitant administration of the
three different nsNSAIDs with hydrochlorothiazide
did not attenuate the antihypertensive effect of the
diuretic. This sentiment of clinical insignificance was
echoed by the same authors in a later study
(Koopmans et al. 1986) with more patients designed
with 98% power to confirm their earlier findings.
As cardiovascular trials progressed and the use of
aspirin (a noncompetitive inhibitor of COX-1) was

advocated in the secondary prevention of myocardial
infarction and ischemic stroke, the concern grew that
aspirin could potentially inhibit the efforts of ACEIs
in vivo. ACEIs suppress the conversion of angiotensin
1 (AT1) to AT2, thereby reducing the potent vaso-
constrictive activities of AT2. During this process,
the levels of BK (a potent vasodilator) are increased.
BK has been found to stimulate the release of PGE in
several tissues, possibly providing a synergistic effect
to lower systemic blood pressure through increased
vasodilation.
To evaluate the effects of PG inhibition on the
actions of ACEIs, Moore et al. studied the effects of
high-dose aspirin and indomethacin on the plasma
PG concentrations in 31 sodium-restricted patients
with essential hypertension. Eighteen of the 31
patients were administered a single dose of
captopril with either aspirin or indomethacin at
anti-inflammatory treatment doses to be compared
to individuals receiving captopril alone. Serial blood
samples were taken from all patients to assess plasma
renin activity and levels of AT2, BK, and the meta-
bolites of PGE2 (PGE-M), TxA2, and PGI2. Serial
supine blood pressure measurements were taken at
each blood draw. The patients received a total of five
doses of aspirin or indomethacin every 6 h, and at
48 h after the first captopril administration, the entire
process was repeated. After the captopril initiation,
blood pressure and AT2 levels decreased, and BK
levels and PGE-M increased as expected. In the 10
patients that received indomethacin, the blood pres-
sure response to captopril was reduced from 23 to
10 mmHg (a decrease of over 40%), and the PGE-
M increased after captopril administration was com-
pletely diminished, but there was no significant
change in AT2 or BK levels. The aspirin-treated
patients exhibited no significant changes in blood
pressure but did exhibit a mean increase in PGE-M
that was statistically significant when compared to
the PGE-M decrease in the indomethacin group.
The authors suggest that PGE2 must mediate some
portion of captoprils hypotensive effect and that PG
inhibition by indomethacin further blunts the blood
pressure response. The findings regarding aspirin use
in this study contradict those found in other studies
and could perhaps have to do with the longevity of
the study time frame. In a prospective cohort study of
aspirin in combination with enalapril, it was deter-
mined that low aspirin doses (100 mg daily for 5 days)
had no effect on the hypotensive properties of ena-
lapril, but at doses of 300 mg per day for 5 days,
over 50% of the patients experienced a significant
NSAIDs and Cardiovascular Toxicity 329
inhibition of the ACEI hypotensive effects. The
extent of inhibition was greater in those patients
classified as having severe hypertension by the inves-
tigators compared to those with mild to moderate
hypertension. The authors concluded that low-dose
aspirin therapy had no effect on blood pressure
where higher-dosed aspirin could interfere with the
antihypertensive effects of enalapril. These findings,
although interesting, have little bearing on most car-
diovascular patients as the benefit of COX-1
inhibition of platelet aggregation is found to out-
weigh the risk of ACEI or beta-blocker interactions
given the fact that most patients are on combination
therapies with multiple antihypertensive medica-
tions. However, this controversy is still highly
debated among clinicians.
Clinical correlation of these results would be
required for true determination as to the significance
of these findings. One way to do this is to assess blood
pressure control in patients over a longer period of
time than an inpatient admission for study purposes.
Conlin et al. (2000) assessed the effects of indometha-
cin in patients receiving captopril or losartan (an
ARB) on ambulatory and clinic blood pressure mea-
surements. Since ARBs do not increase BK levels the
way that ACEIs do (thereby there would be little
increase in PGE2 concentrations with ARB treatment
compared to ACEI), it was hypothesized that any
reduction in losartan efficacy would be minimal
compared to that of captopril in the presence of
indomethacin. Patients were randomized to 6 weeks
of double-blind treatment with captopril or losartan.
At the end of these 6 weeks, patients underwent 24 h
of ambulatory blood pressure monitoring and clinic
blood pressure levels were also obtained on two of
the monitored days. Sustained-release indomethacin
(75 mg daily) was then administered for one addi-
tional week with captopril or losartan. Patients
returned for an additional 24 h of ambulatory mea-
surements and clinic measurements. The addition of
indomethacin resulted in a statistically significant
increase in the 24-h mean systolic and diastolic
blood pressures in both treatment groups (losartan:
3.8 mmHg systolic, 2.2 mmHg diastolic and captopril:
4.6 mmHg systolic and 2.7 mmHg diastolic; all mea-
surements with p < 0.001). When further evaluated, it
was found that daytime blood pressures were affected
in both treatment arms by indomethacin, but
nighttime and clinic blood pressures were only sig-
nificantly affected in the captopril arm. The increases
in blood pressure seen were small (35 mmHg sys-
tolic and 23 mmHg diastolic) but represented a 40%
330 Mechanisms of Drug-Induced Cardiovascular Toxicity
loss in their antihypertensive effect. This study
showed that indomethacin blunted the antihyperten-
sive effects of captopril when measured for 24 h
continuously as well as standard clinic measure-
ments. The reductions in losartan efficacy seen with
indomethacin in the 24-h continuous measurements
were largely driven by the attenuation of daytime
blood pressure lowering. The authors felt that this
study agreed with previous data regarding ACEI and
indomethacin and stated that indomethacin attenu-
ated the hypotensive effects of captopril and losartan.
With the emergence of the COX-2-specific inhi-
bitors, it was unknown if drugs such as celecoxib
could also attenuate the effectiveness of ACEI. In a
study of celecoxibs effects on lisinopril, 178 patients
with uncomplicated hypertension and controlled on
lisinopril were randomly assigned to celecoxib or
matching placebo. Upon review of the 24-h ambula-
tory blood pressure monitoring, celecoxib induced a
small increase in average systolic (2.6 mmHg) and
diastolic (1.5 mmHg) blood pressures that were not
significant when compared to the modest changes in
the placebo group (1.0 mmHg systolic and 0.3 mmHg
diastolic). The increases in the celecoxib-treated arm
were more likely to occur 4 h after the a.m. and p.m.
doses but then appeared to trend downward prior to
the next dose. As a measure of safety, body weight
was compared from baseline and during treatment.
The average change in the placebo arm was 0.06
 0.47 kg and 0.16  0.37 kg in the celecoxib group.
Only one patient (1%) in the celecoxib group devel-
oped edema where there were no reported cases in
the placebo group, and no patient in either group
developed a blood urea nitrogen level above the
upper limits of normal. The authors felt that they
had shown that celecoxib at doses approved for the
treatment of osteoarthritis (also the maximal recom-
mended dose) was not associated with increases in
body weight, edema, changes in renal function, or
inhibition of lisinoprils antihypertensive effects.
In conclusion, results from published studies have
determined that NSAIDs have the ability to increase
blood pressure secondary to PG synthesis inhibition
and alterations in the RAAS. Decreased production
of the endogenous natriuretic PGs, PGE2, and
PGF2 affect the delicate balance of sodium and
water in the body. While otherwise healthy patients
could perhaps compensate for these alterations in
homeostasis, patients with conditions that predispose
them to fluid balance problems (i.e., CHF, chronic
renal insufficiency, preexisting hypertension, and
advanced age) could be more likely to experience
increases in blood pressure and associated cardiovas-
cular events.
6.18.3.2 Congestive Heart Failure
CHF is defined as a condition of decreased cardiac
output. Over 5 million adults carry a diagnosis of
heart failure and over 550 000 new cases are diag-
nosed each year (Hunt et al. 2005). CHF is largely a
condition of the elderly and can present as shortness
of breath, extremity and pulmonary edema, acute
renal failure, chest pain, and dysrhythmias. There
are two main etiologies of heart failure: ischemic
and nonischemic with over 70% of all cases being
ischemic in nature.
Neurohormonal regulation in CHF is complicated
and intimately associated with renal homeostasis and
overall renal function. Control of this disease process
requires a delicate balance of peripheral vascular resis-
tance, fluid status and natriuresis, and prevention of
cardiac tissue remodeling. To decrease morbidity and
mortality of heart failure, it is essential to regulate the
effects of renin, angiotensin, norepinephrine, and
aldosterone on the myocardium. These endogenous
substances are most often associated with the kidney,
but have also been shown to exist in the myocardium
of monkeys and rats. Studies have shown that these
extrarenal RAAS can function independently from the
systemic vasculature and the systemic renin levels
(Lindpainter et al. 1989).
Based on the pathophysiology of the disease, the
medications required to decrease morbidity and mor-
tality are obvious. These drug classes include ACEI
(or angiotensin receptor blockers) to decrease the
impact of AT2, beta-adrenergic blockers to decrease
the effect of norepinephrine on the failing heart, and
aldosterone antagonists to decrease the harmful
remodeling effects attributed to increased aldoster-
one levels. To improve morbidity, tight control of
the sodium and water balance in the kidney is
imperative.
As discussed in the previous section, COX-2 has
been found to be a highly inducible enzyme resulting
in the production of PG that works to regulate all of
the above functions and assists the medications given
to decrease morbidity and mortality in this ulti-
mately fatal disease. Therefore, inhibition of COX-
2 (whether selectively or nonselectively) could easily
tip the balance in an unfavorable direction for CHF
patients based on the actions of PG in the kidney.
To further illustrate the complexities of COX in
the myocardial tissues, there is concern that some

aspects of PG synthesis could be detrimental in the
failing heart. The COX-2 isoenzyme can be induced
by hypoxia, a condition often attributed to heart
failure either by the ischemic nature of the disease
or because of a reduced cardiac output that is unable
to meet the oxygen demands of the myocardium, or
both. In a hypoxic state, COX-2 is induced by
nuclear factor-kappa B (NF-kappa B) in endothelial
cells (Schmedtje et al. 1997; Wong et al. 1998). Since
COX-2 is known to be induced by inflammation, it is
logical that the enzyme can be induced by inflamma-
tory cytokines such as tumor necrosis factor-alpha
produced in heart failure (Torre-Amione et al. 1996).
Upon further study, it was found that COX-2 was
expressed more readily in infarcted myocardial cells
and less in the noninfarcted cells of hearts that were
failing secondary to ischemic heart disease (Wong
et al. 1998). Along this same line, the COX-2 enzyme
is weakly expressed in cells of a dilated cardiomyo-
pathy, cells in which there is frequently extensive
myocardial fibrosis. When put together, this data
suggests that ischemia and inflammatory mediators
could be responsible for COX-2 induction in the
failing myocardium, and the resulting PG formation
could lead to further damage in already damaged
cells. This concept still requires further study as the
exact mechanism, and time line of damage remains
unclear; but at this time it is thought that the pre-
sence of COX-2 is associated with myocardial tissue
scarring that leads to worsening heart failure.
ACEIs are considered part of the backbone of
therapy for CHF to reduce the actions of AT2. As
in previously discussed studies, it was determined
that PGE2 and BK assist the actions of these medica-
tions, and inhibition of PGE2 with nsNSAIDs could
diminish the vasodilatory effect of ACEI in the kid-
ney resulting in a decreased natriuresis (Townend
et al. 1995). Based on the large number of studies that
have reproduced similar findings, it is apparent that
COX-1 and COX-2 inhibition can affect the actions
of these very important medications and should be
used cautiously in this population.
Fluid status is an imperative component to CHF
management. The roles of PGE2 and PGI2 have been
well defined in this process. In otherwise healthy
individuals, inhibition of endogenous PG synthesis
would not greatly affect renal function (especially
with short-term therapy), but in those with under-
lying renal dysfunction due to advancing age,
pathology, or reduced cardiac output, this could be
radically different. Healthy individuals have other
compensatory mechanisms including the ability to
NSAIDs and Cardiovascular Toxicity 331
increase the adrenergic tone, renin secretion, and
the use of dopamine in the body to compensate
(Dunn 1983). Patients with CHF and chronic renal
insufficiency (both often found in elderly patients)
would be more likely to become PG dependent as
their other compensatory mechanisms are already
maximized. Therefore, inhibition of these important
PGs could greatly affect the ability of the kidney to
regulate sodium and water retention. Given that the
natural actions of PGE2 and PGF2 in the ascending
loop of Henle and collecting duct are to decrease
sodium reabsorption by inhibition of chloride trans-
port (a mechanism analogous to the action of loop
diuretics), inhibition of these PGs would be analo-
gous to removing loop diuretics from the CHF
patients medication regimen. Inhibition of PGI2
would decrease GFR and further reduce the effec-
tiveness of the nephron in regulating the sodium and
water status. These actions together would result in
fluid accumulation in the periphery (characterized as
peripheral edema in the CHF patient) and in the
lungs (contributing to the shortness of breath often
experienced by these patients, increasing pulmonary
pressures, and an increased workload on an already
failing heart ultimately resulting in worsening car-
diac output and decreased renal perfusion). PGE2
and PGI2 levels increase in response to elevated
norepinephrine and AT2 levels. Both of these neuro-
hormones are consistently upregulated in CHF
patients as they tend to exist in a state of high adre-
nergic tone, hence leading back to the notion that
CHF patients are PG dependent to maintain their
fluid status. Because of this vicious circle of events,
the use of NSAIDs in CHF is relatively contraindi-
cated in the guidelines for chronic heart failure
management (Hunt et al. 2005).
When the incidence of NSAID-associated CHF
was examined in the Rotterdam Study (Feenstra et al.
2002), it was found that NSAID use was associated
with relapses of CHF but not a primary incident of
CHF. The use of NSAIDs in elderly patients with
heart failure was also associated with an increased
risk of hospitalization for heart failure (Heerdink et al.
1998). These data did not delineate the difference
between nsNSAID and COX-2 selective inhibitor
use. Based on the dates of the studies, it is very likely
that the majority of the patients were on the tradi-
tional nsNSAIDs.
COX-2 selective inhibitors have not fared well in
studies of patients with CHF either. A retrospective
cohort study divided otherwise well-matched elderly
patients into three treatment groups (rofecoxib,
332 Mechanisms of Drug-Induced Cardiovascular Toxicity
celecoxib, and nsNSAIDs) and followed them for-
ward in time to assess admission rates for heart
failure. Each of these study arms was compared to
non-NSAID users in the same population. The pre-
valence of heart failure was consistent among the
groups at baseline as was the use of other cardiovas-
cular-related medications. In patients with a history
of CHF admissions within the last 3 years, those
taking rofecoxib and nsNSAIDs were at a signifi-
cantly higher risk of readmission when compared to
celecoxib (Mamdani et al. 2004). These data are con-
sistent with those reported from other retrospective
studies designed to assess these associations (Hudson
et al. 2005), and large prospective studies of coxibs
will be discussed later in this chapter.
In summary, the toxicities of NSAIDs in this
population are well documented but the delineation
of which toxicity is worse; drug-induced hyperten-
sion, drugdrug interactions with clinically proven
treatment regimens, or drug-induced sodium and
fluid imbalances may vary among patients depending
on a number of variables, including disease severity,
genetics, and compliance with treatment regimens.
With the complexities of heart failure, pathophysiol-
ogy with regard to the role of endogenous PG
synthesis, defining a single true and absolute toxicity
of this drug class, would be nearly impossible. The
clinical controversy of NSAID use in these patients is
difficult but the accumulating data suggest that
NSAID use can be associated with an increased risk
of heart failure exacerbation, especially in those with
a previous diagnosis of heart failure. Based on those
data, these drugs should be used sparingly in CHF
patients, and, when deemed necessary, the patients
should be closely monitored for signs and symptoms
of toxicity.
6.18.3.3 Acute Myocardial Infarction
Aspirin, in daily doses ranging from 81 to 325 mg is
currently indicated for secondary prevention of
thrombosis status post acute myocardial infarction
(AMI), cerebrovascular accident (CVA), atrial fibril-
lation (in low to moderate risk patients), and
peripheral vascular disease, and is also indicated for
primary prophylaxis in diabetes mellitus. The proven
benefits of COX-1 inhibition resulting in decreased
TxA2 activity and the resulting inhibition of platelet
aggregation has changed clinical practice over the
last three decades where most patients are now on a
daily aspirin.
Concern, as of late, has turned toward the per-
ceived increased risk of cardiovascular events in
patients taking the selective COX-2 inhibitors. In
recent years, two selective COX-2 inhibitors (rofe-
coxib and valdecoxib) have been withdrawn from the
market after an increased risk of thromboembolism
was found in clinical trials.
The only selective COX-2 inhibitor still available
on the US market, celecoxib, was found to have no
effect on platelet aggregation ex vivo when compared
to the nsNSAID, ibuprofen, despite minor but
detectable inhibition of the COX-1 isoenzyme
(McAdam et al. 1999). Despite its platelet-sparing
action in this study, celecoxib was found to suppress
the secretion of metabolites of PGI2 after a single
dose. This would possibly suggest a role of COX-2 in
the synthesis of PGI2. The lack of platelet activity in
this study was attributed to the very minor inhibition
of plasma TxA2 as evidenced by minimal suppression
of thromboxane B2 (TxB2; the urinary metabolite of
TxA2). Based on this information, it can be deduced
that celecoxib has relatively little effect on platelet
aggregation.
The CLASS trial (Silverstein et al. 2000) was a
double-blind trial conducted in 8059 patients rando-
mized to receive celecoxib or nsNSAID (ibuprofen
or diclofenac) therapy. The primary end point of the
trial was the incidence of upper GI ulcers or ulcer
complications in patients with osteo- or rheumatoid
arthritis. Patients requiring the use of aspirin due to
cardiovascular comorbidities were included, and all
adverse effects were stratified by the use of aspirin in
the final comparisons. After the predefined 6 months
of treatment, it was determined that the rate of car-
diovascular events (defined as CVA, AMI, and
angina) was not statistically different in the celecoxib
versus NSAID arms (0.9 vs 1.0%). No differences in
cardiovascular events were found between the treat-
ment arms when stratified for aspirin use. The two
NSAIDs used in this study have low platelet aggre-
gation inhibitory effects (ibuprofen 80% and
diclofenac 40%) (FDA Advisory Committee 2001)
and would not be as effective as aspirin with docu-
mented 92% platelet aggregation inhibition in terms
of cardioprotection from thrombotic events; there-
fore, the choice to permit low-dose aspirin therapy in
the trial was a sound decision, and the use of aspirin
was well matched at baseline between the groups.
In the VIGOR study (Bombardier et al. 2000),
8076 patients were randomly assigned to a daily
dose of 50 mg rofecoxib or 1000 mg naproxen in
two divided doses. Safety end points were largely

those relating to GI tolerability, but rates of mortality
and ischemic events were briefly mentioned in the
final publication. The rate of discontinuance of study
drug due to ADRs was 0.2%, but the rate of myocar-
dial infarction was significantly lower in the
naproxen group (0.1%) when compared to the rofe-
coxib group (0.4%) (number needed to harm 333).
Patients on chronic aspirin therapy were excluded
from the trial as were those with a previous cardio-
vascular or cerebrovascular event. This difference in
myocardial infarction was rationalized by the authors
based on the thought that naproxen inherently inhib-
ited platelet aggregation (an effect similar to aspirin);
therefore, patients taking regular naproxen might
have been afforded the same benefits as those who
routinely take aspirin. The antiplatelet action of
naproxen has been demonstrated previously and
found to be similar to that of aspirin (mean platelet
aggregation inhibition of naproxen 93% compared to
low-dose aspirin at 92%) (FDA Advisory Committee
2001). Based on the findings of this trial, the manu-
facturers of rofecoxib then amended other study
protocols to include aspirin at doses less than
100 mg per day for cardioprotection to alleviate this
question as a possible confounder in future research.
The risk of myocardial infarction in the CLASS
and VIGOR trials was compared to that of a meta-
analysis of 48 540 patients (Mukherjee et al. 2001). In
this meta-analysis, 25 133 patients were treated with
aspirin and 23 407 were given placebo. The annual
rate of myocardial infarction in the placebo group of
the meta-analysis was 0.52% (Sanmuganathan et al.
2001). The annual rate of myocardial infarction in
the VIGOR trial was 0.74 and 0.80% in the CLASS
trial. Both of these figures were statistically signifi-
cant when compared to the placebo group in the
meta-analysis (p 0.04 and p 0.02, respectively).
The authors of the meta-analysis argued that the
rates of myocardial infarction in both trials were
possibly greater than the general population with
rofecoxib possibly having worse effects than
celecoxib.
In March 2005, the results of the APPROVe trial
evaluating the safety and efficacy of rofecoxib versus
placebo and the risk of recurrent neoplastic polyps in
patients with a history of colorectal cancer were
published (Bresalier et al. 2005). Based on the hazard
ratios of 2.8 (95% CI 1.445.45) for thrombotic car-
diac events (including AMI, fatal myocardial
infarction, sudden death from cardiovascular causes,
and unstable angina) and 2.32 (95% CI 0.896.74) for
cerebrovascular events (including ischemic stroke,
NSAIDs and Cardiovascular Toxicity 333
fatal ischemic stroke, and transient ischemic attack),
the drug company decided to withdraw rofecoxib
from the market voluntarily.
With the release of the VIGOR and APPROVe
data, the safety board of the Adenoma Prevention
with Celecoxib (APC) trial decided that they should
evaluate their presently collected data and evaluate
the risk for cardiovascular events. This was a rando-
mized controlled trial of celecoxib 400 mg daily,
800 mg daily, and placebo in the prevention of ade-
nomatous polyps. The study was stopped early when
it was determined that patients in the treatment arms
of the study were 23 times more likely to experience
the composite end point of death from cardiovascular
causes, myocardial infarction, stroke, or heart failure.
The results of the various components of the compo-
site end point were consistent with the primary end
point. The use of aspirin was consistent among the
three treatment arms at 29.331.4% and higher than
the aspirin use in the CLASS trial.
The reason for the thrombotic events seen in
these trials with selective COX-2 inhibitors remains
unclear. Besides the possible increases in blood pres-
sure discussed previously in this chapter, it is also
thought that an imbalance of COX-2 and COX-1
inhibition could lend toward unopposed thrombosis
formation. Platelet aggregation is largely driven by
the COX-1-mediated actions of TxA2 in the platelets
themselves. PGI2 activity was originally thought to
be mediated by COX-1 activity in the vascular
endothelium, but studies in mice and humans proved
this incorrect and showed that COX-2 was the more
predominant source (FitzGerald 2004). If PGI2 is
inhibited and vasodilation is therefore inhibited, the
increasing shear stress within the vessel could
increase the risk of thrombotic events. This reduction
of COX-2-derived PGI2 could then increase blood
pressure, accelerate atherogenesis due to increased
laminar sheer stress, and expose patients to the rup-
ture of an atherosclerotic plaque. In patients already
at risk for such an event (i.e., previous myocardial
infarction, stroke, transient ischemic attack, or
cancer), this drug-induced pathology could be
increasingly deleterious.
These studies were all looking at durations of ther-
apy that ranged from months to years. Retrospective
reviews of elderly patients receiving NSAID therapy
(COX-1 or COX-2 inhibitors) report conflicting results.
In one study, elderly patients prescribed short-term
selective COX-2 inhibitors or naproxen experienced
no increased risk of acute myocardial infarction when
compared to a control group (Mamdani et al. 2003).
334 Mechanisms of Drug-Induced Cardiovascular Toxicity
In contrast, a retrospective review of patients pre-
scribed coxibs or nsNSAIDs showed a 2455%
increase in the risk of myocardial infarction even after
adjusting for potential confounders including comor-
bidities. The numbers needed to harm for diclofenac,
rofecoxib, and ibuprofen in patients aged greater than
65 years who had been prescribed these drugs within 3
months prior to their index event were 521, 695, and
1005, respectively. These numbers were considerably
lower when compared to patients between the ages of
25 and 65 (1066, 1833, and 2444, respectively) empha-
sizing the fact that greater caution is warranted in
elderly patients.
In conclusion, the exact mechanism of increased
thrombotic events and selective COX-2 inhibition is
still unclear but has resulted in the removal of two
drugs, rofecoxib and valdecoxib, from the US market.
Elderly patients receiving nsNSAIDs or coxibs may
be at higher risk of acute myocardial infarction with
even short-term exposure to these medications, and
it is still unclear if the antiplatelet effects of aspirin
could prevent further events in these patients due to
its relatively low use in the reported trials.
6.18.4 Conclusion
The mechanisms in which drugs in this class (both
selective and nonselective) induced toxicities are
complex and reach over multiple organ systems.
The patients who are most likely to receive
NSAIDs and coxibs are those who are also the most
likely to suffer cardiovascular toxicities based on
comorbidities. CHF, hypertension, chronic renal
insufficiency, and coronary disease are all diseases
of the elderly population as are osteo- or rheumatoid
arthritis and chronic pain. Given the over-the-
counter status of many medications in this class, the
true clinical impact of these toxicities is difficult to
calculate. But overall, the risk of cardiovascular end
points has not been specifically assessed in prospec-
tive, randomized trials of these medications they
are usually assessed as secondary end points, which
are not powered to detect a true effect. The like-
lihood of industry-sponsored trials assessing the
cardiovascular safety (specifically) is relatively low
given the large amount of speculative data already
published. The population data presented in this
chapter is largely retrospective in nature that cannot
be used to assess a causal relationship. These data do
appear to have sound scientific basis in the pharma-
cology and biological research done in animals and
humans. The interactions between the cardiovascular
system and the renal homeostasis are clear, and based
on research in each of these disease states presented,
a theoretical line can be drawn between the normal
human physiology, the pathology of the disease
states, and the associated medications and their
toxicities.
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