Cardiovascular Complications Related to COX-2 Inhibitors
The potential association of cardiovascular complications with the use
of selective COX-2 inhibitors (coxibs) has been of continued interest
to clinicians and has been the subject of several recent studies publications
in medical journals as well as two previous ACR Hotlines (“Update:
Safety Issues Related to NSAIDs and COX-2 Inhibitors” released in April
2002, available at http://www.rheumatology.org/publications/hotline/0402cox2.asp,
and “Selective COX-2 Inhibitors as Risk Factors for Cardiovascular Events” released
August 2001, available at http://www.rheumatology.org/publications/hotline/0801acox2.asp ).
Substantial media coverage of data from a poster on “Risk of Acute Myocardial
Infarction and Sudden Cardiac Death with Use of COX-2 Selective and Non-Selective
NSAIDS” presented at the 20 th International Conference on Pharmacoepidemiology
and Therapeutic Risk Management, August 22-25, 2004 in Bordeaux, France,
has renewed interest in this topic. This study was funded by an FDA contract
with Kaiser Permanente.
Acute Myocardial Infarction
The poster, which was presented by David
Graham, MD, and colleagues, assessed the risk of acute myocardial infarction
and sudden cardiac death among nearly 1.4 million members of Kaiser Permanente
of California who were treated with coxibs or traditional NSAIDs between
1/99 and 12/01. Low dose aspirin and over-the-counter NSAID use were not
captured in the electronic medical records, but were quite similar between
rofecoxib and celecoxib users when assessed by survey. There were a total
of 8,199 acute cardiac events in the study cohort (6,675 acute MI, and
1,524 cases of sudden cardiac death, or SCD). Using a nested case-control
design and controlling for other cardiovascular risk factors, each case
(persons with a cardiovascular outcome) was matched with four controls.
The main data of interest are presented below.
Table 1. The relative risk of acute cardiac events (either AMI
or sudden death)
Adjusted OR (95% CI)
-Rofecoxib <25 mg
-Rofecoxib >25 mg
From this data, the authors conclude that rofecoxib > 25mg/day was
associated with a 3-fold elevated risk of AMI or SCD. There was no increased
risk for celecoxib. As the authors acknowledge, the very small number
of cases and controls using high dose rofecoxib (10 cases and 8 controls
among 26,748 total patients treated with rofecoxib) create a wide confidence
interval. However, these data are consistent with another recent observational
database study of a large Medicare population . In this study, researchers
at Harvard Medical School conducted a case-control study that included
10,895 cases and 43,580 controls. Rofecoxib at any dosage was associated
with an elevated risk of AMI compared with celecoxib (RR = 1.24, 95% CI
1.05 - 1.46). Rofecoxib > 25 mg/day was associated with a relative
risk of 1.70 (95% CI 1.07 - 2.71) compared with high dose celecoxib. The
risk was highest in the first 90 days after starting rofecoxib and was
not elevated after the first three months.
The Phase III trials with
rofecoxib suggested a possible increase in blood pressure that has been
investigated by two subsequent studies. One trial randomized over 1000
patients with OA with known hypertension to rofecoxib 25 mg or celecoxib
200 mg per day . The primary endpoint of this study was clinically
significant changes in systolic and diastolic blood pressure. By the end
of the six week trial, 14.9% of patients randomized to rofecoxib met the
pre-specified definition of systolic hypertension (an increase in systolic
BP by 20 mm Hg to a level of at least 140 mm Hg) versus 6.9% for celecoxib
(p < 0.01). There were similar trends
in diastolic blood pressure but these did not meet the statistical significance
threshold. An observational study among Medicare beneficiaries without
prior hypertension also found an increased risk of new blood pressure
elevations requiring anti-hypertensive treatment for patients using rofecoxib
compared with celecoxib (odds ratio = 1.6, 95% CI 1.2 - 2.1) or a traditional
NSAID (OR = 1.4, 95% CI 1.1 - 1.9) .
Congestive Heart Failure
A recent observational
study from Ontario raised important concerns about rofecoxib in elderly
patients with respect to CHF . This study included over 100,000 patients
over 65 and compared with risk of an admission for CHF among patients
using coxibs, traditional NSAIDs or neither. Compared with patients using
no NSAID, patients taking rofecoxib at any dosage had an adjusted relative
risk of CHF admission of 1.8 (95% CI 1.5 - 2.2).
Those taking a traditional NSAID also had an increased risk of CHF (RR
1.4, 95% CI 1.0 - 1.9). However, celecoxib users were at no increased risk
(RR 1.0, 95% CI 0.8 - 1.3).
The Bottom Line:
• The VIGOR RCT  and
analyses of several observational datasets have found an increased risk
of acute myocardial infarction with the use of rofecoxib at dosages above
25 mg per day. More studies are needed to define the magnitude and duration
of this increased risk.
• Data from several sources are consistent in finding an increased
risk of hypertension and congestive heart failure in patients taking rofecoxib.
• When using any coxib or traditional NSAID, clinicians
need to be aware of potential adverse events including AMI, hypertension,
and CHF. Clinicians need to weigh such risks against anticipated benefits,
and consider issues such as dose, risk factors, and comorbid conditions.
This HOTLINE is being provided to inform readers of these recent studies.
Readers are reminded that some of these data have been presented in abstract
Hotline Authors: Daniel Solomon, MD, MPH; Arthur Kavanaugh,
MD; Eric L. Matteson, MD, MPH
Disclosure: Dr. Solomon
has been the recipient of research grants from Pfizer and Merck. Dr. Kavanaugh
and Dr. Matteson have no conflict of interest regarding the material discussed
in this ACR Hotline.
Hotline is provided by the ACR Communications and Marketing Committee
as a service to members. This Hotline reflects the views of the authors
and does not represent a position statement of the College.
1. Solomon DH , Schneeweiss S, Glynn RJ, Kiyota Y, Levin R, Mogun H,
Avorn J. Relationship
Between Selective Cyclooxygenase-2 Inhibitors and Acute Myocardial Infarction
in Older Adults. Circulation 2004; 109: 2068
2. Whelton A. White WB. Bello AE. Puma JA. Fort JG. SUCCESS-VII Investigators.
of celecoxib and rofecoxib on blood pressure and edema in patients > or
=65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol
3. Solomon DH, Schneeweiss S, Levin R, Avorn J. Relationship
between COX-2 specific inhibitors and hypertension. Hypertension
2004; 44: 140 - 145.
4. Mamdani M, Juurlink DN, Lee DS, Rochon PA, Kopp A, Naglie G, Austin
PC, Laupacis A, Stukel TA. Cyclo-oxygenase-2
inhibitors versus non-selective non-steroidal anti-inflammatory drugs
and congestive heart failure outcomes in elderly patients: a population-based
cohort study. Lancet. 2004; 363(9423):1751-1756.
5. Bombardier C, Laine L, Reicin, A, et al. Comparison
of upper gastrointestinal toxicity of rofecoxib and naproxen in patients
with rheumatoid arthritis. N
Engl J Med. 2000;343: 1520-8.
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