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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 Hypertension 325 Drugdrug interactions in hypertension 328 Congestive Heart Failure 330 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

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

324 Mechanisms of Drug-Induced Cardiovascular Toxicity

NSAID. This would be one with limited gastrointest- Arachidonic acid

inal (GI) effects, minimal drugdrug interactions,
and limited effect on other organ systems. Owing to
the complex nature of these medications and the COX-1 COX-2
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. PGG2

6.18.2 NSAID Mechanism of Action COX-1 COX-2

NSAIDs are classified by the enzymes they inhibit.

To date, there are two recognized enzymes respon- PGH2
sible for the conversion of arachidonic acid (AA) to
the eicosanoids responsible for the inflammatory cas- PGD2, PGE2, PGF2, PGI2
cade and maintenance of cardiovascular homeostasis:
cyclooxygenases 1 and 2 (COX-1 and COX-2). Figure 1 The isoenzymes COX-1 and COX-2 are 60%
These eicosanoids are generally produced within homologous and responsible for the formation of PGG2 and
PGH2 from arachidonic acid. PGG2 and PGH2 are precursors
the tissue they act upon and are thereby termed as
to many various prostaglandins controlling vasodilation and
autocrine in nature. Based on this fact, it is evident vasoconstriction in various body tissues and TxA2, which is
that COX-1 and COX-2 are found in various tissues responsible for vasoconstriction and platelet aggregation.
in the body and are specific to the needs of those COX-1, cyclooxygenase 1; COX-2, cyclooxygenase 2; PGD2,
tissues. prostaglandin D2; PGE2, prostaglandin E2; PGF2 ,
COX-1 is a constitutive enzyme and is responsible prostaglandin F2 ; PGG2, prostaglandin
G2; PGH2, prostaglandin H2; PGI2, prostaglandin I2 also
for basic physiologic processes including protection known as prostacyclin; TxA2, thromboxane A2.
of the GI tract from endogenous stomach acids, renal
perfusion, vasoconstriction, and platelet aggregation.
Based on these actions, the COX-1 enzyme is present
course of platelet degranulation, TxA2 recruits addi-
in the stomach, intestines, kidneys, blood vessels, and
tional platelets to the site of vascular damage and
platelets. The COX-2 isoenzyme has an amino acid
then induces localized vasoconstriction through
sequence that is 60% homologous to COX-1
(Catella-Lawson et al. 1999). This enzyme has been decreased formation of cyclic adenosine monopho-
termed inducible as it is readily found in response to sphate (cAMP). PGI2 is primarily synthesized by the
inflammatory mediators, tumor promoters, and vascular endothelium and works in opposition to
growth factors (Hla and Neilson 1992; Jones et al. TxA2. This endogenous chemical induces vasodila-
1993; Smith et al. 1996) and is expressed by vascular tion by increased production of cAMP and decreases
endothelium, macrophages, leukocytes, and fibro- platelet aggregation by inhibition of vessel adhesion
blasts. Products of these two enzymes include factors.
prostaglandin G2 (PGG2) and prostaglandin H2 The chemical structures for the various NSAIDs
(PGH2), both of which are precursors for a number vary, but all are classified based on their selectivity
of other prostaglandins (PGs) and thromboxanes for either COX-1 or COX-2. Those that are more
including prostaglandin E2 (PGE2), prostaglandin selective for COX-2 are generally thought to exhibit
F2 (PGF2 ), thromboxane A2 (TxA2), and prosta- fewer adverse drug effects than those with mixed
cyclin (PGI2) (Figure 1). COX-1 and COX-2 actions. As COX-1 is found
PGE2 is produced by many body tissues. In terms largely in the GI tract, side effects of COX-1 enzy-
of the cardiovascular system, PGE2 is responsible for matic inhibition include ulceration and bleeding.
peripheral vasodilation and angiogenesis, and has Fundamentally, nonselective NSAIDs inhibit both
been implicated in inflammatory processes (Harada COX-1 and COX-2 resulting in the decreased pro-
et al. 1998). PGF2 is a vasoactive eicosanoid found in duction of protective PGs in the GI system. Research
equilibrium with PGE2 resulting in further periph- into the two isoenzymes has driven the desire to
eral vasodilation. TxA2 is produced primarily by develop medications with higher COX-2 specificity
platelets and promotes platelet aggregation. In the 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
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- et al. 1990; Hypertension Detection and Follow-Up
ity of the various NSAIDs is described in Table 1. Program Cooperative Group 1984).
The role of PG vasculature functions has been
studied using the nonselective NSAID, indomethacin,
6.18.3 Cardiovascular Toxicities to inhibit PG synthesis. Blumberg et al. (1977) studied
the capacity of perfused mesenteric arterial vascular
Owing to the complex nature of the eicosanoid sys- beds to synthesize PGs. Strips of rat stomach and chick
tem and the numerous body systems affected by rectum were perfused with the mesenteric artery beds
these endogenous chemicals, toxicities of the drugs of anesthetized rabbits. Angiotensin 2 (AT2) was then
in this class are numerous. Next to GI effects, those of injected across the assay tissues where a considerable
the cardiovascular system are the most predominant muscular contraction was noted. The mesenteric efflu-
followed by those of the renal system. Documented ent was then assayed and was found to contain
cardiovascular adverse effects include hypertension, significant amounts of PGE in comparison to baseline.
heart failure exacerbations, myocardial infarction, The influence of AT2, bradykinin (BK), and AA on
and stroke. Although the exact mechanisms of these mesenteric vascular resistance was also studied. To do
effects are still somewhat unclear, there is an ever this, indomethacin was introduced into the interven-
growing body of research and evidence pointing tion group of tissues, and these results were then
toward a few key theories. compared to a control group (no indomethacin).
Infusion of indomethacin resulted in a significant
increase of perfusion pressures with AT2 when com- Hypertension
pared to the control group (up to 37  11 mmHg vs
Hypertension is a driving factor in most cardiovas- 21  4 mmHg). The responses of the same tissues
cular diseases. The ALLHAT study (ALLHAT to BK and AA were significantly blunted by
Collaborative Research Group 2000) showed that indomethacin compared to that of the control
sustained increases in systolic blood pressure result tissues (16  3 mmHg vs 37  7 mmHg and
in a 1020% increase in the risk of congestive heart 3  3 mmHg vs 42  4 mmHg, respectively). It
failure (CHF). Other large studies have shown that was expected that inhibition of PG synthesis by indo-
the risk of stroke increases 1520% and angina 12% methacin would enhance the vasopressor actions of
with even modestly elevated blood pressures (Collins AT2, and indeed, this is what happened. The changes
326 Mechanisms of Drug-Induced Cardiovascular Toxicity

in perfusion pressures were dose dependent with AT2 certainly increase systemic blood pressures, quite
(increased pressures), BK (decreased pressures), and possibly to clinical significance.
AA. Based on this information, the authors were able In a retrospective review of New Jersey Medicaid
to conclude that PGE is locally synthesized and patients receiving NSAID therapy, it was found that
involved in the vasodilation of the microcirculation. patients aged 65 years and older were more likely to
It was also apparent that indomethacin worked to have antihypertensive therapy initiated when com-
augment the vasoconstrictive actions of AT2 and inhib- pared to controls (Gurwitz et al. 1994). The primary
ited the vasodilatory actions of BK and AA through objective of this case-control study was to determine
reduced concentrations of PGE locally. It was also if the use of NSAIDs increased the risk for initiation
determined that BK and PGE worked synergistically of predefined antihypertensive medications in an
to promote a greater vasodilation in the presence of older patient population. A total of 9411 patient
AT2. This study illustrates one of the proposed records were reviewed from November 1981 to
mechanisms of NSAID-induced hypertension: inhibi- February 1990 and compared to a control group of
tion of vasodilatory PGE synthesis and increased 9629 patients. NSAID users were divided into three
peripheral vascular resistance. groups: former, recent, and current users depending
The second proposed mechanism of NSAID- on the record of NSAID prescriptions in relation to
induced hypertension is decreased natriuresis. the initiation of an antihypertensive medication.
Renal homeostasis (specifically fluid balance) is lar- Recent users (within 60 days) were two times more
gely regulated by localized PG synthesis in the renal likely to have been initiated on an antihypertensive
cortex and is intimately involved in both local medication (OR 2.01, 95% CI, 1.892.14). A dose
(within the kidney) and systemic blood pressure response relationship was also observed in this study
maintenance through the reninangiotensinaldos- with the odds of antihypertensive medication initia-
terone system (RAAS). Distal tubule reabsorption of tion increasing based on the observed daily dose of
sodium and water, antagonism of antidiuretic hor- the NSAID. The odds ratio for lower doses was 1.83,
mone, and redistribution of renal blood flow from medium doses 2.12, and high doses 2.39. All of these
cortical to juxtamedullary regions are all regulated ratios were statistically significant with a number
by PG and easily antagonized with NSAID adminis- needed to harm of 20 patients in the high-dose
tration (Clive and Stroff 1984; Oates et al. 1988). Side category. Clinically, this would mean that for every
effects of NSAID use in susceptible patients, such as 20 patients started on NSAID therapy, one patient
those with CHF, include edema and sodium reten- will require a new antihypertensive medication to be
tion resulting in increased systolic and diastolic added to their existing drug regimen. Given the
pressures. These effects will usually occur early in massive numbers of patients taking NSAIDs (either
treatment and are easily reversible with the cessation prescribed by a practitioner or self-care over-the-
of the offending agent. Most occurrences are minor counter use), the number of patients requiring addi-
(subclinical in nature) with a prevalence of sympto- tional antihypertensive therapy could be staggering.
matic edema occurring in 35% of reported cases The authors suggest that the results of their study
(Whelton and Hamilton 1991). may show that NSAIDs increase the risk of hyper-
PGE2 and PGF2 work to inhibit chloride trans- tension in an elderly population; however, the study
port in the ascending loop of Henle and in the design (retrospective review) prevents a conclusion
collecting duct, thereby decreasing sodium reabsorp- of an actual causal relationship.
tion (Stokes 1979; Stokes and Kokko 1977). This The preceding study did not differentiate
action in the loop of Henle is analogous to the between the different NSAIDs in terms of COX-1
mechanism of action of loop diuretics. PGE1 also versus COX-2 effects in their patient population.
works to antagonize the actions of vasopressin (anti- Wang et al. (2007) performed a retrospective cohort
diuretic hormone) resulting in a decreased water study evaluating the incidence of new onset hyper-
permeability and resorption in the collecting duct. tension patients taking celecoxib versus those taking
The actions of these PGs induce a large endogenous nonselective NSAIDs (nsNSAIDs). Patients with a
natriuresis that is further augmented by the action of previous diagnosis of hypertension or any NSAID
PGI2 in the glomerulus to maintain the glomerular use within 180 days of the index date were excluded.
filtration rate (GFR). Inhibition of these endogenous Celecoxib users were matched with nsNSAID users
natriuretics combined with the drug-induced in a 1:2 fashion for age, sex, number of unique drugs,
increase in peripheral vascular resistance could and a propensity score calculated to determine the
NSAIDs and Cardiovascular Toxicity 327

probability of celecoxib use (e.g., sex age, and prior safety profile to ibuprofen and diclofenac, whereas
GI events, GI harmful drug use, GI protective drug rofecoxib was found to exhibit greater risks of renal
use, comorbidities). After a multivariate analysis of (and therefore cardiac) toxicity than the nsNSAIDs
the 51 444 patients (17 148 were celecoxib users and and celecoxib. The authors concluded that their
34 296 were nsNSAID users) was performed, it was results were appropriate based on other data pre-
determined that celecoxib and nsNSAID users had viously collected on these two COX-2 inhibitors.
similar hazard ratios of being diagnosed with hyper- Since the introduction of the newer COX-2-
tension within a 1 year time frame (OR 1.025; 95% specific inhibitors (coxibs) to the market, postmarket-
CI 0.9311.128; p 0.613). These results were also ing surveillance of cardiovascular events has
controlled for aspirin use among these patients yield- intensified. The ability of nsNSAIDs to increase
ing no significant changes in the data. blood pressure is well documented in the literature,
Zhao et al. (2001) performed a retrospective but it is unknown how the coxibs compare to their
review of adverse drug reactions (ADRs) associated older relatives. Safety data from existing coxib trials
with celecoxib and rofecoxib, two COX-2-specific have discussed the incidence of hypertension, but
inhibitors. The primary objective was to see if the none have been powered to detect a true incidence
differences in ADRs found in the literature would be among their study participants. In a meta-analysis of
corroborated in real-life practice. This was evaluated COX-2 inhibitors and their effects on blood pressure,
by analysis of a worldwide ADR reporting system Aw et al. (2005) attempted to address this question.
maintained by the World Health Organization/ Fifteen trials published before 2004 that reported
Uppsala Monitoring Center (WHO/UMC). An algo- blood pressure data, continued for greater than 4
rithm was developed by the WHO/UMC in hopes of weeks, included more than 50 patients, and were pub-
detecting early patterns in reported data and exam- lished in the English language were included. A
ines the variation of these patterns over time. The clinically relevant increase in blood pressure was
predefined end points monitored by these algorithms determined to be an increase of 20 mmHg systolic
included water retention, abnormal renal function, (or an absolute value > 140 mmHg) or 15 mmHg dia-
acute renal failure, nephritis, cardiac failure, and stolic (or an absolute value > 90 mmHg). In the trials
hypertension. Two thousand seven hundred and comparing coxibs to the nsNSAIDs, the relative risk
twenty ADRs for rofecoxib and 8434 ADRs for cel- (RR) of developing hypertension was no greater in the
ecoxib were evaluated over the course of 11 months coxib groups than in the nsNSAID groups. But, in
for celecoxib and 7 months for rofecoxib based on trials comparing rofecoxib to celecoxib, the RR of
their approval dates by the US Food and Drug developing a clinically important increase in systolic
Administration. The rate of adverse events exceeded blood pressure was 1.5 (95% CI, 1.02.26). Upon
the expectations for both celecoxib and rofecoxib, but further assessment, it was determined that patients
rofecoxibs rates of ADRs far exceeded those of cel- taking rofecoxib were statistically more likely to
ecoxib. The majority of these ADRs were related to develop hypertension when compared to placebo
the renal system providing credence to the theories and celecoxib (OR 2.63, 95% CI 1.424.85 and OR
of hypertension induced by these drugs. Patients 1.78, 95% CI 1.172.69, respectively). It was also noted
taking rofecoxib were more likely to retain water, that there was a disproportionate increase in systolic
3.4 times more likely to experience abnormal renal blood pressure compared to diastolic blood pressure.
function, and 5 times more likely to have an episode This was of special concern to the authors as there is a
of cardiac failure when compared to celecoxib known relationship between increased systolic blood
patients. Overall, rofecoxib experienced ADRs at a pressure and cardiovascular risk as defined by the
rate significantly greater than celecoxib in five out of Framingham data (Kannel 2000).
six renal-related classifications. The severity of the When evaluating the contributions of rofecoxib
ADRs reported with rofecoxib was also greater than and celecoxib data to the pool, it was postulated
celecoxib with fatal renal failure and fatal cardiac that the differences seen between these two drugs
failure (2.8 and 4.4 times higher, respectively.) To may be related to their specific pharmacokinetic
put these findings into perspective, the authors com- and pharmacodynamic properties. Rofecoxib is
pleted a similar analysis of ibuprofen and diclofenac metabolized by cytosol reductase and can competi-
(both nsNSAIDs). The ibuprofen and diclofenac tively (especially at higher doses) inhibit the
findings were then compared to those of rofecoxib metabolism of aldosterone. This would potentially
and celecoxib. Celecoxib was found to have a similar increase the action of aldosterone in vivo, increasing
328 Mechanisms of Drug-Induced Cardiovascular Toxicity

sodium and water resorption in the collecting duct, when indomethacin was discontinued. Twenty-four
and exacerbate cardiac remodeling (Liew and Krum hour excretion of PGF2 -M fell 67% in the proprano-
2002). It has also been noted that celecoxib may lol group and 57% in the thiazide-treated group while
inhibit carbonic anhydrase in the proximal convo- taking indomethacin indicating an inhibition of PG
luted tubule resulting in a diuretic effect similar to synthesis. No significant changes were found in crea-
that of acetazolamide (FitzGerald and Patrono 2001). tinine clearance, urinary sodium excretion, or plasma
This could potentially offset the negative effect on electrolyte concentrations during the study. The
natriuresis caused by COX inhibition. These two authors hypothesized that the actions of both antihy-
distinctions in pharmacology could also lend to the pertensive medications may be partially dependent on
noticeable differences in the ADR profiles between vasodilatory PG synthesis (such as PGI2) to exert their
celecoxib and rofecoxib. It could be postulated that full effect. Alternatively, it was also thought that the
the possible diuretic-like action of celecoxib could antihypertensive effects of these medications could
lend toward its favorable clinical profile compared to have been blunted by the sodium and water retention
rofecoxib, but the degree of clinical relevancy is still that occurred with indomethacin administration. The
unknown. authors did not control dietary sodium intake during
the study period, but the increase in blood pressure was Drugdrug interactions consistent with the weight gain in both groups. Overall,
in hypertension the authors hypothesized that the administration of
Given the mechanism of action of COX inhibitors propranolol or thiazide diuretics likely induced the
and their use in vitro to study the roles of various PGs production of PG in the kidney adding to their inher-
(especially those with actions similar to medications ent antihypertensive effects. These findings seemed to
used to treat cardiovascular diseases), it is reasonable correlate with the findings of Durao et al. (1977) who
to assume that NSAIDs would likely inhibit certain proposed that chronic beta-adrenergic receptor block-
antihypertensive medications. Research has focused ade may induce vasodilatory PG synthesis since
on drugs such as thiazide and loop diuretics, beta- indomethacin could attenuate the actions of proprano-
adrenergic receptor blockers, angiotensin-converting lol in humans. The question of whether thiazides
enzyme inhibitors (ACEIs), and angiotensin receptor induce PG synthesis continues to be debated and is
blockers (ARBs). All of these drugs involve actions yet to be fully understood.
upon the kidney and could therefore be greatly To evaluate the possibility of NSAIDthiazide
affected by alterations in PG actions. interactions, a triple crossover study of hydrochloro-
Watkins et al. (1980) published their data assessing thiazide, indomethacin, naproxen, and sulindac was
the hypotensive effect of thiazide diuretics and completed in 10 patients with essential hypertension
propranolol with concomitant indomethacin adminis- (Koopmans et al. 1984). No changes in blood pres-
tration. Patients were stabilized on either propranolol sures were seen with sulindac or naproxen at 2 or 4
or a combination of amiloride and hydrochlorothiazide weeks, but after 2 weeks of indomethacin adminis-
in this crossover study. Indomethacin (50 mg adminis- tration, a statistically significant increase in supine
tered twice daily) was initiated in both groups, and blood pressure of 6/3 mmHg was found, and the
patients were monitored for changes in weight, supine readings subsequently decreased to pretreatment
and erect blood pressure, and PGF2 -M urinary excre- levels at week 4 of indomethacin treatment. There
tion. (PGF2 -M is the major urinary excreted was also a significant increase in weight with indo-
metabolite of PGF2 and is more easily quantified methacin (at both 2 and 4 week assessments) that was
than its parent compound.) One of the original 15 not seen with sulindac or naproxen when compared
patients was forced to withdraw from the study sec- to baseline. Based on this information, the authors
ondary to an acute GI bleed; therefore, only 14 patients concluded that concomitant administration of the
completed the study. During the 2 weeks of indo- three different nsNSAIDs with hydrochlorothiazide
methacin administration in both groups, patients did not attenuate the antihypertensive effect of the
experienced a statistically significant increase in body diuretic. This sentiment of clinical insignificance was
weight of 1 kg that was reversed upon cessation of echoed by the same authors in a later study
indomethacin. There was a significant increase in the (Koopmans et al. 1986) with more patients designed
mean supine blood pressure in both groups (13/ with 98% power to confirm their earlier findings.
9 mmHg in the thiazide group and 14/5 mmHg in As cardiovascular trials progressed and the use of
the propranolol group) that returned to baseline aspirin (a noncompetitive inhibitor of COX-1) was
NSAIDs and Cardiovascular Toxicity 329

advocated in the secondary prevention of myocardial inhibition of the ACEI hypotensive effects. The
infarction and ischemic stroke, the concern grew that extent of inhibition was greater in those patients
aspirin could potentially inhibit the efforts of ACEIs classified as having severe hypertension by the inves-
in vivo. ACEIs suppress the conversion of angiotensin tigators compared to those with mild to moderate
1 (AT1) to AT2, thereby reducing the potent vaso- hypertension. The authors concluded that low-dose
constrictive activities of AT2. During this process, aspirin therapy had no effect on blood pressure
the levels of BK (a potent vasodilator) are increased. where higher-dosed aspirin could interfere with the
BK has been found to stimulate the release of PGE in antihypertensive effects of enalapril. These findings,
several tissues, possibly providing a synergistic effect although interesting, have little bearing on most car-
to lower systemic blood pressure through increased diovascular patients as the benefit of COX-1
vasodilation. inhibition of platelet aggregation is found to out-
To evaluate the effects of PG inhibition on the weigh the risk of ACEI or beta-blocker interactions
actions of ACEIs, Moore et al. studied the effects of given the fact that most patients are on combination
high-dose aspirin and indomethacin on the plasma therapies with multiple antihypertensive medica-
PG concentrations in 31 sodium-restricted patients tions. However, this controversy is still highly
with essential hypertension. Eighteen of the 31 debated among clinicians.
patients were administered a single dose of Clinical correlation of these results would be
captopril with either aspirin or indomethacin at required for true determination as to the significance
anti-inflammatory treatment doses to be compared of these findings. One way to do this is to assess blood
to individuals receiving captopril alone. Serial blood pressure control in patients over a longer period of
samples were taken from all patients to assess plasma time than an inpatient admission for study purposes.
renin activity and levels of AT2, BK, and the meta- Conlin et al. (2000) assessed the effects of indometha-
bolites of PGE2 (PGE-M), TxA2, and PGI2. Serial cin in patients receiving captopril or losartan (an
supine blood pressure measurements were taken at ARB) on ambulatory and clinic blood pressure mea-
each blood draw. The patients received a total of five surements. Since ARBs do not increase BK levels the
doses of aspirin or indomethacin every 6 h, and at way that ACEIs do (thereby there would be little
48 h after the first captopril administration, the entire increase in PGE2 concentrations with ARB treatment
process was repeated. After the captopril initiation, compared to ACEI), it was hypothesized that any
blood pressure and AT2 levels decreased, and BK reduction in losartan efficacy would be minimal
levels and PGE-M increased as expected. In the 10 compared to that of captopril in the presence of
patients that received indomethacin, the blood pres- indomethacin. Patients were randomized to 6 weeks
sure response to captopril was reduced from 23 to of double-blind treatment with captopril or losartan.
10 mmHg (a decrease of over 40%), and the PGE- At the end of these 6 weeks, patients underwent 24 h
M increased after captopril administration was com- of ambulatory blood pressure monitoring and clinic
pletely diminished, but there was no significant blood pressure levels were also obtained on two of
change in AT2 or BK levels. The aspirin-treated the monitored days. Sustained-release indomethacin
patients exhibited no significant changes in blood (75 mg daily) was then administered for one addi-
pressure but did exhibit a mean increase in PGE-M tional week with captopril or losartan. Patients
that was statistically significant when compared to returned for an additional 24 h of ambulatory mea-
the PGE-M decrease in the indomethacin group. surements and clinic measurements. The addition of
The authors suggest that PGE2 must mediate some indomethacin resulted in a statistically significant
portion of captoprils hypotensive effect and that PG increase in the 24-h mean systolic and diastolic
inhibition by indomethacin further blunts the blood blood pressures in both treatment groups (losartan:
pressure response. The findings regarding aspirin use 3.8 mmHg systolic, 2.2 mmHg diastolic and captopril:
in this study contradict those found in other studies 4.6 mmHg systolic and 2.7 mmHg diastolic; all mea-
and could perhaps have to do with the longevity of surements with p < 0.001). When further evaluated, it
the study time frame. In a prospective cohort study of was found that daytime blood pressures were affected
aspirin in combination with enalapril, it was deter- in both treatment arms by indomethacin, but
mined that low aspirin doses (100 mg daily for 5 days) nighttime and clinic blood pressures were only sig-
had no effect on the hypotensive properties of ena- nificantly affected in the captopril arm. The increases
lapril, but at doses of 300 mg per day for 5 days, in blood pressure seen were small (35 mmHg sys-
over 50% of the patients experienced a significant tolic and 23 mmHg diastolic) but represented a 40%
330 Mechanisms of Drug-Induced Cardiovascular Toxicity

loss in their antihypertensive effect. This study increases in blood pressure and associated cardiovas-
showed that indomethacin blunted the antihyperten- cular events.
sive effects of captopril when measured for 24 h
continuously as well as standard clinic measure- Congestive Heart Failure
ments. The reductions in losartan efficacy seen with
indomethacin in the 24-h continuous measurements CHF is defined as a condition of decreased cardiac
were largely driven by the attenuation of daytime output. Over 5 million adults carry a diagnosis of
blood pressure lowering. The authors felt that this heart failure and over 550 000 new cases are diag-
study agreed with previous data regarding ACEI and nosed each year (Hunt et al. 2005). CHF is largely a
indomethacin and stated that indomethacin attenu- condition of the elderly and can present as shortness
ated the hypotensive effects of captopril and losartan. of breath, extremity and pulmonary edema, acute
With the emergence of the COX-2-specific inhi- renal failure, chest pain, and dysrhythmias. There
bitors, it was unknown if drugs such as celecoxib are two main etiologies of heart failure: ischemic
could also attenuate the effectiveness of ACEI. In a and nonischemic with over 70% of all cases being
study of celecoxibs effects on lisinopril, 178 patients ischemic in nature.
with uncomplicated hypertension and controlled on Neurohormonal regulation in CHF is complicated
lisinopril were randomly assigned to celecoxib or and intimately associated with renal homeostasis and
matching placebo. Upon review of the 24-h ambula- overall renal function. Control of this disease process
tory blood pressure monitoring, celecoxib induced a requires a delicate balance of peripheral vascular resis-
small increase in average systolic (2.6 mmHg) and tance, fluid status and natriuresis, and prevention of
diastolic (1.5 mmHg) blood pressures that were not cardiac tissue remodeling. To decrease morbidity and
significant when compared to the modest changes in mortality of heart failure, it is essential to regulate the
the placebo group (1.0 mmHg systolic and 0.3 mmHg effects of renin, angiotensin, norepinephrine, and
diastolic). The increases in the celecoxib-treated arm aldosterone on the myocardium. These endogenous
were more likely to occur 4 h after the a.m. and p.m. substances are most often associated with the kidney,
doses but then appeared to trend downward prior to but have also been shown to exist in the myocardium
the next dose. As a measure of safety, body weight of monkeys and rats. Studies have shown that these
was compared from baseline and during treatment. extrarenal RAAS can function independently from the
The average change in the placebo arm was 0.06 systemic vasculature and the systemic renin levels
 0.47 kg and 0.16  0.37 kg in the celecoxib group. (Lindpainter et al. 1989).
Only one patient (1%) in the celecoxib group devel- Based on the pathophysiology of the disease, the
oped edema where there were no reported cases in medications required to decrease morbidity and mor-
the placebo group, and no patient in either group tality are obvious. These drug classes include ACEI
developed a blood urea nitrogen level above the (or angiotensin receptor blockers) to decrease the
upper limits of normal. The authors felt that they impact of AT2, beta-adrenergic blockers to decrease
had shown that celecoxib at doses approved for the the effect of norepinephrine on the failing heart, and
treatment of osteoarthritis (also the maximal recom- aldosterone antagonists to decrease the harmful
mended dose) was not associated with increases in remodeling effects attributed to increased aldoster-
body weight, edema, changes in renal function, or one levels. To improve morbidity, tight control of
inhibition of lisinoprils antihypertensive effects. the sodium and water balance in the kidney is
In conclusion, results from published studies have imperative.
determined that NSAIDs have the ability to increase As discussed in the previous section, COX-2 has
blood pressure secondary to PG synthesis inhibition been found to be a highly inducible enzyme resulting
and alterations in the RAAS. Decreased production in the production of PG that works to regulate all of
of the endogenous natriuretic PGs, PGE2, and the above functions and assists the medications given
PGF2 affect the delicate balance of sodium and to decrease morbidity and mortality in this ulti-
water in the body. While otherwise healthy patients mately fatal disease. Therefore, inhibition of COX-
could perhaps compensate for these alterations in 2 (whether selectively or nonselectively) could easily
homeostasis, patients with conditions that predispose tip the balance in an unfavorable direction for CHF
them to fluid balance problems (i.e., CHF, chronic patients based on the actions of PG in the kidney.
renal insufficiency, preexisting hypertension, and To further illustrate the complexities of COX in
advanced age) could be more likely to experience the myocardial tissues, there is concern that some
NSAIDs and Cardiovascular Toxicity 331

aspects of PG synthesis could be detrimental in the increase the adrenergic tone, renin secretion, and
failing heart. The COX-2 isoenzyme can be induced the use of dopamine in the body to compensate
by hypoxia, a condition often attributed to heart (Dunn 1983). Patients with CHF and chronic renal
failure either by the ischemic nature of the disease insufficiency (both often found in elderly patients)
or because of a reduced cardiac output that is unable would be more likely to become PG dependent as
to meet the oxygen demands of the myocardium, or their other compensatory mechanisms are already
both. In a hypoxic state, COX-2 is induced by maximized. Therefore, inhibition of these important
nuclear factor-kappa B (NF-kappa B) in endothelial PGs could greatly affect the ability of the kidney to
cells (Schmedtje et al. 1997; Wong et al. 1998). Since regulate sodium and water retention. Given that the
COX-2 is known to be induced by inflammation, it is natural actions of PGE2 and PGF2 in the ascending
logical that the enzyme can be induced by inflamma- loop of Henle and collecting duct are to decrease
tory cytokines such as tumor necrosis factor-alpha sodium reabsorption by inhibition of chloride trans-
produced in heart failure (Torre-Amione et al. 1996). port (a mechanism analogous to the action of loop
Upon further study, it was found that COX-2 was diuretics), inhibition of these PGs would be analo-
expressed more readily in infarcted myocardial cells gous to removing loop diuretics from the CHF
and less in the noninfarcted cells of hearts that were patients medication regimen. Inhibition of PGI2
failing secondary to ischemic heart disease (Wong would decrease GFR and further reduce the effec-
et al. 1998). Along this same line, the COX-2 enzyme tiveness of the nephron in regulating the sodium and
is weakly expressed in cells of a dilated cardiomyo- water status. These actions together would result in
pathy, cells in which there is frequently extensive fluid accumulation in the periphery (characterized as
myocardial fibrosis. When put together, this data peripheral edema in the CHF patient) and in the
suggests that ischemia and inflammatory mediators lungs (contributing to the shortness of breath often
could be responsible for COX-2 induction in the experienced by these patients, increasing pulmonary
failing myocardium, and the resulting PG formation pressures, and an increased workload on an already
could lead to further damage in already damaged failing heart ultimately resulting in worsening car-
cells. This concept still requires further study as the diac output and decreased renal perfusion). PGE2
exact mechanism, and time line of damage remains and PGI2 levels increase in response to elevated
unclear; but at this time it is thought that the pre- norepinephrine and AT2 levels. Both of these neuro-
sence of COX-2 is associated with myocardial tissue hormones are consistently upregulated in CHF
scarring that leads to worsening heart failure. patients as they tend to exist in a state of high adre-
ACEIs are considered part of the backbone of nergic tone, hence leading back to the notion that
therapy for CHF to reduce the actions of AT2. As CHF patients are PG dependent to maintain their
in previously discussed studies, it was determined fluid status. Because of this vicious circle of events,
that PGE2 and BK assist the actions of these medica- the use of NSAIDs in CHF is relatively contraindi-
tions, and inhibition of PGE2 with nsNSAIDs could cated in the guidelines for chronic heart failure
diminish the vasodilatory effect of ACEI in the kid- management (Hunt et al. 2005).
ney resulting in a decreased natriuresis (Townend When the incidence of NSAID-associated CHF
et al. 1995). Based on the large number of studies that was examined in the Rotterdam Study (Feenstra et al.
have reproduced similar findings, it is apparent that 2002), it was found that NSAID use was associated
COX-1 and COX-2 inhibition can affect the actions with relapses of CHF but not a primary incident of
of these very important medications and should be CHF. The use of NSAIDs in elderly patients with
used cautiously in this population. heart failure was also associated with an increased
Fluid status is an imperative component to CHF risk of hospitalization for heart failure (Heerdink et al.
management. The roles of PGE2 and PGI2 have been 1998). These data did not delineate the difference
well defined in this process. In otherwise healthy between nsNSAID and COX-2 selective inhibitor
individuals, inhibition of endogenous PG synthesis use. Based on the dates of the studies, it is very likely
would not greatly affect renal function (especially that the majority of the patients were on the tradi-
with short-term therapy), but in those with under- tional nsNSAIDs.
lying renal dysfunction due to advancing age, COX-2 selective inhibitors have not fared well in
pathology, or reduced cardiac output, this could be studies of patients with CHF either. A retrospective
radically different. Healthy individuals have other cohort study divided otherwise well-matched elderly
compensatory mechanisms including the ability to patients into three treatment groups (rofecoxib,
332 Mechanisms of Drug-Induced Cardiovascular Toxicity

celecoxib, and nsNSAIDs) and followed them for- Concern, as of late, has turned toward the per-
ward in time to assess admission rates for heart ceived increased risk of cardiovascular events in
failure. Each of these study arms was compared to patients taking the selective COX-2 inhibitors. In
non-NSAID users in the same population. The pre- recent years, two selective COX-2 inhibitors (rofe-
valence of heart failure was consistent among the coxib and valdecoxib) have been withdrawn from the
groups at baseline as was the use of other cardiovas- market after an increased risk of thromboembolism
cular-related medications. In patients with a history was found in clinical trials.
of CHF admissions within the last 3 years, those The only selective COX-2 inhibitor still available
taking rofecoxib and nsNSAIDs were at a signifi- on the US market, celecoxib, was found to have no
cantly higher risk of readmission when compared to effect on platelet aggregation ex vivo when compared
celecoxib (Mamdani et al. 2004). These data are con- to the nsNSAID, ibuprofen, despite minor but
sistent with those reported from other retrospective detectable inhibition of the COX-1 isoenzyme
studies designed to assess these associations (Hudson (McAdam et al. 1999). Despite its platelet-sparing
et al. 2005), and large prospective studies of coxibs action in this study, celecoxib was found to suppress
will be discussed later in this chapter. the secretion of metabolites of PGI2 after a single
In summary, the toxicities of NSAIDs in this dose. This would possibly suggest a role of COX-2 in
population are well documented but the delineation the synthesis of PGI2. The lack of platelet activity in
of which toxicity is worse; drug-induced hyperten- this study was attributed to the very minor inhibition
sion, drugdrug interactions with clinically proven of plasma TxA2 as evidenced by minimal suppression
treatment regimens, or drug-induced sodium and of thromboxane B2 (TxB2; the urinary metabolite of
fluid imbalances may vary among patients depending TxA2). Based on this information, it can be deduced
on a number of variables, including disease severity, that celecoxib has relatively little effect on platelet
genetics, and compliance with treatment regimens. aggregation.
With the complexities of heart failure, pathophysiol- The CLASS trial (Silverstein et al. 2000) was a
ogy with regard to the role of endogenous PG double-blind trial conducted in 8059 patients rando-
synthesis, defining a single true and absolute toxicity mized to receive celecoxib or nsNSAID (ibuprofen
of this drug class, would be nearly impossible. The or diclofenac) therapy. The primary end point of the
clinical controversy of NSAID use in these patients is trial was the incidence of upper GI ulcers or ulcer
difficult but the accumulating data suggest that complications in patients with osteo- or rheumatoid
NSAID use can be associated with an increased risk arthritis. Patients requiring the use of aspirin due to
of heart failure exacerbation, especially in those with cardiovascular comorbidities were included, and all
a previous diagnosis of heart failure. Based on those adverse effects were stratified by the use of aspirin in
data, these drugs should be used sparingly in CHF the final comparisons. After the predefined 6 months
patients, and, when deemed necessary, the patients of treatment, it was determined that the rate of car-
should be closely monitored for signs and symptoms diovascular events (defined as CVA, AMI, and
of toxicity. 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 Acute Myocardial Infarction
NSAIDs used in this study have low platelet aggre-
Aspirin, in daily doses ranging from 81 to 325 mg is gation inhibitory effects (ibuprofen 80% and
currently indicated for secondary prevention of diclofenac 40%) (FDA Advisory Committee 2001)
thrombosis status post acute myocardial infarction and would not be as effective as aspirin with docu-
(AMI), cerebrovascular accident (CVA), atrial fibril- mented 92% platelet aggregation inhibition in terms
lation (in low to moderate risk patients), and of cardioprotection from thrombotic events; there-
peripheral vascular disease, and is also indicated for fore, the choice to permit low-dose aspirin therapy in
primary prophylaxis in diabetes mellitus. The proven the trial was a sound decision, and the use of aspirin
benefits of COX-1 inhibition resulting in decreased was well matched at baseline between the groups.
TxA2 activity and the resulting inhibition of platelet In the VIGOR study (Bombardier et al. 2000),
aggregation has changed clinical practice over the 8076 patients were randomly assigned to a daily
last three decades where most patients are now on a dose of 50 mg rofecoxib or 1000 mg naproxen in
daily aspirin. two divided doses. Safety end points were largely
NSAIDs and Cardiovascular Toxicity 333

those relating to GI tolerability, but rates of mortality fatal ischemic stroke, and transient ischemic attack),
and ischemic events were briefly mentioned in the the drug company decided to withdraw rofecoxib
final publication. The rate of discontinuance of study from the market voluntarily.
drug due to ADRs was 0.2%, but the rate of myocar- With the release of the VIGOR and APPROVe
dial infarction was significantly lower in the data, the safety board of the Adenoma Prevention
naproxen group (0.1%) when compared to the rofe- with Celecoxib (APC) trial decided that they should
coxib group (0.4%) (number needed to harm 333). evaluate their presently collected data and evaluate
Patients on chronic aspirin therapy were excluded the risk for cardiovascular events. This was a rando-
from the trial as were those with a previous cardio- mized controlled trial of celecoxib 400 mg daily,
vascular or cerebrovascular event. This difference in 800 mg daily, and placebo in the prevention of ade-
myocardial infarction was rationalized by the authors nomatous polyps. The study was stopped early when
based on the thought that naproxen inherently inhib- it was determined that patients in the treatment arms
ited platelet aggregation (an effect similar to aspirin); of the study were 23 times more likely to experience
therefore, patients taking regular naproxen might the composite end point of death from cardiovascular
have been afforded the same benefits as those who causes, myocardial infarction, stroke, or heart failure.
routinely take aspirin. The antiplatelet action of The results of the various components of the compo-
naproxen has been demonstrated previously and site end point were consistent with the primary end
found to be similar to that of aspirin (mean platelet point. The use of aspirin was consistent among the
aggregation inhibition of naproxen 93% compared to three treatment arms at 29.331.4% and higher than
low-dose aspirin at 92%) (FDA Advisory Committee the aspirin use in the CLASS trial.
2001). Based on the findings of this trial, the manu- The reason for the thrombotic events seen in
facturers of rofecoxib then amended other study these trials with selective COX-2 inhibitors remains
protocols to include aspirin at doses less than unclear. Besides the possible increases in blood pres-
100 mg per day for cardioprotection to alleviate this sure discussed previously in this chapter, it is also
question as a possible confounder in future research. thought that an imbalance of COX-2 and COX-1
The risk of myocardial infarction in the CLASS inhibition could lend toward unopposed thrombosis
and VIGOR trials was compared to that of a meta- formation. Platelet aggregation is largely driven by
analysis of 48 540 patients (Mukherjee et al. 2001). In the COX-1-mediated actions of TxA2 in the platelets
this meta-analysis, 25 133 patients were treated with themselves. PGI2 activity was originally thought to
aspirin and 23 407 were given placebo. The annual be mediated by COX-1 activity in the vascular
rate of myocardial infarction in the placebo group of endothelium, but studies in mice and humans proved
the meta-analysis was 0.52% (Sanmuganathan et al. this incorrect and showed that COX-2 was the more
2001). The annual rate of myocardial infarction in predominant source (FitzGerald 2004). If PGI2 is
the VIGOR trial was 0.74 and 0.80% in the CLASS inhibited and vasodilation is therefore inhibited, the
trial. Both of these figures were statistically signifi- increasing shear stress within the vessel could
cant when compared to the placebo group in the increase the risk of thrombotic events. This reduction
meta-analysis (p 0.04 and p 0.02, respectively). of COX-2-derived PGI2 could then increase blood
The authors of the meta-analysis argued that the pressure, accelerate atherogenesis due to increased
rates of myocardial infarction in both trials were laminar sheer stress, and expose patients to the rup-
possibly greater than the general population with ture of an atherosclerotic plaque. In patients already
rofecoxib possibly having worse effects than at risk for such an event (i.e., previous myocardial
celecoxib. infarction, stroke, transient ischemic attack, or
In March 2005, the results of the APPROVe trial cancer), this drug-induced pathology could be
evaluating the safety and efficacy of rofecoxib versus increasingly deleterious.
placebo and the risk of recurrent neoplastic polyps in These studies were all looking at durations of ther-
patients with a history of colorectal cancer were apy that ranged from months to years. Retrospective
published (Bresalier et al. 2005). Based on the hazard reviews of elderly patients receiving NSAID therapy
ratios of 2.8 (95% CI 1.445.45) for thrombotic car- (COX-1 or COX-2 inhibitors) report conflicting results.
diac events (including AMI, fatal myocardial In one study, elderly patients prescribed short-term
infarction, sudden death from cardiovascular causes, selective COX-2 inhibitors or naproxen experienced
and unstable angina) and 2.32 (95% CI 0.896.74) for no increased risk of acute myocardial infarction when
cerebrovascular events (including ischemic stroke, compared to a control group (Mamdani et al. 2003).
334 Mechanisms of Drug-Induced Cardiovascular Toxicity

In contrast, a retrospective review of patients pre- humans. The interactions between the cardiovascular
scribed coxibs or nsNSAIDs showed a 2455% system and the renal homeostasis are clear, and based
increase in the risk of myocardial infarction even after on research in each of these disease states presented,
adjusting for potential confounders including comor- a theoretical line can be drawn between the normal
bidities. The numbers needed to harm for diclofenac, human physiology, the pathology of the disease
rofecoxib, and ibuprofen in patients aged greater than states, and the associated medications and their
65 years who had been prescribed these drugs within 3 toxicities.
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-
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