CO-抑制剂在心血管疾病中的应用课件.ppt

1、Most commonly used medications in the US by survey data#1:acetaminophen#2:ibuprofen#3:aspirin 50%of users on for cardiovascular prophylaxisAmong most frequently prescribed meds to those over 65OTC analgesic use underreported to healthcare providers and 10-40%of those prescribed NSAIDs concomitantly

2、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 Each year in the US:Over 30 billion OTC NSAID tablets sold($2 billion)Over 70 million NSAID prescriptions writtenNSAIDs have been potentially implicated in 16,500 deaths and 100,0

3、00 hospitalizations for adverse events;most are due to GI bleeds or renal impairmentThese 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 adv

4、erse GI and renal events,over half of patients over 65 have been prescribed NSAIDs.Wolfe,NEJM 1999;340:1888-1899Curhan,Arch Intern Med 2002;162:2204-2208Tamblyn,Ann Intern Med 1997;127:429-438Use of non-aspirin NSAIDs in conjunction with aspirin for primary prophylaxis may increase the risk of first

5、 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 Use of NSAIDS in conjuncti

6、on 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

7、 alone Similar risks were found among patients in ASA alone,ASA plus diclofenac,and ASA plus other(non-Ibuprofen)NSAIDS.Lancet 2003;361:573-4Vascular injuryPlatelet adhesion Binding to exposed vWF/collagenPlatelet activationADP,5HT,PF4,etc are releasedSignals cause COX conversion of arachidonic acid

8、 to thromboxane in plateletsPlatelet aggregationMediated by thromboxaneDense network of platelet-fibrinogen bridges form occlusive thrombusBraunwald,Heart Disease 2001Aspirin irreversibly inactivates COX,inhibiting thromboxane production.Braunwald,Heart Disease 2001COX-1 is expressed constituitively

9、 in many tissues.In the GI tract,COX-1 results in cytoprotective prostacyclin productionIn platelets,COX-1 activation results in Thromboxane SynthesisPlatelet aggregationVasoconstrictionSmooth muscle proliferationCOX-2 is induced at sites of inflammation.In the endothelium,COX-2 production of prosta

10、cyclin inhibits the actions of thromboxaneInhibits platelet aggregationVasodilator 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.S

11、elective 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 Rofecoxib(Vioxx)(50 mg qd)vs.naproxen(500 mg bid)8,076 patients with rheuma

12、toid arthritisExcluded patients on ASA or with CV events requiring ASA1o endpoint:GI events reduced in rofecoxib groupHigher CV event rates among patients treated with rofecoxibMI 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

13、 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 naproxenNEJM 2000;343:1520-8 Celecoxib(400 mg bid)vs.ibuprofen(800 mg tid)

14、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 bleedi

15、ng rates in celecoxib arm vs.NSAID alone(6.0%vs 3.1%)The two comparator arms(diclofenac and ibuprofen)have relatively weak antiplatelet effectsJAMA 2000;284:1247-55 Mukherjee et al(JAMA 2001)Compared MI rates from RCTs(including VIGOR and CLASS)with 23,407 patients in placebo arms of primary prevent

16、ion 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 prev

17、ention*Reicin et al,AJC 2002 White et al,AJC 2002 Mamdani et al,Arch Int Med 2003 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.

18、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 Aspirin:Irreversibly acetylates cyclooxygenase in platelets Inhibits COX-1 166 times more than COX-

19、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

20、 dosing cycle),which may explain beneficial effects of aspirin relative to these agents.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 patien

21、ts)From 3rd US Preventive Task Force;Ann Int Med 2002;136(2):157-60 Naproxen:non-selective NSAID with greater COX-1 activity*95%inhibition of thromboxane synthesis 88%inhibition of platelet aggregation Observational case-control studies have suggested possible cardioprotective effect not seen with o

22、ther non-selective NSAIDS,and benefits in comparison to other agents(e.g.ibuprofen).*J Clin Pharm 2000;40:1109-20 Arch Int Med 2002,Vol 162*Lancet 2002;359:118-23Prior occupancy of the catalytic site by ibuprofen may prevent aspirin from gaining access to its target serine.Catella-Lawson,NEJM 2001;3

23、45:1809-1817 Crossover Study(Single Doses of Each Medication)Aspirin 2 hours prior to ibuprofen,then reversed Aspirin 2 hours prior to acetaminophen,then reversed Aspirin 2 hours prior to rofecoxib,then reversed Parallel-Group Study with Multiple Daily Doses of NSAIDs Aspirin,then ibuprofen tid star

24、ting 2 hours later Aspirin,then diclofenac bid starting 2 hours laterCatella-Lawson,NEJM 2001;345:1809-1817Catella-Lawson,NEJM 2001;345:1809-1817Catella-Lawson,NEJM 2001;345:1809-1817Mean inhibition of cyclooxygenase-1 activity as assessed by measurement of serum thromboxane B2 and inhibition of pla

25、telet aggregation after six days of therapy.Despite initial inhibition of COX-1 activity by Ibuprofen,Ibuprofen prior to ASA inhibited anti-COX-1 effects of ASA Not seen when ASA was administered prior to ibuprofen Acetaminophen had no significant intrinsic or antagonistic effects on anti-COX-1 acti

26、vity Similar results were seen with rofecoxib(COX-2 selective agent)Catella-Lawson,NEJM 2001;345:1809-1817 No intrinsic anti-COX 2 effects of ASA were seen All effects on Prostaglandin production were seen after administration of the other agents Consistent with the known half-lives of these agents.

27、Ibuprofen:up to 80%inhibition that was transient Acetaminophen:up to 50%inhibition that was transient Rofecoxib:80%inhibition that was sustainedCatella-Lawson,NEJM 2001;345:1809-1817Catella-Lawson,NEJM 2001;345:1809-1817Mean inhibition of cyclooxygenase-1 activity as assessed by measurement of serum

28、 thromboxane B2 and inhibition of platelet aggregation after six days of therapy.Multiple Daily Doses of ibuprofen antagonized the anti-COX-1 effects of ASA Allowed recovery of thromboxane synthesis and platelet aggregation These findings persisted even though ASA was administered 2 hours prior to t

29、he daily dose of ibuprofen This effect was not seen with diclofenacCatella-Lawson,NEJM 2001;345:1809-1817 Commonly used OTC doses of NSAIDs may inhibit the antiplatelet effects of aspirin via competitive binding to COX-1.Patients who use aspirin for cardiovascular prophylaxis and self medicate with the OTC analgesic ibuprophen may risk reducing aspirins antiplatelet effect.Acetaminophen and naproxen do not appear to share this property and may be taken with aspirin without affecting its antiplatelet effects.