COX-2抑制剂在心血管疾病中的应用
Use of Analgesics
Most commonly used medications in the US by survey data
#1: acetaminophen
#2: ibuprofen
#3: aspirin – 50% of users on for cardiovascular prophylaxis
Among most frequently prescribed meds to those over 65
OTC analgesic use underreported to healthcare providers and 10-40% of those prescribed NSAIDs concomitantly use OTC NSAIDs
Kaufman, JAMA 2002; 287: 337-344
Hensrud, Mayo Clin Proc 1999; 74: 443-447
Eliason, J Am Board FP 1996; 9: 249-253
Use of Analgesics
Each year in the US:
Over 30 billion OTC NSAID tablets sold (~$2 billion)
Over 70 million NSAID prescriptions written
NSAIDs have been potentially implicated in ~16,500 deaths and ~100,000 hospitalizations for adverse events; most are due to GI bleeds or renal impairment
These admits cost the healthcare system ~$2 billion.
Treatment of NSAID-related gastrointestinal side effects accounts for one third of the cost of arthritis therapy
Even though advanced age is well-known factor for adverse GI and renal events, over half of patients over 65 have been prescribed NSAIDs.
Wolfe, NEJM 1999; 340: 1888-1899
Curhan, Arch Intern Med 2002; 162: 2204-2208
Tamblyn, Ann Intern Med 1997; 127: 429-438
Use of non-aspirin NSAIDs in conjunction with aspirin for primary prophylaxis may increase the risk of first MI
22,000 male physicians on aspirin 325 mg QOD or placebo
Aspirin use was associated with a 44% relative risk reduction of first MI
Concomitant NSAID use for ? 60 days/yr associated with increased risk of first MI (RR 2.86; 95% CI 1.25-6.56)
Kurth, Circulation 2003; 108: 1191-1195
Possible Adverse Interactions between NSAIDs and ASA: Physician’s Health Study
Possible Adverse Interactions between NSAIDs and ASA
Use of NSAIDS in conjunction with ASA in patients after 1st CV admission (angina, MI, CVA, TIA, PVD)
7,107 patients
Administration of ibuprofen with aspirin was associated with an increased risk of all-cause mortality (adjusted HR 1.93, 95% CI 1.30-2.87, p=0.001) and CV mortality (1.73, 1.05-2.84, p=0.031) compared to administration of ASA alone
Similar risks were found among patients in ASA alone, ASA plus diclofenac, and ASA plus other (non-Ibuprofen) NSAIDS.
Lancet 2003; 361: 573-4
Platelets in Hemostasis
Vascular injury
Platelet adhesion
Binding to exposed vWF/collagen
Platelet activation
ADP, 5HT, PF4, etc are released
Signals cause COX conversion of arachidonic acid to thromboxane in platelets
Platelet aggregation
Mediated by thromboxane
Dense network of platelet-fibrinogen bridges form occlusive thrombus
Braunwald, Heart Disease 2001
Antiplatelet Action of Aspirin
Aspirin irreversibly inactivates COX, inhibiting thromboxane production.
Braunwald, Heart Disease 2001
The Balance of COX-1 and COX-2
COX-1 is expressed constituitively in many tissues.
In the GI tract, COX-1 results in cytoprotective prostacyclin production
In platelets, COX-1 activation results in Thromboxane Synthesis
Platelet aggregation
Vasoconstriction
Smooth muscle proliferation
COX-2 is induced at sites of inflammation.
In the endothelium, COX-2 production of prostacyclin inhibits the actions of thromboxane
Inhibits platelet aggregation
Vasodilator
The Balance of COX-1 and COX-2: A Simplified Model
In vivo, there is a balance of COX-1 and COX-2 activity resulting in maintenance of vascular hemostasis.
Non-selective NSAIDS act by suppressing both COX-1 and COX-2 activity, with generally no net effect on hemostasis.
Selective COX-2 Inhibitors, by inhibiting COX-2 and allowing COX-1 activation (COX-1 is unopposed), have the potential for potentiating thrombosis and vasoconstriction.
? Increased CV risks in retrospective non-randomized analyses
Selective COX-2 Inhibitors and Cardiovascular Outcomes VIGOR: The Vioxx Gastrointestinal Outcomes Research Study
Rofecoxib (Vioxx) (50 mg qd) vs. naproxen (500 mg bid)
8,076 patients with rheumatoid arthritis
Excluded patients on ASA or with CV events requiring ASA
1o endpoint: GI events reduced in rofecoxib group
Higher CV event rates among patients treated with rofecoxib
MI rate of 0.4% vs. 0.1% (95% CI 0.1% to 0.6% for rofecoxib)
38% of events occurred in the 3.9% of patients who qualified as aspirin candidates (for secondary prophylaxis)
Among pts without indication for ASA prophylaxis, MI rates did not differ between rofecoxib and naproxen
? Untoward effect of rofecoxib among pts not treated with ASA or beneficial effect of naproxen
NEJM 2000; 343:1520-8
Selective COX-2 Inhibitors and Cardiovascular Outcomes CLASS: Celecoxib Long-term Arthritis Safety Study
Celecoxib (400 mg bid) vs. ibuprofen (800 mg tid) or diclofenac (75 mg bid). Naproxen not evaluated.
8,059 patients, majority with osteoarthritis
Patients were permitted to take ASA (22%) unlike VIGOR
No difference in MI rates among groups
Similar rates of CV and cerebrovascular events
No differences in non-ASA subgroup (underpowered though)
Reduced bleeding rates in celecoxib arm vs. NSAID alone (6.0% vs 3.1%)
The two comparator arms (diclofenac and ibuprofen) have relatively weak antiplatelet effects
JAMA 2000; 284:1247-55
Pooled Analyses of COX-2 Selective Agents
Mukherjee et al (JAMA 2001)
Compared MI rates from RCT’s (including VIGOR and CLASS) with 23,407 patients in placebo arms of primary prevention trials of ASA, and found higher MI rates among patients taking refecoxib and celecoxib
Annualized MI rates: 0.52% for placebo; rofecoxib 0.74% (p=0.04); celecoxib 0.80% (p=0.02)
? confounded by comparisons of different groups of patients: txd pts with inflammation compared to placebo pts from primary prevention
*Reicin et al, AJC 2002
White et al, AJC 2002
Mamdani et al, Arch Int Med 2003
Pooled Analyses of COX-2 Selective Agents
Konstam et al (Circulation 2001)
28,000 patients from rofecoxib clinical trials
No difference in CV events between rofecoxib vs. NSAIDS other than naproxen
Higher risk of thrombotic events with rofecoxib vs. naproxen (RR 1.69 with 95% CI 1.07-2.69).
Other studies have demonstrated no differences between COX-2 selective agents vs. non-Naproxen NSAIDS*
*Reicin et al, AJC 2002
White et al, AJC 2002
Mamdani et al, Arch Int Med 2003
NSAIDS and COX-1 Suppression
Aspirin: Irreversibly acetylates cyclooxygenase in platelets
Inhibits COX-1 166 times more than COX-2
95% suppression of COX-1 activity is necessary to inhibit Thromboxane-dependent platelet aggregation
This degree of COX-1 suppression is achieved with low-dose ASA (92% inhibition of aggregation with 81 mg)
Other NSAIDS produce variable reversible COX-1 suppression with time-dependency (relative to the dosing cycle), which may explain beneficial effects of aspirin relative to these agents.
Aspirin
Secondary prevention
>20% reduction in vascular events
Primary prevention: consistent reduction in CV events may be offset by an increase in hemorrhagic stroke and other bleeding events (especially in low-risk patients)
From 3rd US Preventive Task Force; Ann Int Med 2002; 136(2): 157-60
Naproxen
Naproxen: non-selective NSAID with gre